WO2022251541A9 - Macrocycles and complexes with radionuclides useful in targeted radiotherapy of cancer - Google Patents

Macrocycles and complexes with radionuclides useful in targeted radiotherapy of cancer Download PDF

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WO2022251541A9
WO2022251541A9 PCT/US2022/031196 US2022031196W WO2022251541A9 WO 2022251541 A9 WO2022251541 A9 WO 2022251541A9 US 2022031196 W US2022031196 W US 2022031196W WO 2022251541 A9 WO2022251541 A9 WO 2022251541A9
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independently
occurrence
formula
compound
och
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WO2022251541A1 (en
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Nikki THIELE
Justin J. Wilson
Aohan HU
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Cornell University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • a compound of any one of Formula I, Formula II, Formula III, and Formlua IV is provided te thereof, wherein A 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is the other 3 4 one of Y and Y is O; one of Y 5 and Y 6 is or , and the other one of Y 5 and Y 6 is O, or Y 5 and Y 6 are each independently
  • a compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formula IVA is provided or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the compound; A 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O; one of Y 5 and Y 6 is , , or , and the other one of Y 5 and Y 6 is O, or Y 5 and Y 6 are each independently , , ,
  • the present technology provides a targeting compound useful in, e.g., useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), where the targeting compound is of any one of Formula V, Formula VI, Formula VII, and Formula VIII or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the targeting compound;
  • a 5 , A 6 , A 7 , and A 8 are each independently or ;
  • R 1 is or ;
  • R 2 is independently at each occurrence , , or ;
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O;
  • one of Y 3 and Y 4 is , , , or , and the other one of
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula I, Formula II, Formula III, and Formlua IV or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide.
  • a modified antibody, modified antibody fragment, or modified binding peptide is provided that includes a linkage arising from conjugation of a compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formlua IVA or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide.
  • compositions e.g., pharmaceutical compositions
  • medicaments comprising any of one of the embodiments of the compounds disclosed herein, any one of the embodiments of the targeting compounds disclosed herein, or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology disclosed herein, and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively refered to as “pharmaceutically acceptable carrier” unless otherwise specified).
  • pharmaceutically acceptable carrier one or more excipients or fillers
  • FIG.1 shows stability constants of Ln 3+ complexes formed with py-macrodipa and macrodipa plotted versus ionic radii
  • FIG.3 shows crystal structures of (a) [La(py-macrodipa)] + , (b) [Lu(py-macrodipa)] + , and (c) [Sc(py-macrodipa)(OH2)] + complexes.
  • Thermal ellipsoids are drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity. Only one of the two [La(py-macrodipa)] + or [Sc(py-macrodipa)(OH 2 )] + complexes in the asymmetric unit is shown.
  • FIGs.4A-4C show DFT-computed standard free energies regarding the conformational toggle of Ln 3+ ⁇ py-macrodipa (FIGs.4A-4B) and Ln 3+ ⁇ macrodipa (FIG.4C) complexes.
  • FIG.5 shows calculated strain energies ( ⁇ GS°) values for Ln 3+ ⁇ py-macrodipa and Ln 3+ ⁇ macrodipa systems.
  • FIG.6 shows 1 H NMR spectrum of compound A5 (500 MHz, CDCl3, 25 °C).
  • FIG.7 shows 13 C NMR spectrum of compound of A5 (126 MHz, CDCl3, 25 °C).
  • FIG.8 shows 1 H NMR spectrum of compound A6 (500 MHz, CDCl 3 , 25 °C).
  • FIG.9 shows 13 C NMR spectrum of compound A6 (126 MHz, CDCl 3 , 25 °C).
  • FIG.10 shows 1 H NMR spectrum of compound A8 (500 MHz, MeOD, 25 °C).
  • FIG.13 shows 1 H NMR spectrum of compound A8 (500 MHz, D 2 O, 25 °C).
  • FIG.14 shows 13 C NMR spectrum of compound A8 (126 MHz, D2O, 25 °C).
  • FIG.15 shows ESI-HRMS of compound A9.
  • FIG.16 shows 1 H NMR spectrum of dimethyl ester of compound A10 (500 MHz, MeOD, 25 °C).
  • FIG.17 shows ESI-HRMS of dimethyl ester of compound A10.
  • FIG.18 shows 1 H NMR spectrum of compound A10 (500 MHz, D 2 O, 25 °C).
  • FIG.19 shows ESI-HRMS of compound A10.
  • FIG.20 shows 1 H NMR spectrum of py-macrodipa-NCS (A11) (500 MHz, DMSO, 25 °C).
  • FIG.21 shows ESI-HRMS of py-macrodipa-NCS (A11).
  • FIG. 22 shows HPLC chromatogram of purified py-macrodipa-NCS.
  • FIG.23 shows aqueous stability of py-macrodipa-NCS over time examined by HPLC.
  • FIG. 24 shows HPLC chromatogram of purified Hf(IV)-py-macrodipa.
  • FIG.25 shows stability constants of Ln 3+ complexes formed with EDTA, OBETA, and macropa plotted versus ionic radii.
  • FIG.26 shows stability constants of Ln 3+ complexes formed with macrodipa and macrotripa plotted versus ionic radii.
  • FIG.28 shows crystal structures of (a) [La(macrodipa)] + , (b) [Lu(macrodipa)(OH 2 )] + , and (c) [La(macrotripa)] + complexes. Thermal ellipsoids are drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity. Only one of the two [La(macrodipa)] + complexes in the asymmetric unit is shown. [0037] FIG.29 shows DFT-computed standard free energies for the conformational equilibrium (eq 4) of Ln 3+ -macrodipa complexes.
  • FIG.30 shows depiction of the conformational toggle present in Ln 3+ -Macrodipa and Ln 3+ -macrotripa complex systems.
  • FIG.31 shows 1 H NMR (500 MHz, CDCl 3 , 25 °C) and 13 C ⁇ 1 H ⁇ NMR (126 MHz, CDCl3, 25 °C) spectra of 3.
  • FIG. 32 shows 1H NMR (500 MHz, D 2 O, pD ⁇ 8 by NaOD, 25 °C) and 13C ⁇ 1H ⁇ NMR (126 MHz, D 2 O, pD ⁇ 8 by NaOD, 25 °C) spectra of macrodipa. Acetonitrile was added as an internal reference.
  • FIG 34 shows ESI HRMS of 3 MeCN was used as the mobile phase.
  • FIG.35 shows ESI-HRMS of 5. MeCN was used as the mobile phase.
  • FIG.36 shows ESI-HRMS of macrodipa. MeCN was used as the mobile phase.
  • FIG.37 shows ESI-HRMS of 9. MeCN was used as the mobile phase.
  • FIG.38 shows ESI-HRMS of macrotripa. MeCN was used as the mobile phase.
  • FIG.39 shows HPLC chromatogram of macrodipa. Method: 0–5 min, 90% H 2 O/MeOH; 5–25 min, 90% ⁇ 0% H 2 O/MeOH.
  • FIG. 40 shows HPLC chromatogram of macrotripa. Method: 0–5 min, 90% H 2 O/MeOH; 5–25 min, 90% ⁇ 0% H 2 O/MeOH.
  • FIG.50 shows representative stability constant determination of Tb-macrodipa system by potentiometric titration.
  • cTb 9 ⁇ 10 -4 M
  • cmacrodipa 1 ⁇ 10 -3 M.
  • Initial volume V 15 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.893.
  • Initial volume V 15 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 1.229.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.836.
  • FIG.63 shows representative stability constant determination of Gd-macrotripa system by potentiometric titration.
  • FIG.64 shows representative stability constant determination of Tb-macrotripa system by potentiometric titration.
  • cTb 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.811.
  • FIG.65 shows representative stability constant determination of Dy-macrotripa system by potentiometric titration.
  • FIG.66 shows representative stability constant determination of Ho-macrotripa system by potentiometric titration.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.873.
  • FIG.66 shows representative stability constant determination of Ho-macrotripa system by potentiometric titration.
  • cHo 9 ⁇ 10 -4 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.807.
  • FIG.67 shows representative stability constant determination of Er-macrotripa system by potentiometric titration.
  • FIG.68 shows representative stability constant determination of Tm-macrotripa system by potentiometric titration.
  • cTm 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 1.809.
  • FIG.68 shows representative stability constant determination of Tm-macrotripa system by potentiometric titration.
  • cTm 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.824.
  • FIG.69 shows representative stability constant determination of Yb-macrotripa system by potentiometric titration.
  • cYb 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.759.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.571.
  • FIG.113 shows stacked 1 H NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrodipa complexes.
  • FIG.114 shows stacked 13 C ⁇ 1 H ⁇ NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrodipa complexes. Due to the limited sensitivity on 13 C nucleus, only the major Conformation B is observed in the 13 C ⁇ 1 H ⁇ spectrum of Y 3+ -macrodipa complex.
  • FIG.117 shows stacked 1 H NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrotripa complexes. The 1 H spectrum of Y 3+ -macrotripa clearly shows the presence of only the Conformation B.
  • FIG.118 shows stacked 13 C ⁇ 1 H ⁇ NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrotripa complexes.
  • FIG.120 shows 1 H NMR spectrum (500 MHz, D 2 O, pD ⁇ 6, 25 °C) of [La(macrodipa)][ClO4] crystals.
  • FIG.121 shows 1 H NMR spectrum (500 MHz, CD3OD, 25 °C) of [Lu(macrodipa)(OH2)][PF6] crystals.
  • FIG.122 shows 1 H NMR spectrum (500 MHz, DMSO-d6, 25 °C) of [La(Hmacrotripa)][BPh4] crystals.
  • FIG.124 shows ESI-HRMS of La-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.125 shows ESI-HRMS of Lu-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.126 shows ESI-HRMS of La-macrotripa complex. MeCN was used as the mobile phase [00135]
  • FIG.127 shows ESI-HRMS of Lu-macrotripa complex. MeCN was used as the mobile phase.
  • FIG.128 shows DFT-optimized structure of [Lu(macrotripa)(OH2)] complex.
  • FIG.130 shows 1 H NMR spectrum (500 MHz, CD 3 OD, 25 °C) of the synthetic intermediate that is hydrolyzed to yield py-macrodiphoshpho.
  • FIG.131 shows 1 H NMR spectrum (500 MHz, D2O, 25 °C) of py-macrodiphoshpho. DETAILED DESCRIPTION [00140] The following terms are used throughout as defined below. [00141] As used herein and in the appended claims, singular articles such as “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
  • substituted refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • a substituted group is substituted with one or more substituents, unless otherwise specified.
  • a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e., SF5), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amid
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
  • C m -C n such as C 1 -C 12 , C 1 -C 8 , or C 1 -C 6 when used before a group refers to that group containing m to n carbon atoms
  • Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Alkyl groups may be substituted or unsubstituted.
  • substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.
  • Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Bi- and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like.
  • Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted one or more times with, non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.
  • Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • cycloalkylalkyl groups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms.
  • Cycloalkylalkyl groups may be substituted or unsubstituted. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group.
  • Alkenyl groups include straight and branched chain alkyl groups as defined above, wo carbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds.
  • Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
  • Cycloalkenyl groups include cycloalkyl groups as defined above, having at least one double bond between two carbon atoms.
  • Cycloalkenyl groups may be substituted or unsubstituted. In some embodiments the cycloalkenyl group may have one, two or three double bonds but does not include aromatic compounds. Cycloalkenyl groups have from 4 to 14 carbon atoms, or, in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.
  • Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.
  • Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms.
  • Alkynyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to –C ⁇ CH, -C ⁇ CCH3, -CH 2 C ⁇ CCH3, -C ⁇ CCH 2 CH(CH 2 CH3) 2 , among others.
  • Alkynyl groups may be substituted or unsubstituted.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • the aryl groups are phenyl or naphthyl.
  • Aryl groups may be substituted or unsubstituted.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Representative substituted aryl groups may be mono- substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms.
  • Aralkyl groups may be substituted or unsubstituted.
  • Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl.
  • Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
  • Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms.
  • heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members.
  • Heterocyclyl groups encompass aromatic, partially unsaturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups.
  • heterocyclyl group includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups may be substituted or unsubstituted.
  • Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
  • substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl,
  • Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3-dihydro indolyl groups. Heteroaryl groups may be substituted or unsubstituted. Thus, the phrase “heteroaryl groups” includes fused ring compounds as well as includes heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted.
  • Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl ti f th R t ti h t l l lkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl.
  • Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.
  • Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.
  • Groups described herein having two or more points of attachment i.e., divalent, trivalent, or polyvalent
  • divalent alkyl groups are alkylene groups
  • divalent aryl groups are arylene groups
  • divalent heteroaryl groups are divalent heteroarylene groups, and so forth.
  • Substituted groups having a single point of attachment to the compound of the present technology are not referred to using the “ene” designation.
  • chloroethyl is not referred to herein as chloroethylene.
  • Such groups may further be substituted or unsubstituted.
  • Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
  • branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
  • cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Alkoxy groups may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
  • alkanoyl and alkanoyloxy as used herein can refer, respectively, to – C(O)–alkyl and –O–C(O)–alkyl groups, where in some embodiments the alkanoyl or alkanoyloxy groups each contain 2–5 carbon atoms.
  • aryloyl and “aryloyloxy” respectively refer to –C(O)–aryl and –O–C(O)–aryl groups.
  • aryloxy and “arylalkoxy” refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.
  • carboxylic acid refers to a compound with a –C(O)OH group.
  • carboxylate refers to a –C(O)O – group.
  • a “protected carboxylate” refers to a –C(O)O-G where G is a carboxylate protecting group.
  • Carboxylate protecting groups are well known to one of ordinary skill in the art. An extensive list of protecting groups for the carboxylate group functionality may be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G.
  • R 70 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • amide includes C- and N-amide groups, i.e., -C(O)NR 71 R 72 , and –NR 71 C(O)R 72 groups, respectively.
  • R 71 and R 72 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • the amide is –NR 71 C(O)-(C1-5 alkyl) and the group is termed "carbonylamino,” and in others the amide is –NHC(O)-alkyl and the group is termed "alkanoylamino.”
  • the term “nitrile” or “cyano” as used herein refers to the –CN group.
  • Urethane groups include N- and O-urethane groups, i.e., -NR 73 C(O)OR 74 and -OC(O)NR 73 R 74 groups, respectively.
  • R 73 and R 74 are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • R 73 may also be H.
  • amine or “amino” as used herein refers to –NR 75 R 76 groups, wherein R 75 and R 76 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH 2 , methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
  • sulfonamido includes S- and N-sulfonamide groups, i.e., -SO 2 NR 78 R 79 and –NR 78 SO 2 R 79 groups, respectively.
  • R 78 and R 79 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • the sulfonamido is – NHSO 2 -alkyl and is referred to as the "alkylsulfonylamino" group.
  • thiol refers to —SH groups
  • sulfides include —SR 80 groups
  • sulfoxides include —S(O)R 81 groups
  • sulfones include -SO 2 R 82 groups
  • sulfonyls include — SO 2 OR 83 .
  • R 80 , R 81 , R 82 , and R 83 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the sulfide is an alkylthio group, -S-alkyl.
  • urea refers to –NR 84 -C(O)-NR 85 R 86 groups.
  • R 84 , R 85 , and R 86 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to –C(NR 87 )NR 88 R 89 and –NR 87 C(NR 88 )R 89 , wherein R 87 , R 88 , and R 89 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to –NR 90 C(NR 91 )NR 92 R 93 , wherein R 90 , R 91 , R 92 and R 93 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • halogen or “halo” as used herein refers to bromine, chlorine, fluorine, or iodine.
  • the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
  • hydroxyl as used herein can refers to –OH.
  • imide refers to –C(O)NR 98 C(O)R 99 , wherein R 98 and R 99 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term “imine” refers to –CR 100 (NR 101 ) and –N(CR 100 R 101 ) groups, wherein R 100 and R 101 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R 100 and R 101 are not both simultaneously hydrogen.
  • nitro as used herein refers to an –NO 2 group.
  • the term “trifluoromethyl” as used herein refers to –CF 3 .
  • trifluoromethoxy refers to –OCF3.
  • zido refers to –N 3 .
  • trialkyl ammonium refers to a –N(alkyl) 3 group. A trialkylammonium group is positively charged and thus typically has an associated anion, such as halogen anion.
  • trifluoromethyldiazirido refers .
  • isocyano refers to –NC.
  • isothiocyano refers to –NCS.
  • compositions described herein are within the scope of the present technology and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, he compound of the present technology has a basic group, such as, for example, an amino group
  • pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid
  • inorganic acids such
  • the compound of the present technology when it has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine).
  • alkali and earth alkali metals e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+
  • ammonia or organic amines e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
  • Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.
  • Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • quinazolinones may exhibit the following isomeric forms, which are referred to as tautomers of each other: .
  • guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other: .
  • all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology.
  • Stereoisomers of compounds also known as optical isomers
  • Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated.
  • compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
  • the compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • the macrocycles currently in use e.g., DOTA
  • the macrocycles currently in use generally form complexes of insufficient stability with radionuclides, particularly for radionuclides of larger size, such as actinium, radium, bismuth, and lead isotopes.
  • Such instability results in dissociation of the radionuclide from the macrocycle, and this results in a lack of selectivity to targeted tissue, which also results in toxicity to non-targeted tissue.
  • the present technology provides new macrocyclic complexes that are substantially more stable than those of the conventional art.
  • these new complexes can advantageously target cancer cells more effectively, with substantially less toxicity to non-targeted tissue than complexes of the art.
  • the new complexes can advantageously be produced at room temperature, in contrast to DOTA-type complexes, which generally require elevated temperatures (e.g., at least 80 °C) for complexation with the radionuclide.
  • the present technology also may employ alpha-emitting radionuclides instead of beta radionuclides. Alpha- emitting radionuclides are of much higher energy, and thus substantially more potent, than beta- emitting radionuclides.
  • a compound of any one of Formula I, Formula II, Formula III, and Formlua IV is provided or a pharmaceutically acceptable salt and/or solvate thereof, wherein R 1 is or ; R 2 is independently at each occurrence , , or ; R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O; one of Y 5 and Y 6 is , , or , and the other one of Y 5 and Y 6 is O, or Y 5 and Y 6 are each independently , , , or ; one of Y 7 and Y 8 is , , or , and the other one one of Formula I, ,
  • a compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formula IVA is provided (IIIA) (IVA) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the compound; A 1 , A 2 , A 3 , and A 4 are each independently or ; R 1 is or ; R 2 is independently at each occurrence , , or ; R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O; one of Y 5 and Y 6 is , , or , and the other one of Y 5 and Y 6 is ,
  • M 1 is independently at each occurrence actinium-225 ( 225 Ac 3+ ), lanthanum-132 ( 132 La 3+ ), lanthanum-135 ( 135 La 3+ ), lutetium-177 ( 177 Lu 3+ ), indium-111 ( 111 In 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and/or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium- 226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), uranium-230, scandium-44 ( 44 Sc 3+ ), scandium-47 ( 47 Sc 3+ ), gallium-67 ( 67 Ga 3+ ), or gall
  • the present technology provides a targeting compound useful in, e.g., useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), where the targeting compound is of any one of Formula V, Formula VI, Formula VII, and Formula VIII or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the targeting compound;
  • a 5 , A 6 , A 7 , and A 8 are each independently or ;
  • R 1 is or ;
  • R 2 is independently at each occurrence , , or ;
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is , , , or , and the other one of
  • M 1 of the targeting compound may independently at each occurrence actinium-225 ( 225 Ac 3+ ), lanthanum-132 ( 132 La 3+ ), lanthanum-135 ( 135 La 3+ ), lutetium- 177 ( 177 Lu 3+ ), indium-111 ( 111 In 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and/or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), uranium-230, scandium-44 ( 44 Sc 3+ ), scandium-47 ( 47 Sc 3+ ), gallium-67 ( 67 Ga 3+ ), or gall
  • the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof.
  • PSMA prostate specific membrane antigen
  • PSMA binding peptides include, but are not limited to, those according to the following structure where nn is 0, 1, or 2, and P 1 , P 2 , and P 3 are each independently H, methyl, benzyl, 4- methoxybenzyl, or tert-butyl. In any embodiment herein, it may be that each of P 1 , P 2 , and P 3 are H.
  • Somatostatin illustrated in Scheme A, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein.
  • somatostatin receptors There are five known somatostatin receptors, all being G protein-coupled seven transmembrane receptors: SST1 (SSTR1); SST2 (SSTR2); SST3 (SSTR3); SST4 (SSTR4); and SST5 (SSTR5).
  • Exemplary somatostatin receptor agonists include somatostatin itself, lanreotide, octreotate, octreotide, pasireotide, and vapreotide.
  • Scheme A [00206] Many neuroendocrine tumors express SSTR2 and the other somatostatin receptors.
  • somatostatin agonists e.g., Octreotide, Lanreotide
  • SSTR2 receptors Long acting somatostatin agonists
  • Zatelli MC et al., (Apr 2007).
  • Octreotide is an octapeptide that mimics natural somatostatin but has a significantly longer half-life in vivo.
  • Octreotide is used for the treatment of growth hormone producing tumors (acromegaly and gigantism), when surgery is contraindicated, pituitary tumors that secrete thyroid stimulating hormone (thyrotropinoma), diarrhea and flushing episodes associated with carcinoid syndrome, and diarrhea in people with vasoactive intestinal peptide-secreting tumors (VIPomas).
  • Lanreotide is used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome.
  • Pasireotide is a somatostatin analog with an increased affinity to SSTR5 compared to other somatostatin agonists and is approved for treatment of Cushing's disease and acromegaly.
  • Vapreotide is used in the treatment of esophageal variceal bleeding in patients with cirrhotic liver disease and AIDS related diarrhea.
  • Bombesin is a peptide originally isolated from the skin of the European fire-bellied toad (Bombina bombina). In addition to stimulating gastrin release from G cells, bombesin activates at least three different G-protein-coupled receptors: BBR1, BBR2, and BBR3, where such activity includes agonism of such receptors in the brain. Bombesin is also a tumor marker for small cell carcinoma of lung, gastric cancer, pancreatic cancer, and neuroblastoma.
  • Bombesin receptor agonists include, but are not limited to, BBR-1 agonists, BBR-2 agonists, and BBR-3 agonists.
  • Seprase or Fibroblast Activation Protein (FAP), such as Fibroblast Activation Protein-alpha (FAP-alpha)
  • FAP Fibroblast Activation Protein-alpha
  • Seprase binding compounds include seprase inhibitors.
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any embodiment dislclosed herein of any one of Formula I, Formula II, Formula III, Formula IA, Formula IIA, and Formula IIIA (or pharmaceutically acceptable salt and/or solvate thereof), with an antibody, antibody fragment, or binding peptide.
  • the antibody includes belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab,
  • the antibody fragment includes an antigen-binding fragment of belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendet
  • Targeting compounds may be prepared by a process that includes reacting with R 22 - W 1 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes –X 1 -W 2 group, where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R 21 refers to the portion of the compound other than the –X 1 -W 2 group (this R 21 portion referred to as “macrocycle R 21 ”).
  • R 22 may be conjugated to macrocycle R 21 by reaction of complementary chemical functional groups W 1 and W 2 to form linker L 3 .
  • R 22 -W 1 may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen- binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof).
  • W 1 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where W 2 may be selected to selectively react with W 1 in order to provide L 3 of the targeting compound.
  • Targeting compounds may be prepared by a process that includes reacting with R 24 - W 1 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes a –W 3 group, where Table C provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R 23 refers to the portion of the compound other than the –W 3 group (this R 23 portion is referred to as “macrocycle R 23 ”). As such, R 24 may be conjugated to macrocycle R 23 by reaction of complementary chemical functional groups W 3 and W 4 to form linker L 4 .
  • R 24 -W 4 may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen- binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof).
  • W 4 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table C, where W 3 may be selected to selectively react with W 4 in order to provide L 4 of the target compound. Table C.
  • Targeting compounds may be prepared by a process that includes reacting with R 26 - W 6 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes a –W 5 group, where Table D provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R 25 refers to the portion of the compound other than the –W 5 group (this R 25 portion is referred to as “macrocycle R 25 ”). As such, R 26 may be conjugated to macrocycle R 25 by reaction of complementary chemical functional groups W 5 and W 6 to form linker L 5 .
  • R 26 -W 6 may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen- binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof).
  • W 6 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table D, where W 5 may be selected to selectively react with W 6 in order to provide L 5 of the target compound.
  • amide coupling is a well-known route, where – as an example – lysine residues on the antibody surface react with terminal activated carboxylic acid esters to generate stable amide bonds.
  • Amide coupling is typically mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are detailed elsewhere.
  • cysteine coupling reactions may be employed to conjugate prosthetic molecules with thiol-reactive termini to protein surfaces through exposed thiol side chains on cysteine residues on the protein (e.g., antibody) surface.
  • cysteine residues readily form disulfide linkages with nearby cysteine residues under physiological conditions, rather than existing as free thiols, some cysteine coupling strategies may rely upon selective reduction of disulfides to generate a higher number of reactive free thiols.
  • Cysteine coupling techniques known in the art include, but are not limited to, cys alkylation reactions, cysteine rebridging reactions, and cys-aryl coupling using organometallic palladium reagents.
  • ADCs Antibody-Drug Conjugates
  • Protein conjugation strategies using non-natural amino acid side chains are also well-known in the art. For example, “click chemistries” provide access to conjugated proteins, by rapid and selective chemical transformations under a diverse range of reaction conditions. Click chemistries are known to yield peptide conjugates with limited by-product formation, despite the presence of unprotected functional groups, in aqueous conditions.
  • CuAAC copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction
  • the CuAAC click reaction may be carried out in the presence of ligands to enhance reaction rates.
  • ligands may include, for example, polydentate nitrogen donors, including amines (e.g., tris(triazolyl)methyl amines) and pyridines. (See Liang & Astruc, supra, at 2934 (collecting examples); P.L.
  • Cu-free click methods are also known in the art for delivery of therapeutic and/or diagnostic agents, such as radionuclides (e.g., 18 F), chemotherapeutic agents, dyes, contrast agents, fluorescent labels, chemiluminescent labels, or other labels, to protein surfaces. Cu-free click methods may permit stable covalent linkage between target molecules and prosthetic groups.
  • Cu-free click chemistry may include reacting an antibody or antigen-binding fragment, which has been modified with a non-natural amino acid side chain that includes an activating moiety such as a cyclooctyne (e.g., dibenzocyclooctyne (DBCO)), a nitrone or an azide group, with a prosthetic group that presents a corresponding or complementary reactive moiety, such as an azide, nitrone or cyclooctyne (e.g., DBCO).
  • an activating moiety such as a cyclooctyne (e.g., dibenzocyclooctyne (DBCO)
  • DBCO dibenzocyclooctyne
  • a prosthetic group that presents a corresponding or complementary reactive moiety, such as an azide, nitrone or cyclooctyne (e.g., DBCO).
  • the prosthetic group may include an azide, nitrone, or similar reactive moiety.
  • the prosthetic group may present a complementary cyclooctyne, alkyne, or similar reactive moiety.
  • Cu-free click reactions may be carried out at room temperature, in aqueous solution, in the presence of phosphate-buffered saline (PBS).
  • the prosthetic group may be radiolabeled (e.g., with 18 F) or may be conjugated to any alternative diagnostic and/or therapeutic agent (e.g., a chelating agent). (See id. at 531.)
  • a chelating agent e.g., a chelating agent
  • the compounds of any embodiment and aspect herein of the present technology may be a tripartite compound. However, such tripartite compounds are not restricted to compositions including Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA.
  • a tripartite compound in an aspect, includes a first domain that has relatively low but still specific affinity for serum albumin (e.g., 0.5 to 50 x 10 -6 M), a second domain including a chelating moiety such as but not limited to those described herein, and a third domain that includes tumor targeting moiety (TTT) having relatively high affinity for a tumor antigen (e.g., 0.5 to 50 x 10 -9 M).
  • TTTT tumor targeting moiety
  • somatostatin peptide receptor-2 SSTR2
  • gastrin- releasing peptide receptor SSTR2
  • FAP-alpha gastrin- releasing peptide receptor
  • incretin receptors glucose-dependent insulinotropic polypeptide receptors
  • VIP-1 NPY
  • folate receptor LHRH
  • ⁇ v ⁇ 3 an overexpressed peptide receptor
  • NET noradrenaline transporter
  • TTT is independently at each occurrence a binding domain for a somatostatin peptide receptor-2 (SSTR2), a gastrin-releasing peptide receptor, a seprase (FAP- alpha), an incretin receptor, a glucose-dependent insulinotropic polypeptide receptor, VIP-1, NPY, a folate receptor, LHRH, ⁇ v ⁇ 3, an overexpressed peptide receptor, a neuronal transporter (e.g., noradrenaline transporter (NET)), a receptor for a tumor associated protein (such as EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2,TF-antigen, endothelial specific markers, neuropeptide Y, uPAR, TAG-72, CCK analogs, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, GLP-1, CXCR4, Hepsin, TMPRSS2, caspaces, Alpha V beta six, cMET, or combination of
  • L 501 is independently at each occurrence absent, -C(O)-, -C(O)-NR 4 -, -C(O)-NR 5 -C1- C12 alkylene-,-C1-C12 alkylene-C(O)-, -C(O)-NR 6 -C1-C12 alkylene-C(O)-, - arylene-, –O(CH 2 CH 2 O) r –CH 2 CH 2 C(O)–, –O(CH 2 CH 2 O) rr –CH 2 CH 2 C(O)– NH–, –O(CH 2 CH 2 O)rrr–CH 2 CH 2 —, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or a combination of any two or more thereof, where r is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, rr is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, rrr is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9,
  • the radionuclide may be 177 Lu 3+ , 175 Lu 3+ , 45 Sc 3+ , 66 Ga 3+ , 67 Ga 3+ , 68 Ga 3+ , 69 Ga 3+ , 71 Ga 3+ , 89 Y 3+ , 86 Y 3+ , 89 Zr 4+ , 90 Y 3+ , 99m Tc +1 , 111 In 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 152 Dy 3+ , 149 Tb 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , 160 Gd 3+ , 188 Re +1 ,
  • the radionuclide may be an alpha-emitting radionuclide such as 213 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2+ , 212 Pb 2+ , or 212 Pb 4+ .
  • it may be the tripartite compounds of Formulas L-LIV are of Formulas LV-LIX
  • L 503 is independently at each occurrence absent, -C(O)-, -C1-C12 alkylene-,-C1-C12 alkylene-C(O)-, -C 1 -C 12 alkylene-NR 10 -, -arylene-, –(CH 2 CH 2 O) z –CH 2 CH 2 C(O)–, – (CH 2 CH 2 O)zz–CH 2 CH 2 C(O)–NH–, –(CH 2 CH 2 O)zzz–CH 2 CH 2 –, an amino acid, –CH(CO2H)– (CH 2 )4–, –CH(CO2H)–(CH 2 )4–NH–, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, 19, or 20 amino acids, or a combination of any two or more thereof, where z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, 19, or 20 amino acids, or a combination
  • the albumin-binding moiety plays a role in modulating the rate of blood plasma clearance of the compounds in a subject, thereby increasing circulation time and compartmentalizing the cytotoxic action of cytotoxin-containing domain and/or imaging capability of the imaging agent-containing domain in the plasma space instead of normal organs and tissues that may express antigen.
  • this component of the structure is believed to interact reversibly with serum proteins, such as albumin and/or cellular elements.
  • the affinity of this albumin-binding moiety for plasma or cellular components of the blood may be configured to affect the residence time of the compounds in the blood pool of a subject.
  • the albumin binding-moiety may be configured so that it binds reversibly or non-reversibly with albumin when in blood plasma. In any embodiment herein, the albumin binding-moiety may be selected such that the binding affinity of the compound with human serum albumin is about 5 ⁇ M to about 15 ⁇ M.
  • the albumin-binding moiety of any embodiment herein may include a short- chain fatty acid, medium-chain chain fatty acid, a long-chain fatty acid, myristic acid, a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanoic acid, a substituted or unsubstituted naphthalene acylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2-(4-iodophenyl)acetic acid, a substituted or unsubstituted 3-(4-iodophenyl)propionic acid, or a substituted or unsubstituted 4-(4-iodophenyl)
  • Y 502 , Y 503 , Y 504 , and Y 505 are independently H, halo, or alkyl
  • X 503 , X 504 , X 505 , and X 506 are each independently O or S
  • aa is independently at each occurrence 0, 1, or 2
  • bb is independently at each occurrence 0 or 1
  • cc is independently at each occurrence 0 or 1
  • dd is independently at each occurrence 0, 1, 2, 3, or 4.
  • Y 503 is I and each of Y 501 , Y 502 , Y 503 , Y 504 , and Y 505 are each independently H.
  • the CHEL of the tripartite compounds is a chelator as provided in the compounds of Formula I, II, III, IA, IIA, or IIIA.
  • tripartite compound may be a targeting compound of Formula II where R 22 , R 24 , R 26 , and R 28 are each independently
  • TTT may be any embodiment disclosed herein.
  • W 501 is –C(O)–, –(CH 2 )ww–, or –(CH 2 )oo–NH2-C(O)–; mm is 0 or 1; ww is 1 or 2; oo is 1 or 2;and P 501 , P 502 , and P 503 are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl. In any embodiment herein, it may be that each of P 501 , P 502 , and P 503 are H.
  • the tripartite compounds of the present technology include variations on any of the three domains: e.g., the domain including the chelator, the domain including the albumin- binding group, or the domain including the tumor targeting moiety.
  • compositions e.g., pharmaceutical compositions
  • medicaments comprising any of one of the embodiments of the compounds disclosed herein, any one of the embodiments of the targeting compounds disclosed herein, any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology disclosed herein, or any one of the embodiments of the tripartite compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively refered to as “pharmaceutically acceptable carrier” unless otherwise specified).
  • compositions may be used in the methods and treatments described herein.
  • the pharmaceutical composition may include an effective amount of any embodiment of the compounds of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA.
  • a method of treating a subject includes administering a targeting compound of the present technology to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of the present technology to the subject.
  • the subject suffers from cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”).
  • the administering includes administering an effective amount of any embodiment of the compounds of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA.
  • the subject may suffer from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase (FAP-alpha), or a combination of any two or more thereof and/or mammalian tissue overexpressing PSMA.
  • the mammalian tissue of any embodiment disclosed herein may include one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer.
  • the subject may suffer from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • the composition e.g., pharmaceutical composition
  • medicament may be formulated for parenteral administration.
  • the composition e.g., pharmaceutical composition
  • the administering step of the method may include parenteral administration.
  • the administering step of the method may include intraveneous administration.
  • the effective amount may be determined in relation to a subject. “Effective amount” refers to the amount of a compound or composition required to produce a desired effect.
  • an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use including, but not limited to, the treatment of e.g., one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • a glioma e.g., a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder
  • an effective amount includes amounts or dosages that are capable of reducing symptoms associated with e.g., one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer, such as, for example, reduction in proliferation and/or metastasis of prostate cancer, breast cancer, or bladder cancer.
  • a glioma a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder
  • the effective amount may be from about 0.01 ⁇ g to about 1 mg of the compound per gram of the composition, and preferably from about 0.1 ⁇ g to about 500 ⁇ g of the compound per gram of the composition.
  • a “subject” or “patient” is a mammal, such as a cat, dog, rodent or primate.
  • the subject is a human, and, preferably, a human suffering from or suspected of suffering from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • the term “subject” and “patient” can be used interchangeably.
  • the pharmaceutical composition may be packaged in unit dosage form.
  • the unit dosage form is effective in treating one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • a glioma a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinom
  • a unit dosage including a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations may also be adjusted or modified by a physician skilled in the art.
  • a unit dosage for a patient comprising a compound of the present technology may vary from 1 ⁇ 10 –4 g/kg to 1 g/kg, preferably, 1 ⁇ 10 –3 g/kg to 1.0 g/kg. Dosage of a compound of the present technology may also vary from 0.01 mg/kg to 100 mg/kg or, preferably, from 0.1 mg/kg to 10 mg/kg.
  • Suitable unit dosage forms include, but are not limited to powders, tablets, pills, capsules, lozenges. suppositories. patches. nasal sprays, injectibles, implantable sustained-release formulations, rnucoadherent films, topical varnishes, lipid complexes, etc.
  • the pharmaceutical compositions may be prepared by mixing one or more of the compounds, any one of the targeting compounds, or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology, or any embodiment of the tripartite compound of the present technology, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with cancer and/or a mammalian tissue overexpressing PSMA.
  • the compounds and compositions described herein may be used to prepare formulations and medicaments that treat e.g., prostate cancer, breast cancer, or bladder cancer.
  • compositions may be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions may be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injections.
  • the following dosage forms are given by way of example and should not be construed as limiting the instant present technology.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive.
  • Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • compositions and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents may be added for oral or parenteral administration.
  • suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
  • Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • sterile oils may be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • Compounds of the present technology may be administered to the lungs by inhalation through the nose or mouth.
  • Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aqueous and nonaqueous aerosols are typically used for delivery of compounds of the present technology by inhalation.
  • pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant present technology.
  • compositions may also include, for example, micelles or liposomes, or some other encapsulated form.
  • Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology.
  • Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology.
  • test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75–90%, or 95% or greater, reduction, in one or more symptom(s) caused by, or associated with, the disorder in the subject, compared to placebo–treated or other suitable control subjects.
  • the present technology provides a method of treating cancer by administering an effective amount of the targeting composition of any embodiment disclosed herein to a subject having cancer. Since a cancer cell targeting agent can be selected to target any of a wide variety of cancers, the cancer considered herein for treatment is not limited.
  • the cancer can be essentially any type of cancer.
  • antibodies or peptide vectors can be produced to target any of a wide variety of cancers.
  • the targeting compositions described herein are typically administered by injection into the bloodstream, but other modes of administration, such as oral or topical administration, are also considered.
  • the targeting composition may be administered locally, at the site where the target cells are present, i.e., in a specific tissue, organ, or fluid (e.g., blood, cerebrospinal fluid, etc.). Any cancer that can be targeted through the bloodstream is of particular consideration herein.
  • a specific tissue, organ, or fluid e.g., blood, cerebrospinal fluid, etc.
  • Any cancer that can be targeted through the bloodstream is of particular consideration herein.
  • Some examples of applicable body parts containing cancer cells include the breasts, lungs, stomach, intestines, prostate, ovaries, cervix, pancreas, kidney, liver, skin, lymphs, bones, bladder, uterus, colon, rectum, and brain.
  • the cancer can also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors).
  • the cancer may also be a form of leukemia.
  • the cancer is a triple negative breast cancer.
  • a suitable dosage of the targeting composition may be precisely, at least, above, up to, or less than, for example, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or 1500 mg, or a dosage within a range bounded by any of the foregoing exemplary dosages.
  • composition can be administered in the indicated amount by any suitable schedule, e.g., once, twice, or three times a day or on alternate days for a total treatment time of one, two, three, four, or five days, or one, two, three, or four weeks, or one, two, three, four, five, or six months, or within a time frame therebetween.
  • schedule e.g., once, twice, or three times a day or on alternate days for a total treatment time of one, two, three, four, or five days, or one, two, three, or four weeks, or one, two, three, four, five, or six months, or within a time frame therebetween.
  • the composition can be administered until a desired change in the disorder or condition is realized, or when a preventative effect is believed to be provided.
  • Hf(IV)-py-macrodipa [00250] A preliminary Hf(IV)-py-macrodipa synthesis involved mixing HfCl4 and NaOH, and allowing to stir overnight. A chromatogram (FIG.24) was obtained, evidencing complex formation.
  • Ln 3+ Complexes Stability Constants [00252] Metal complex stability constants provide a quantitative measure of the thermodynamic affinity of ligands for metal ions. The magnitudes of these stability constants for different ligands have been useful for assessing their values in different metal chelation applications.
  • K i [H i L] / [H + ][H i ⁇ 1 L] (1)
  • KLnL [LnL] / [Ln 3+ ][LnL] (2)
  • Table 1 Stability Constants of the Ln 3+ Complexes Formed with py-macrodipa, macrodipa, and macropa a 0.1 M KCl, this work. The values in the parentheses are one standard deviation of the last significant figure.
  • FIG.1 plots log K LnL values against the Ln 3+ 6-coordinate ionic radius 14 for py- macrodipa and macrodipa. Similar to macrodipa, py-macrodipa shows a “dual preference” to Ln 3+ ions: a greater affinity to the large and small Ln 3+ than the middle ones, which strongly suggests that the concept of conformational toggle is preserved in the py-macrodipa system. Remarkably, py-macrodipa shows a great improvement in its affinity to Ln 3+ ions compared to macrodipa, with an about 2-log-unit increase in KLnL for large Ln 3+ and about 1-log-unit rise for small Ln 3+ .
  • Ligand py-macrodipa shows comparable affinity to the largest Ln 3+ ions as does macropa; at the same time, it retains high affinity to the smallest Ln 3+ ions for which macropa barely works.
  • Complex Structures—NMR Spectroscopy [00256] To verify the presence of conformational toggle between Conformations A and B in py-macrodipa, we characterized the solution structures of Ln 3+ ⁇ py-macrodipa complexes with La 3+ , Lu 3+ , and Sc 3+ because of their diamagnetisms. Y 3+ , a diamagnetic Ln 3+ analogue, 12 was also included in this NMR study.
  • FIG.2 shows stacked 1 H NMR spectra of these complexes.
  • La 3+ , Y 3+ , Lu 3+ , and Sc 3+ show a monotonic decrease in their ionic radius, spanning widely from 103.2 pm to 74.5 pm.
  • La 3+ ⁇ py-macrodipa is present as the 2-fold symmetric Conformation A
  • Lu 3+ Sc 3+ complexes exist as in the asymmetric Conformation B.
  • X-ray crystallography is a characterization method extensively leveraged in coordination chemistry and capable of helping visualize the complexes. 17 To gain more intuitive insights on the structures of Ln 3+ ⁇ py-macrodipa complexes, we characterized three representative Ln 3+ complexes in the series, La 3+ , Lu 3+ , and Sc 3+ , by X-ray crystallography. Their crystal structures are depicted in FIG.3. [00260] These crystal structures are consistent to what has been deduced from the NMR spectroscopy data.
  • La 3+ ⁇ py-macrodipa complex shows a 10-coodinate Conformation A with a slightly distorted C2 symmetry; whereas the Lu 3+ ⁇ and Sc 3+ ⁇ py-macrodipa complexes reside in an 8-coordinate Conformation B without any apparent symmetry elements.
  • the Lu 3+ and Sc 3+ are highly comparable except for a notable difference.
  • Conformations B0 and B1 are likely for Conformation B, and thus they both were calculated.
  • the conformational switch between Conformers A and B in the aqueous solution can be written as either Eq 3 or 4, where the standard free energy change of these two reactions are annotated as ⁇ G°(A,B0) and ⁇ G°(A,B1), respectively.
  • FIG.4A summarizes computed ⁇ G°(A,B0) and ⁇ G°(A,B1) values across all Ln 3+ , both of which reveal that large Ln 3+ favors Conformation A and small Ln 3+ prefers Conformation B, complying well with the experimental observations.
  • Conformation B1 is systematically favored over B0 in aqueous solution, by ⁇ 30 kJ . mol -1 . Since DFT calculation suggests Conformation B1 is more accessible than B0 in aqueous solution, we focus the following calculations particularly on Conformation B1.
  • Soc.2020, 142, 13500–13506. (10) Li, L.; Jaraquemada-Peláez, M. de G.; Kuo, H.-T.; Merkens, H.; Choudhary, N.; Gitschtaler, K.; Jermilova, U.; Colpo, N.; Uribe-Munoz, C.; Radchenko, V.; Schaffer, P.; Lin, K.-S.; Bénard, F.; Orvig, C. Functionally Versatile and Highly Stable Chelator for 111 In and 177 Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting. Bioconjugate Chem. 2019, 30, 1539–1553.
  • High-performance liquid chromatography consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC-20AT (analytical) pump, and an SPD-20AV UV ⁇ Vis detector monitoring at 270 nm (Shimadzu, Japan).
  • Semipreparative purification was performed using an Epic Polar preparative column, 120 ⁇ , 10 ⁇ m, 25 cm ⁇ 20 mm (ES Industries, West Berlin, NJ) at a flow rate of 14 mL/min.
  • Method P3 0 ⁇ 5 min, 90% H 2 O/MeOH; 5 ⁇ 30 min, 90% ⁇ 0% H 2 O/MeOH. All analytical HPLC runs were carried out with the same method: 0 ⁇ 5 min, 90% H 2 O/MeOH; 5 ⁇ 25 min, 90% ⁇ 0% H 2 O/MeOH.
  • 1H and 13C ⁇ 1H ⁇ NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 and 125.68 MHz for 1 H and 13 C observations, respectively. All these NMR experiments were carried out at 25 °C. High- resolution mass spectra (HRMS) were acquired on a Thermo Scientific Exactive Orbitrap mass spectrometer with a heated electrospray (HESI) ion source.
  • HRMS High- resolution mass spectra
  • CO 2 was excluded from the vessel prior to and during the titrations by an argon flow, which was passed through an aqueous 30 wt% KOH solution.
  • Carbonate-free KOH (0.1 M) was prepared by dissolving KOH pellets (semiconductor grade, 99.99% trace metals basis, Sigma-Aldrich) in freshly boiled water and was standardized by potentiometric titration against potassium hydrogen phthalate.
  • Hydrochloric acid 0.1 M, J.T. Baker was standardized against Tris (base form).
  • Titration solutions were maintained at a constant ionic strength of 0.1 M with KCl (BioUltra, ⁇ 99.5%, Sigma-Aldrich) and were equilibrated for 15 minutes prior to the addition of titrant.
  • the electrode was calibrated before each titration by titrating a solution of standardized HCl with standardized KOH, and the data were analyzed using the program Glee 5 (ver.3.0.21) to obtain the standard electrode potential and slope factor.
  • Ligand stock solutions were made by dissolving the solid ligand in H 2 O, and their exact concentrations were determined based on the end points of the potentiometric titration curves obtained during the protonation constant determinations.
  • the concentrations determined from titration curves matched the concentrations calculated from the ligand masses, where the MWs of the ligands were estimated from the elemental analysis results.
  • Ln 3+ stock solutions were made by dissolving the corresponding LnCl 3 hydrate salts (99.9% purity or higher) in standardized HCl (0.1 M).
  • the exact concentrations were determined by complexometric titrations 6 with a standardized Na2H2EDTA solution (Alfa Aesar ).
  • Protonation constant or stability constant determinations were carried out by titrating an acidic solution containing free ligand or both ligand and metal with standardized KOH.
  • the ligand concentration was 1 mM.
  • both the ligand and metal ion concentrations were around 1 mM.
  • the total analyte volumes were 15–20 mL. Up to 3 min (protonation constant determinations) or 5 min (stability constant determinations) were given as equilibration times before recording the solution pH after the addition of an aliquot of base. The solutions were inspected throughout the titrations for signs of Ln(OH) 3 precipitation.
  • the 1D 1 H NMR spectra of the Y 3+ complexes and all the 13 C ⁇ 1 H ⁇ NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 MHz for 1 H observation and 125.68 MHz for 13 C observation.
  • 2D experiments were performed using the standard Varian pulse sequences HSQCAD, gHMBCAD, gCOSY and ROESYAD as provided in VnmrJ (ver. 3.2). All these NMR experiments were carried out at 25 °C.
  • Table 4 provides peak assignments of NMR spectra on La-macrodipa complex. Table 4. Peak assignments of NMR spectra on La-macrodipa complex [00297] Table 5 provides peak assignments of NMR spectra on Lu-macrodipa complex. Table 5. Peak assignments of NMR spectra on Lu-macrodipa complex.
  • Table 6 provides peak assignments of NMR spectra on La-macrotripa complex. Table 6. Peak assignments of NMR spectra on La-macrotripa complex.
  • Table 7 provides peak assignments of NMR spectra on Lu-macrotripa complex. Table 7. Peak assignments of NMR spectra on Lu-macrotripa complex.
  • X-Ray Crystallography [00301] X-ray quality crystals of La-macrodipa complex were obtained via the following procedure. Caution! Perchlorate salts should be handled as potentially explosive compounds. Do not apply vacuum or remove these crystals from the mother liquor.
  • macrodipa . 4HCl . 3H2O (27.9 mg, 0.038 mmol) was suspended in i-PrOH (500 ⁇ L). Triethylamine (31.6 ⁇ L, 0.228 mmol) was added to this suspension, and it was then heated to 75 °C for 30 min, causing full dissolution of the ligand.
  • La(ClO4)3 3 X-Ray Crystallography
  • X-ray quality crystals of the Lu-macrodipa complex were obtained via the following procedure. macrodipa . 4HCl . 3H2O (22.2 mg, 0.030 mmol) and LuCl3 . 6H2O (12.8 mg, 0.033 mmol) were dissolved in 500 ⁇ L of H2O. The pH of this solution was adjusted to 4–5 with 1 M NaOH ( ⁇ 145 ⁇ L), added while stirring. This mixture was allowed to stir for 30 min.
  • Solid KPF6 (9.0 mg, 0.049 mmol) was then added, leading to the formation of a white precipitate within several minutes. This suspension was allowed to stir for another 30 min and then transferred into a 2-mL centrifuge tube. It was centrifuged, and the supernatant was removed. The pellet was resuspended in H2O and isolated by centrifugation twice, to dissolve water-soluble impurities. Because the pellet had some solubility in H2O, each washing step led to a loss of mass. Thus, the supernatants afforded by the 3 centrifugations were collected separately.
  • X-ray quality crystals of the La-macrotripa complex were obtained via the following procedure. macrotripa . 5HCl . 2H2O (31.0 mg, 0.035 mmol) and LaCl3 . 7H2O (14.9 mg, 0.040 mmol) were dissolved in 500 ⁇ L of H2O. The pH of this solution was adjusted to ⁇ 6 with 1 M NaOH ( ⁇ 250 ⁇ L), added while stirring.
  • Hydrogen atoms bound to oxygen were located in the difference Fourier synthesis and subsequently refined semi-freely with the help of distance restraints.
  • the isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the Ueq value of the atoms they are linked to (1.5 times for methyl groups).
  • the La- macrodipa dataset contains disordered solvent molecules of H2O that were included in the unit cell but could not be satisfactorily modeled. Therefore, those solvents were treated as diffuse contributions to the overall scattering without specific atom positions using the solvent mask routine in Olex2.15
  • the Lu-macrodipa stucture was refined as a two-component non-merohedral twin, BASF 0.4739(5).
  • CCDC 2003601 ⁇ 2003603 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: +441223 336033.
  • Table 8 provides X-ray crystal data and structure refinement details for La- macrodipa ([La(macrodipa)][ClO 4 ] . DMF), Lu-macrodipa ([Lu(macrodipa)(OH 2 )][PF 6 ] .
  • FIG.120 shows 1 H NMR spectrum (500 MHz, D2O, pD ⁇ 6, 25 °C) of [La(macrodipa)][ClO 4 ] crystals.
  • FIG.121 shows 1 H NMR spectrum (500 MHz, CD 3 OD, 25 °C) of [Lu(macrodipa)(OH 2 )][PF 6 ] crystals.
  • FIG.122 shows 1 H NMR spectrum (500 MHz, DMSO-d6, 25 °C) of [La(Hmacrotripa)][BPh4] crystals.
  • FIG.124 shows ESI-HRMS of La-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.125 shows ESI-HRMS of Lu-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.126 shows ESI-HRMS of La-macrotripa complex. MeCN was used as the mobile phase.
  • FIG. 127 shows ESI-HRMS of Lu-macrotripa complex. MeCN was used as the mobile phase.
  • DFT Calculations [00308] DFT calculations were executed using Gaussian 09.
  • Binding energy ⁇ GB° is the standard free energy for the binding process of a Ln3+ ion to the ligand in the prearranged conformation in the gas phase.
  • Solvation energy ⁇ Gsolv° is the standard free energy associated with moving the complexes from the gas phase into aqueous solution.
  • the formula derivation is represented as below. [00312]
  • the formation reaction of Ln-macrodipa complex in Conf A, [LnLA]+(aq) can be written as Ln3+(aq) + LA2 ⁇ (aq) ⁇ [LnLA]+(aq);
  • ⁇ G°(A) G°(A, aq) ⁇ G°(Ln, aq) ⁇ G°(LA, aq).
  • Eq S4 shows the metal-ligand binding process in the complex formation, and the free energy change for this process is the binding energy for Conf A, ⁇ GB°(A).
  • Eq S15 can be simplified to Eq S19. It shows the competition between Conf A and Conf B are accounted for by three contributions: ⁇ GS°, ⁇ GB°, and ⁇ Gsolv°.
  • ⁇ G° ⁇ GS° + ⁇ GB° + ⁇ Gsolv°.
  • S19 [00322] With Eqs S3 and S10, ⁇ GS° can be obtained by Eq S20. In this case, the unknown G°(L, g) is canceled out.
  • Oxyaapa A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides. Inorg. Chem.2020, 59, 5116–5132.
  • Roca-Sabio A.; Mato-Iglesias, M.; Esteban-Gómez, D.; Tóth, É.; de Blas, A.; Platas- Iglesias, C.; Rodr ⁇ guez-Blas, T. Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides. J. Am. Chem. Soc.2009, 131, 3331–3341. (10) Gottling, H.
  • Potentiometric titrations were performed to determine their protonation constants (K i , Table 14, FIGs. 41-70). To probe the thermody- namic affinities of these ligands for Ln 3+ ions, we conducted potentiometric titrations to obtain their stability constants (KLnL and KLnHL, Table 13). These protonation and stability constants are defined in eqs 1 ⁇ 3, with the concentrations of all species at chemical equilibrium.
  • FIG.26 shows a plot of log K LnL versus the Ln 3+ ionic radius 28 for both macrodipa and macrotripa, which reveals them to be the first known ligands that exhibit type IV selectivity.
  • log KLnL values between Ln 3+ -macrodipa and Ln 3+ - macrotripa systems they are similar for early lanthanides, La 3+ ⁇ Gd 3+ .
  • Ln 3+ -macrodipa reaches a minimum for Dy 3+ and Ho 3+ , whereas for macrotripa the minimum occurs earlier in the series, between Gd 3+ and Tb 3+ .
  • the macrotripa complexes are significantly more stable than those of macrodipa.
  • the 1 H NMR spectra of all four complexes indicate that a single species is present in solution. However, significant differences are apparent in comparing the La 3+ and Lu 3+ complexes.
  • the La 3+ -macrodipa complex is 2-fold symmetric, indicated by one-half the number of 1 H and 13 C resonances relative to the asymmetric Lu 3+ -macrodipa complex.
  • the hydrogen resonances from the methylene groups linking the crown and picolinate donors H-13, H-20 for macrodipa, and H-13, H-20, H-27 for macrotripa; Scheme 6
  • Scheme 6 which are informative due to their proximities to the picolinate donors, are significantly different between the La 3+ and Lu 3+ complexes.
  • Both ligands give rise to identical coordination spheres for the large early lanthanides, like La 3+ , and therefore exhibit only minor differences in their thermodynamic stabilities.
  • the inner coordination spheres are nearly identical between macrodipa and macrotripa, but the outer sphere differs due to the hydrogen-bonding interaction with the coordinated water molecule.
  • the differences in thermodynamic stability between the macrodipa and macrotripa complexes of the late lanthanides are most likely a consequence of the hydrogen bonding of the pendent picolinate donor arm. This result highlights how modifying the outer coordination sphere of lanthanide complexes fine-tunes their thermodynamic properties.
  • the SMD solvation model 45,46 was implemented to take the solvent effects into consideration.
  • the ⁇ G° (FIG. 29) is positive for light Ln 3+ and negative for heavy Ln 3+ .
  • This observation is consistent with the experimental results with La 3+ - macrodipa and Lu 3+ -macrodipa complexes attaining Conforma- tions A and B, respectively.
  • ⁇ G° changes its sign between Gd 3+ and Tb 3+ , which indicates the switch of favored conformation. This crossover suggests that the type IV behavior of macrodipa is a consequence of the significant conformational changes that occur when binding Ln 3+ ions of different sizes.
  • ⁇ G° for this conformational change can be broken into three contributors. Specifically, it can be expressed as the sum of the relative ligand strain energies ( ⁇ G S °), relative metal ⁇ ligand binding energies ( ⁇ G B °), and relative solvation energies ( ⁇ Gsolv°) between Conformations A and B. As shown in FIG. 29, ⁇ Gsolv° is positive for all Ln 3+ complexes, which reveals that Conformer A and the noncoordinated water ligand are better solvated in aqueous solution than is Conformer B. Likewise, ⁇ G B ° is positive for all Ln 3+ , which indicates that Conformation A is better suited to neutralize the electrostatic charges of these ions than is Conformation B.
  • Example 4 [00342] In this example, macrodipa and py-macrodipa were evaluated for their ability to complex 225 Ac 3+ and 213 Bi 3+ . Radiolabeling studies were conducted, revealing the efficient incorporation of both 225 Ac 3+ and 213 Bi 3+ by py-macrodipa that matches or surpasses the well- known chelators macropa and DOTA. Incubation in human serum at 37 °C showed that ⁇ 90% of the 225 Ac 3+ ⁇ py-macrodipa complex dissociates after 1 d. The Bi 3+ ⁇ py-macrodipa complex possesses remarkable kinetic inertness in an EDTA transchelation challenge study, surpassing that of Bi 3+ ⁇ macropa.
  • 225 Ac was produced from irradiated thorium ( 232 Th(p,x) 225/227 Ac ⁇ ), herein referred to as 225/227 Ac ⁇ where the “ ⁇ ” symbol denotes “first-pass 225 Ac”, where separation of 225/227 Ac ⁇ from irradiated thorium was performed as described in Robertson, A. K. H.; McNeil, B. L.; Yang, H.; Gendron, D.; Perron, R.; Radchenko, V.; Zeisler, S.; Causey, P.; Schaffer, P.
  • 213 Bi was eluted with freshly prepared 0.2 M NaI/0.1 M HCl solution (300 ⁇ 600 ⁇ L), wherein the bulk of the activity was eluted in the first 150 ⁇ L. Subsequent elutions (with or without 2 mL of 1 mM HCl prewash of the generator) proceeded no earlier than 3 hours after the last elution, therefore optimizing the ratio of 213 Bi to the amount of other radionuclide impurities such as 209 Pb and 209 Bi. The generator was sealed between each elution to minimize evaporation from the resin.
  • TLC imaging was performed using an AR-2000 imaging scanner equipped with PD-10 gas, and analysis of RCYs was carried out using WinScan software (ver.3.14).
  • Method C macropa and DOTA – aluminum backed silica TLC plates (TLC-SG, silica gel 60, F 254 , MERCK, Germany), with citrate buffer (0.4 M, pH 4.0).
  • py-macrodipa is able to achieve significantly higher radiochemical yields than its analogue macrodipa and the conventional chelator DOTA, which also required high temperatures for radiolabeling. Radiochemical yields of approximately 75% and 65% are obtained when using low py-macrodipa concentrations of 10 ⁇ 6 M and 10 ⁇ 8 M for 225 Ac 3+ and 213 Bi 3+ , respectively. With respect to 225 Ac 3+ chelation, py- macrodipa was slightly less effective than macropa, but was better at radiolabeling 213 Bi 3+ .
  • UV–Vis spectra were recorded on a Shimadzu UV-1900 UV ⁇ Vis spectrometer with a 1-cm quartz cuvette.
  • a stock solution of EDTA (150 mM) was prepared in H 2 O, and its pH was adjusted to 5.0 with NMe 4 OH.
  • the concentrations of macrodipa and py-macrodipa were determined by potentiometric titrations, as described in our prior work.
  • the ligand (0.3 ⁇ mol) and metal (0.3 ⁇ mol) were mixed in a cuvette and diluted to 2980 ⁇ L with 0.1 M HOAc/NMe 4 OAc buffer (pH 5.0) to form the complex in situ. After allowing the solution to equilibrate for 15 min, 20 ⁇ L of the EDTA stock solution was added, giving a final complex and EDTA concentrations of 100 ⁇ M and 1 mM, respectively. Upon addition of EDTA, the reaction was monitored immediately by UV–Vis spectroscopy at 25 °C, for up to 5 weeks. The absorbance at 284 nm were plotted as a function of time.
  • the benzyl-protected macrocyclic backbone 2 was constructed in two steps commencing from commercially available 2,6-Bis(bromomethyl)pyridine and 2- benzylaminoethanol. The benzyl groups were then removed by reduction with H 2 over a Pd/C catalyst to yield the desired dipyridyl macrocycle 3. Subsequent installation of the two picolinate pendent arms via alkylation and acidic deprotection afforded dipy-macrodipa. The identity and purity of the intermediates and final product were verified by NMR spectroscopy, mass spectrometry, and analytical HPLC.
  • H2O ⁇ 18 M ⁇ . cm
  • Organic solvents were of ACS grade or higher. All other reagents were purchased from commercial sources and used without further purification.
  • the chelator dipy- macrodipa were synthesized following Scheme x.6-Bromomethylpyridine-2-carboxylic methyl ester was prepared as previously described.
  • High-performance liquid chromatography HPLC consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC-20AT (analytical) pump, and an SPD-20AV UV ⁇ Vis detector monitoring at 270 nm (Shimadzu, Japan).
  • Method P1 0 ⁇ 20 min, 95% H2O/MeOH; 20 ⁇ 25 min, 95% ⁇ 0% H2O/MeOH; Method P2: 0 ⁇ 10 min, 90% H 2 O/MeOH; 10 ⁇ 50 min, 90% ⁇ 0% H 2 O/MeOH. All analytical HPLC runs were carried out with the same method: 0 ⁇ 5 min, 90% H2O/MeOH; 5 ⁇ 25 min, 90% ⁇ 0% H2O/MeOH. [00355] NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 and 125.68 MHz for 1 H and 13 C observations, respectively.
  • Titration solutions were maintained at a constant ionic strength of 0.1 M with KCl (BioUltra, ⁇ 99.5%, Sigma-Aldrich) and were equilibrated for 15 minutes prior to the addition of titrant.
  • the electrode was calibrated before each titration by titrating a solution of standardized HCl with standardized KOH, and the data were analyzed using the program Glee (ver.3.0.21) to obtain the standard electrode potential and slope factor.
  • Glee ver.3.0.21
  • Ligand stock solutions were made by dissolving the solid ligand in H2O, and their exact concentrations were determined based on the end points of the potentiometric titration curves obtained during the protonation constant measurements. The concentrations determined from titration curves matched the concentrations calculated from the ligand masses using molecular weights obtained from elemental analysis results.
  • Ln 3+ stock solutions were made by dissolving the corresponding LnCl 3 hydrate salts (99.9% purity or higher) in standardized HCl (0.1 M). The exact concentrations were determined by complexometric titrations with a standardized Na 2 H 2 EDTA solution (Alfa Aesar). See Wuhan University.
  • the total analyte volumes were 15–20 mL. Up to 3 min (protonation constant determinations) or 5 min (stability constant determinations) were given as equilibration times before recording the solution pH after the addition of an aliquot of base. During the stability constant determinations, the solutions were inspected throughout the titrations for signs of Ln(OH)3 precipitation. Data points of the titration curves were excluded from analysis if any precipitate was observed. These titration data were refined with Hyperquad 2013 software (see Gans, P.; Sabatini, A.; Vacca, A. Investigation of Equilibria in Solution. Determination of Equilibrium Constants with the HYPERQUAD Suite of Programs.
  • c 0.1 M KCl from Hu, A.; MacMillan, S. N.; Wilson, J. J. Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern for the Lanthanide Ions. J. Am. Chem. Soc.2020, 142, 13500–13506.
  • d 0.1 M KCl from Roca- Sabio, A.; Mato-Iglesias, M.; Esteban-Gómez, D.; Tóth, É.; de Blas, A.; Platas- Iglesias, C.; Rodr ⁇ guez-Blas, T. Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides. J. Am.
  • a stock solution of DTPA (200 mM) was prepared in H 2 O, and its pH was adjusted to 7.4 with NMe4OH.
  • the concentrations of dipy-macrodipa and Ln 3+ stock solutions were determined by potentiometric titrations, as described in Section X.
  • the ligand (0.3 ⁇ mol) and metal (0.3 ⁇ mol) were mixed in a cuvette and diluted to 2850 ⁇ L with 0.1 M MOPS buffer (pH 7.4) to form the complex in situ. After allowing the solution to equilibrate for 5 min, 150 ⁇ L of the DTPA stock solution was added, giving a final complex and DTPA concentrations of 100 ⁇ M and 10 mM, respectively.
  • High-performance liquid chromatography consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC- 20AT (analytical) pump, and an SPD-20AV UV ⁇ Vis detector monitoring at 270 nm (Shimadzu, Japan).
  • Fmoc- ⁇ -L-alanine (199 mg, 0.64 mmole) was coupled to the resin using PyBOP (167 mg, 0.32 mmole) as coupling reagent in the presence of DIEA (112 ⁇ L, 0.64 mmol) within 12 h.
  • the resin was treated with mixture of 20% piperidine in DMF in order to remove Fmoc group.
  • ⁇ -Ala-PSMA-617 was cleaved from the resin by treatment with a mixture of TFA/TIS/H 2 O (95%/2.5%/2.5%).
  • this reaction mixture is filtered and injected into the preparative HPLC system to purify the product (Method: 0–10 min, 90% H 2 O/MeCN; 10–40 min, 90% ⁇ 0% H 2 O/MeCN). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield py- macrodipa-PSMA as white fluffy solid (0.114 g).
  • Radiolabeling of py-macrodipa-PSMA to provide [ 135 La]La–py-macrodipa- PSMA Radio-HPLC analysis was carried out on the Shimadzu HPLC-20AR equipped with a binary gradient, pump, UV–Vis detector, autoinjector and a Laura radiodetector on a Phenomenex Luna (5 ⁇ m, 150 mm x 3 mm, 100 ⁇ ). (HPLC METHOD).
  • 132/135 LaCl 3 was obtained from the Engle Lab at University of Wisconsin-Madison. Py-macrodipa-PSMA (6 ⁇ L, 1 mM, 20% DMSO in 0.5 M NaOAc buffer, pH 5.5) was combined with 132/135 La (537 ⁇ Ci, 66 ⁇ L) and additional NaOAc buffer (320 ⁇ L, 20% DMSO in NaOAc). Quantitative radiolabeling was achieved in 20 min at room temperature and studies were performed without further purification.
  • a range includes each individual member.
  • a group having 1-3 cells refers to groups having 1, 2, or 3 cells.
  • a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.
  • a 5 , A 6 , A 7 , and A 8 are each independently or ;
  • R 1 is or ;
  • R 2 is independently at each occurrence , , or ;
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O;
  • one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O;
  • one of Y 5 and Y 6 is , , or , and the other one
  • the targeting compound of Paragraph H wherein the targeting compound is of any one of Formula V-1, Formula VI-1, and Formula VII-1 or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the targeting compound; R 2 is independently at each occurrence one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O; one of Y 5 and Y 6 is , , or , and the other one of Y 5 and Y 6 is O, or Y 5 and Y 6 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 are independently at each occurrence H or –X 1 –L 3 –R 22 ; Z 1 is independently at each occurrence OH or NH–L 4 –
  • R 22 , R 24 , and R 26 each independently at each occurrence comprise belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab,
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula I, Formula II, Formula III, and Formula IV or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide, (III) (IV) wherein A 1 , A 2 , A 3 , and A 4 are each independently or ; R 1 is or ; R 2 is independently at each occurrence , , or ; R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O; one of Y 5 and Y 6 is , , or , and the other
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph M wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of Formula I-1, Formula II-1, and Formula III-1 O.
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph M or Paragraph N wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine
  • P The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs M-O, wherein the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof.
  • PSMA prostate specific membrane antigen
  • somatostatin receptor agonist e.g., a bombesin receptor agonist
  • a seprase binding compound e.g., a FAP-alpha binding compound
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula IA, Formula IIA, and Formula IIIA or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide, (IIIA) (IVA) wherein M 1 is a radionuclide chelated in the compound; A 1 , A 2 , A 3 , and A 4 are each independently or ; R 1 is or ; R 2 is independently at each occurrence , , or ; R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O;
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph R wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of any one of Formula IA-1, Formula IIA-1, and Formula IIIA-1 T.
  • the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvaluma
  • V The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-U, wherein the binding peptide comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof.
  • PSMA prostate specific membrane antigen
  • W The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-V, wherein the compound of Formula IA is of Formula IA-2 or a pharmaceutically acceptable salt and/or solvate thereof.
  • X A composition comprising a pharmaceutically acceptable carrier and a compound of any one of Paragraphs A-L.
  • a composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of Paragraphs H-L or comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs M-W.
  • a pharmaceutical composition useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) in a subject wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of any one of Paragraphs H-L or a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs M-W.
  • PSMA prostate specific membrane antigen
  • the pharmaceutical composition of Paragraph Z wherein the pharmaceutical composition comprises an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide.
  • AB The pharmaceutical composition of Paragraph Z or Paragraph AA, where the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof, and/or mammalian tissue overexpressing PSMA.
  • composition of any one of Paragraphs Z-AB wherein the subject suffers from one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, AD.
  • any one of Paragraphs Z-AC wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • a glioma a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcino
  • the pharmaceutical composition of any one of Paragraphs Z-AD wherein the pharmaceutical composition is formulated for intraveneous administration, optionally comprising sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • AF The pharmaceutical composition of any one of Paragraphs Z-AE, wherein the effective amount of the compound is from about 0.01 ⁇ g to about 10 mg of the compound per gram of the pharmaceutical composition.
  • AG The pharmaceutical composition of any one of Paragraphs Z-AF, wherein the pharmaceutical composition is provided in an injectable dosage form.
  • AH injectable dosage form
  • a method of treating a subject comprising administering a targeting compound of any one of Paragraphs H-L to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one Paragraphs M-W.
  • AI comprising administering a targeting compound of any one of Paragraphs H-L to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one Paragraphs M-W.
  • the method of Paragraph AH wherein the subject suffers from cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) AJ.
  • PSMA prostate specific membrane antigen
  • the method of Paragraph AH or Paragraph AI wherein the method comprises administering an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide AK.
  • any one of Paragraphs AH-AJ wherein the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), when administered to a subject.
  • AL The method of any one of Paragraphs AH-AK, wherein the mammalian tissue comprises one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer.
  • AM metastatic cancer
  • any one of Paragraphs AH-AL wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • AN The method of any one of Paragraphs AH-AM, wherein the administering comprises parenteral administration.
  • AO The method of any one of Paragraphs AH-AM, wherein the administering comprises parenteral administration.

Abstract

The present disclosure relates to compounds (including compounds chelating radionuclides) as well as compositions including such compounds useful in targeted radiotherapy. For example, a compound of any one of Formula I, Formula II, Formula III, and Formlua IV is provided or a pharmaceutically acceptable salt and/or solvate thereof. Equivalents of such compounds are also disclosed.

Description

MACROCYCLES AND COMPLEXES WITH RADIONUCLIDES USEFUL IN TARGETED RADIOTHERAPY OF CANCER CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Appl. No. 63/193,583 filed on May 26, 2021 which is incorporated herein by reference in its entirety for any and all purposes. U.S. GOVERNMENT RIGHTS [0002] This invention was made with government support under R21EB027282 and R01EB02925 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD [0003] The present technology generally relates to macrocycles and complexes of such macrocycles with radionuclides, compositions including such macrocycles and complexes, and methods of use. SUMMARY [0004] In an aspect, a compound of any one of Formula I, Formula II, Formula III, and Formlua IV is provided
Figure imgf000003_0001
te thereof, wherein A1, A2, A3, and A4 are each independently
Figure imgf000004_0001
Figure imgf000004_0002
R2 is independently at each occurrence
Figure imgf000004_0003
R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is
Figure imgf000004_0005
or , and the other one of Y1 and Y2 is O;
Figure imgf000004_0006
one of Y3 and Y4 is
Figure imgf000004_0007
the other 3 4
Figure imgf000004_0004
one of Y and Y is O; one of Y5 and Y6 is or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , or one of Y7 and Y8 is or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , or Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or X1 W2 Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. [0005] In a related aspect, a compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formula IVA is provided
Figure imgf000007_0001
or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the compound; A1, A2, A3, and A4 are each independently
Figure imgf000007_0003
Figure imgf000007_0004
R2 is independently at each occurrence
Figure imgf000007_0002
R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. [0006] In a further related aspect, the present technology provides a targeting compound useful in, e.g., useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), where the targeting compound is of any one of Formula V, Formula VI, Formula VII, and Formula VIII
Figure imgf000010_0001
or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the targeting compound; A5, A6, A7, and A8 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or X1 L3 R22 Z1 is independently at each occurrence OH or NH–L4–R24; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –L5–R26; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; L3, L4 , and L5 are independently at each occurrence a bond or a linker group; and R22, R24, and R26 each independently at each occurrence comprise an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase- containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin. [0007] In a further related aspect, a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula I, Formula II, Formula III, and Formlua IV or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide. In a related aspect, a modified antibody, modified antibody fragment, or modified binding peptide is provided that includes a linkage arising from conjugation of a compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formlua IVA or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide. [0008] The present technology also provides compositions (e.g., pharmaceutical compositions) and medicaments comprising any of one of the embodiments of the compounds disclosed herein, any one of the embodiments of the targeting compounds disclosed herein, or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology disclosed herein, and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively refered to as “pharmaceutically acceptable carrier” unless otherwise specified). The compositions may be used in the methods and treatments described herein. BRIEF DESCRIPTION OF THE DRAWINGS [0009] FIG.1 shows stability constants of Ln3+ complexes formed with py-macrodipa and macrodipa plotted versus ionic radii [0010] FIG.2 shows 1H NMR spectra of La3+−, Y3+−, Lu3+−, and Sc3+−py-macrodipa complexes (600 MHz, D2O, pD = 7, 25 °C). [0011] FIG.3 shows crystal structures of (a) [La(py-macrodipa)]+, (b) [Lu(py-macrodipa)]+, and (c) [Sc(py-macrodipa)(OH2)]+ complexes. Thermal ellipsoids are drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity. Only one of the two [La(py-macrodipa)]+ or [Sc(py-macrodipa)(OH2)]+ complexes in the asymmetric unit is shown. [0012] FIGs.4A-4C show DFT-computed standard free energies regarding the conformational toggle of Ln3+−py-macrodipa (FIGs.4A-4B) and Ln3+−macrodipa (FIG.4C) complexes. [0013] FIG.5 shows calculated strain energies (ΔGS°) values for Ln3+−py-macrodipa and Ln3+−macrodipa systems. [0014] FIG.6 shows 1H NMR spectrum of compound A5 (500 MHz, CDCl3, 25 °C). [0015] FIG.7 shows 13C NMR spectrum of compound of A5 (126 MHz, CDCl3, 25 °C). [0016] FIG.8 shows 1H NMR spectrum of compound A6 (500 MHz, CDCl3, 25 °C). [0017] FIG.9 shows 13C NMR spectrum of compound A6 (126 MHz, CDCl3, 25 °C). [0018] FIG.10 shows 1H NMR spectrum of compound A8 (500 MHz, MeOD, 25 °C). [0019] FIG.11 shows 13C NMR spectrum of compound A8 (126 MHz, MeOD, 25 °C; number of scans (ns) =128). [0020] FIG.12 shows 13C NMR spectrum of compound A8 (126 MHz, MeOD, 25 °C; ns=1024). [0021] FIG.13 shows 1H NMR spectrum of compound A8 (500 MHz, D2O, 25 °C). [0022] FIG.14 shows 13C NMR spectrum of compound A8 (126 MHz, D2O, 25 °C). [0023] FIG.15 shows ESI-HRMS of compound A9. [0024] FIG.16 shows 1H NMR spectrum of dimethyl ester of compound A10 (500 MHz, MeOD, 25 °C). [0025] FIG.17 shows ESI-HRMS of dimethyl ester of compound A10. [0026] FIG.18 shows 1H NMR spectrum of compound A10 (500 MHz, D2O, 25 °C). [0027] FIG.19 shows ESI-HRMS of compound A10. [0028] FIG.20 shows 1H NMR spectrum of py-macrodipa-NCS (A11) (500 MHz, DMSO, 25 °C). [0029] FIG.21 shows ESI-HRMS of py-macrodipa-NCS (A11). [0030] FIG. 22 shows HPLC chromatogram of purified py-macrodipa-NCS. [0031] FIG.23 shows aqueous stability of py-macrodipa-NCS over time examined by HPLC. [0032] FIG. 24 shows HPLC chromatogram of purified Hf(IV)-py-macrodipa. [0033] FIG.25 shows stability constants of Ln3+ complexes formed with EDTA, OBETA, and macropa plotted versus ionic radii. [0034] FIG.26 shows stability constants of Ln3+ complexes formed with macrodipa and macrotripa plotted versus ionic radii. [0035] FIG.27 shows 1H NMR spectra of macrodipa and macrotripa complexes formed with La3+ and Lu3+ (600 MHz, D2O, pD = 7, 25 °C). [0036] FIG.28 shows crystal structures of (a) [La(macrodipa)]+, (b) [Lu(macrodipa)(OH2)]+, and (c) [La(macrotripa)]+ complexes. Thermal ellipsoids are drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity. Only one of the two [La(macrodipa)]+ complexes in the asymmetric unit is shown. [0037] FIG.29 shows DFT-computed standard free energies for the conformational equilibrium (eq 4) of Ln3+-macrodipa complexes. [0038] FIG.30 shows depiction of the conformational toggle present in Ln3+-Macrodipa and Ln3+-macrotripa complex systems. [0039] FIG.31 shows 1H NMR (500 MHz, CDCl3, 25 °C) and 13C{1H} NMR (126 MHz, CDCl3, 25 °C) spectra of 3. [0040] FIG. 32 shows 1H NMR (500 MHz, D 2 O, pD ≈ 8 by NaOD, 25 °C) and 13C{1H} NMR (126 MHz, D2O, pD ≈ 8 by NaOD, 25 °C) spectra of macrodipa. Acetonitrile was added as an internal reference. [0041] FIG. 33 shows 1H NMR (500 MHz, D 2 O, pD = 6–7 by NaOD, 25 °C) and 13C{1H} NMR (126 MHz, D2O, pD = 6–7 by NaOD, 25 °C) spectra of macrotripa. Acetonitrile was added as an internal reference [0042] FIG 34 shows ESI HRMS of 3 MeCN was used as the mobile phase. [0043] FIG.35 shows ESI-HRMS of 5. MeCN was used as the mobile phase. [0044] FIG.36 shows ESI-HRMS of macrodipa. MeCN was used as the mobile phase. [0045] FIG.37 shows ESI-HRMS of 9. MeCN was used as the mobile phase. [0046] FIG.38 shows ESI-HRMS of macrotripa. MeCN was used as the mobile phase. [0047] FIG.39 shows HPLC chromatogram of macrodipa. Method: 0–5 min, 90% H2O/MeOH; 5–25 min, 90% → 0% H2O/MeOH. [0048] FIG. 40 shows HPLC chromatogram of macrotripa. Method: 0–5 min, 90% H2O/MeOH; 5–25 min, 90% → 0% H2O/MeOH. [0049] FIG.41 shows representative protonation constant determination of macrodipa by potentiometric titrations. cmacrodipa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.904. [0050] FIG.42 shows representative protonation constant determination of macrotripa by potentiometric titrations. cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.281. [0051] FIG.43 shows representative stability constant determination of La-macrodipa system by potentiometric titrations. cLa = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 2.781. [0052] FIG.44 shows representative stability constant determination of Ce-macrodipa system by potentiometric titration. cCe = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 3.206. [0053] FIG.45 shows representative stability constant determination of Pr-macrodipa system by potentiometric titration. cPr = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 3.179. [0054] FIG.46 shows representative stability constant determination of Nd-macrodipa system by potentiometric titration. cNd = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.865. [0055] FIG.47 shows representative stability constant determination of Sm-macrodipa system by potentiometric titration. cSm = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 1.364. [0056] FIG.48 shows representative stability constant determination of Eu-macrodipa system by potentiometric titration. cEu = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.950. [0057] FIG.49 shows representative stability constant determination of Gd-macrodipa system by potentiometric titration. cGd = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 1.233. [0058] FIG.50 shows representative stability constant determination of Tb-macrodipa system by potentiometric titration. cTb = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.893. [0059] FIG.51 shows representative stability constant determination of Dy-macrodipa system by potentiometric titration. cDy = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.808. [0060] FIG.52 shows representative stability constant determination of Ho-macrodipa system by potentiometric titration. cHo = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.925. [0061] FIG.53 shows representative stability constant determination of Er-macrodipa system by potentiometric titration. cEr = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 1.809. [0062] FIG.54 shows representative stability constant determination of Tm-macrodipa system by potentiometric titration cTm = 9 × 10-4 M cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 1.229. [0063] FIG.55 shows representative stability constant determination of Yb-macrodipa system by potentiometric titration. cYb = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.759. [0064] FIG.56 shows representative stability constant determination of Lu-macrodipa system by potentiometric titration. cLu = 9 × 10-4 M, cmacrodipa = 1 × 10-3 M. Initial volume V = 15 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.571. [0065] FIG.57 shows representative stability constant determination of La-macrotripa system by potentiometric titrations. cLa = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 2.568. [0066] FIG.58 shows representative stability constant determination of Ce-macrotripa system by potentiometric titration. cCe = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 2.731. [0067] FIG.59 shows representative stability constant determination of Pr-macrotripa system by potentiometric titration. cPr = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 3.032. [0068] FIG.60 shows representative stability constant determination of Nd-macrotripa system by potentiometric titration. cNd = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 1.493. [0069] FIG.61 shows representative stability constant determination of Sm-macrotripa system by potentiometric titration. cSm = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.868. [0070] FIG.62 shows representative stability constant determination of Eu-macrotripa system by potentiometric titration cEu = 1 × 10-3 M cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.836. [0071] FIG.63 shows representative stability constant determination of Gd-macrotripa system by potentiometric titration. cGd = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.787. [0072] FIG.64 shows representative stability constant determination of Tb-macrotripa system by potentiometric titration. cTb = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.811. [0073] FIG.65 shows representative stability constant determination of Dy-macrotripa system by potentiometric titration. cDy = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.473. [0074] FIG.66 shows representative stability constant determination of Ho-macrotripa system by potentiometric titration. cHo = 9 × 10-4 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.807. [0075] FIG.67 shows representative stability constant determination of Er-macrotripa system by potentiometric titration. cEr = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 1.809. [0076] FIG.68 shows representative stability constant determination of Tm-macrotripa system by potentiometric titration. cTm = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.824. [0077] FIG.69 shows representative stability constant determination of Yb-macrotripa system by potentiometric titration. cYb = 1 × 10-3 M, cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.759. [0078] FIG.70 shows representative stability constant determination of Lu-macrotripa system by potentiometric titration cLu = 1 × 10-3 M cmacrotripa = 1 × 10-3 M. Initial volume V = 20 mL. Data fitting and speciation distribution over the titration pH range are shown. Sigma value of this refinement = 0.571. [0079] FIG.71 shows full-width (top) as well as properly truncated and labeled (bottom) 1H NMR spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrodipa complex. [0080] FIG.72 shows full-width (top) as well as properly truncated and labeled (bottom) 13C{1H} NMR spectrum (126 MHz, D2O, pD = 7, 25 °C) of La-macrodipa complex. [0081] FIG.73 shows full-width HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrodipa complex. [0082] FIG.74 shows properly truncated and labeled HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrodipa complex. [0083] FIG.75 shows full-width HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrodipa complex. [0084] FIG.76 shows properly truncated and labeled HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrodipa complex. [0085] FIG.77 shows full-width COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrodipa complex. [0086] FIG.78 shows properly truncated and labeled COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrodipa complex. [0087] FIG.79 shows full-width ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrodipa complex. [0088] FIG.80 shows properly truncated and labeled ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrodipa complex. [0089] FIG.81 shows full-width (top) as well as properly truncated and labeled (bottom) 1H NMR spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrodipa complex. [0090] FIG.82 shows full-width (top) as well as properly truncated and labeled (bottom) 13C{1H} NMR spectrum (126 MHz, D2O, pD = 7, 25 °C) of Lu-macrodipa complex. [0091] FIG.83 shows full-width HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrodipa complex. [0092] FIG.84 shows properly truncated and labeled HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrodipa complex. [0093] FIG.85 shows full-width HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrodipa complex. [0094] FIG.86 shows properly truncated and labeled HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrodipa complex. [0095] FIG.87 shows full-width COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrodipa complex. [0096] FIG.88 shows properly truncated and labeled COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrodipa complex. [0097] FIG.89 shows full-width ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrodipa complex. [0098] FIG.90 shows properly truncated and labeled ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrodipa complex. [0099] FIG.91 shows full-width (top) as well as properly truncated and labeled (bottom) 1H NMR spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrotripa complex. [00100] FIG.92 shows full-width (top) as well as properly truncated and labeled (bottom) 13C{1H} NMR spectrum (126 MHz, D2O, pD = 7, 25 °C) of La-macrotripa complex. [00101] FIG.93 shows full-width HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrotripa complex. [00102] FIG.94 shows properly truncated and labeled HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrotripa complex. [00103] FIG.95 shows full-width HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrotripa complex. [00104] FIG.96 shows properly truncated and labeled HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrotripa complex. [00105] FIG.97 shows full-width COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrotripa complex. [00106] FIG.98 shows properly truncated and labeled COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrotripa complex. [00107] FIG.99 shows full-width ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La- macrotripa complex. [00108] FIG.100 shows properly truncated and labeled ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of La-macrotripa complex. [00109] FIG.101 shows full-width (top) as well as properly truncated and labeled (bottom) 1H NMR spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrotripa complex. [00110] FIG.102 shows full-width (top) as well as properly truncated and labeled (bottom) 13C{1H} NMR spectrum (126 MHz, D2O, pD = 7, 25 °C) of Lu-macrotripa complex. [00111] FIG.103 shows full-width HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrotripa complex. [00112] FIG.104 shows properly truncated and labeled HSQC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrotripa complex. [00113] FIG.105 shows full-width HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrotripa complex. [00114] FIG.106 shows properly truncated and labeled HMBC spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrotripa complex. [00115] FIG.107 shows full-width COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrotripa complex. [00116] FIG.108 shows properly truncated and labeled COSY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrotripa complex. [00117] FIG.109 shows full-width ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu- macrotripa complex. [00118] FIG.110 shows properly truncated and labeled ROESY spectrum (600 MHz, D2O, pD = 7, 25 °C) of Lu-macrotripa complex. [00119] FIG.111 shows Full-width (top) as well as properly truncated (bottom) 1H NMR spectrum (500 MHz, D2O, pD = 7, 25 °C) of Y-macrodipa complex. [00120] FIG.112 shows full-width (top) as well as properly truncated (bottom) 13C{1H} NMR spectrum (126 MHz, D2O, pD = 7, 25 °C) of Y-macrodipa complex. [00121] FIG.113 shows stacked 1H NMR spectra La3+, Lu3+, and Y3+-macrodipa complexes. The 1H spectrum of Y3+-macrodipa clearly shows the presence of both Conformation A and Conformation B as an equilibrium. [00122] FIG.114 shows stacked 13C{1H} NMR spectra La3+, Lu3+, and Y3+-macrodipa complexes. Due to the limited sensitivity on 13C nucleus, only the major Conformation B is observed in the 13C{1H} spectrum of Y3+-macrodipa complex. [00123] FIG.115 shows full-width (top) as well as properly truncated (bottom) 1H NMR spectrum (500 MHz, D2O, pD = 7, 25 °C) of Y-macrotripa complex. [00124] FIG.116 shows full-width (top) as well as properly truncated (bottom) 13C{1H} NMR spectrum (126 MHz, D2O, pD = 7, 25 °C) of Y-macrotripa complex. [00125] FIG.117 shows stacked 1H NMR spectra La3+, Lu3+, and Y3+-macrotripa complexes. The 1H spectrum of Y3+-macrotripa clearly shows the presence of only the Conformation B. [00126] FIG.118 shows stacked 13C{1H} NMR spectra La3+, Lu3+, and Y3+-macrotripa complexes. The 13C{1H} spectrum of Y3+-macrotripa clearly shows the presence of Conformation B. [00127] FIG.119 shows crystal structure of Lu-macrotripa complex. Due to the poor quality of the crystals, only the connectivity of non-hydrogen atoms is reported. A hydrogen bonding interaction between O8 and O10 is expected based on their spatial proximity to one another. Space group: P21/c; a = 13.5282(3); b = 28.0972(7); c = 20.1340(5); α = 90°; β = 100.225(2)°; γ = 90°. [00128] FIG.120 shows 1H NMR spectrum (500 MHz, D2O, pD ≈ 6, 25 °C) of [La(macrodipa)][ClO4] crystals. [00129] FIG.121 shows 1H NMR spectrum (500 MHz, CD3OD, 25 °C) of [Lu(macrodipa)(OH2)][PF6] crystals. [00130] FIG.122 shows 1H NMR spectrum (500 MHz, DMSO-d6, 25 °C) of [La(Hmacrotripa)][BPh4] crystals. [00131] FIG.123 shows 1H NMR spectrum (500 MHz, D2O, pD = 6–7, 25 °C) of [Lu(macrotripa)(OH2)] crystals. [00132] FIG.124 shows ESI-HRMS of La-macrodipa complex. MeCN was used as the mobile phase. [00133] FIG.125 shows ESI-HRMS of Lu-macrodipa complex. MeCN was used as the mobile phase. [00134] FIG.126 shows ESI-HRMS of La-macrotripa complex. MeCN was used as the mobile phase [00135] FIG.127 shows ESI-HRMS of Lu-macrotripa complex. MeCN was used as the mobile phase. [00136] FIG.128 shows DFT-optimized structure of [Lu(macrotripa)(OH2)] complex. [00137] FIG.129 shows full view (left) and zoomed-in view (right) of all bond critical points located in the DFT-optimized [Lu(macrotripa)(OH2)] structure. The bond critical point of interest is circled. At this critical point, local electron density = 0.07938 a.u., Laplacian of electron density = 0.1646 a.u. [00138] FIG.130 shows 1H NMR spectrum (500 MHz, CD3OD, 25 °C) of the synthetic intermediate that is hydrolyzed to yield py-macrodiphoshpho. [00139] FIG.131 shows 1H NMR spectrum (500 MHz, D2O, 25 °C) of py-macrodiphoshpho. DETAILED DESCRIPTION [00140] The following terms are used throughout as defined below. [00141] As used herein and in the appended claims, singular articles such as “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential. [00142] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term – for example, “about 10 wt.%” would be understood to mean “9 wt.% to 11 wt.%.” It is to be understood that when “about” precedes a term the term is to be construed as disclosing “about” the term as well as the term without modification by “about” – for example, “about 10 wt.%” discloses “9 wt.% to 11 wt.%” as well as disclosing “10 wt.%. [00143] The phrase “and/or” as used in the present disclosure and claims will be understood to mean any one of the recited members individually or a combination of any two or more thereof – for example, “A, B, and/or C” would mean “A, B, C, A and B, A and C, B and C, or the combination of A, B, and C.” [00144] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, C14, P32 and S35 are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein. [00145] In general, “substituted” refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group is substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e., SF5), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like. [00146] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below. [00147] As used herein, Cm-Cn, such as C1-C12, C1-C8, or C1-C6 when used before a group refers to that group containing m to n carbon atoms [00148] Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like. [00149] Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Bi- and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted one or more times with, non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above. [00150] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above. In some embodiments, cycloalkylalkyl groups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. Cycloalkylalkyl groups may be substituted or unsubstituted. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above. [00151] Alkenyl groups include straight and branched chain alkyl groups as defined above, wo carbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, among others. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above. [00152] Cycloalkenyl groups include cycloalkyl groups as defined above, having at least one double bond between two carbon atoms. Cycloalkenyl groups may be substituted or unsubstituted. In some embodiments the cycloalkenyl group may have one, two or three double bonds but does not include aromatic compounds. Cycloalkenyl groups have from 4 to 14 carbon atoms, or, in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl. [00153] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above. [00154] Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Alkynyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to –C≡CH, -C≡CCH3, -CH2C≡CCH3, -C≡CCH2CH(CH2CH3)2, among others. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri- substituted with substituents such as those listed above. [00155] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl 12 or even 6-10 carbon atoms in the ring portions of the groups. In some embodiments, the aryl groups are phenyl or naphthyl. Aryl groups may be substituted or unsubstituted. The phrase “aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Representative substituted aryl groups may be mono- substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above. [00156] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Aralkyl groups may be substituted or unsubstituted. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above. [00157] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms. In some embodiments, heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups encompass aromatic, partially unsaturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase “heterocyclyl group” includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups may be substituted or unsubstituted. Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dih d dithi l h i i l i lid l i d lyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above. [00158] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3-dihydro indolyl groups. Heteroaryl groups may be substituted or unsubstituted. Thus, the phrase “heteroaryl groups” includes fused ring compounds as well as includes heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above. [00159] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl ti f th R t ti h t l l lkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above. [00160] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above. [00161] Groups described herein having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compound of the present technology are designated by use of the suffix, “ene.” For example, divalent alkyl groups are alkylene groups, divalent aryl groups are arylene groups, divalent heteroaryl groups are divalent heteroarylene groups, and so forth. Substituted groups having a single point of attachment to the compound of the present technology are not referred to using the “ene” designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene. Such groups may further be substituted or unsubstituted. [00162] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy groups may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above. [00163] The terms “alkanoyl” and “alkanoyloxy” as used herein can refer, respectively, to – C(O)–alkyl and –O–C(O)–alkyl groups, where in some embodiments the alkanoyl or alkanoyloxy groups each contain 2–5 carbon atoms. Similarly, the terms “aryloyl” and “aryloyloxy” respectively refer to –C(O)–aryl and –O–C(O)–aryl groups. [00164] The terms "aryloxy" and “arylalkoxy” refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above. [00165] The term “carboxylic acid” as used herein refers to a compound with a –C(O)OH group. The term “carboxylate” as used herein refers to a –C(O)O– group. A “protected carboxylate” refers to a –C(O)O-G where G is a carboxylate protecting group. Carboxylate protecting groups are well known to one of ordinary skill in the art. An extensive list of protecting groups for the carboxylate group functionality may be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein and which is hereby incorporated by reference in its entirety and for any and all purposes as if fully set forth herein. [00166] The term “ester” as used herein refers to –COOR70 groups. R70 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. [00167] The term “amide” (or “amido”) includes C- and N-amide groups, i.e., -C(O)NR71R72, and –NR71C(O)R72 groups, respectively. R71 and R72 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is –NR71C(O)-(C1-5 alkyl) and the group is termed "carbonylamino," and in others the amide is –NHC(O)-alkyl and the group is termed "alkanoylamino." [00168] The term “nitrile” or “cyano” as used herein refers to the –CN group. [00169] Urethane groups include N- and O-urethane groups, i.e., -NR73C(O)OR74 and -OC(O)NR73R74 groups, respectively. R73 and R74 are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R73 may also be H. [00170] The term “amine” (or “amino”) as used herein refers to –NR75R76 groups, wherein R75 and R76 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino. [00171] The term “sulfonamido” includes S- and N-sulfonamide groups, i.e., -SO2NR78R79 and –NR78SO2R79 groups, respectively. R78 and R79 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO2NH2). In some embodiments herein, the sulfonamido is – NHSO2-alkyl and is referred to as the "alkylsulfonylamino" group. [00172] The term “thiol” refers to –SH groups, while sulfides include –SR80 groups, sulfoxides include –S(O)R81 groups, sulfones include -SO2R82 groups, and sulfonyls include – SO2OR83. R80, R81, R82, and R83 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. In some embodiments the sulfide is an alkylthio group, -S-alkyl. [00173] The term “urea” refers to –NR84-C(O)-NR85R86 groups. R84, R85, and R86 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein. [00174] The term “amidine” refers to –C(NR87)NR88R89 and –NR87C(NR88)R89, wherein R87, R88, and R89 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00175] The term “guanidine” refers to –NR90C(NR91)NR92R93, wherein R90, R91, R92 and R93 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00176] The term “enamine” refers to –C(R94)=C(R95)NR96R97 and –NR94C(R95)=C(R96)R97, wherein R94, R95, R96 and R97 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00177] The term “halogen” or “halo” as used herein refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine. [00178] The term “hydroxyl” as used herein can refers to –OH. [00179] The term “imide” refers to –C(O)NR98C(O)R99, wherein R98 and R99 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. [00180] The term “imine” refers to –CR100(NR101) and –N(CR100R101) groups, wherein R100 and R101 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R100 and R101 are not both simultaneously hydrogen. [00181] The term “nitro” as used herein refers to an –NO2 group. [00182] The term “trifluoromethyl” as used herein refers to –CF3. [00183] The term “trifluoromethoxy” as used herein refers to –OCF3. [00184] The term “azido” refers to –N3. [00185] The term “trialkyl ammonium” refers to a –N(alkyl)3 group. A trialkylammonium group is positively charged and thus typically has an associated anion, such as halogen anion. [00186] The term “trifluoromethyldiazirido” refers
Figure imgf000033_0001
. [00187] The term “isocyano” refers to –NC. [00188] The term “isothiocyano” refers to –NCS. [00189] The term “pentafluorosulfanyl” refers to –SF5. [00190] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth. [00191] Pharmaceutically acceptable salts of compounds described herein are within the scope of the present technology and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, he compound of the present technology has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the present technology has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine). Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed. [00192] Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, stereochemical or geometric isomeric forms, it should be understood that the present technology encompasses any tautomeric, conformational isomeric, stereochemical and/or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. [00193] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, quinazolinones may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Figure imgf000034_0001
. As another example, guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other:
Figure imgf000035_0001
. Because of the limits of representing compounds by structural formulas, it is to be understood that all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology. [00194] Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology. [00195] The compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry. [00196] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. Also within this disclosure are Arabic numerals referring to referenced citations, the full bibliographic details of which are provided immediately preceding the claims. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the present technology. [00197] The Present Technology [00198] Although targeted radiotherapy has been practiced for some time using macrocyclic complexes of radionuclides, the macrocycles currently in use (e.g., DOTA) generally form complexes of insufficient stability with radionuclides, particularly for radionuclides of larger size, such as actinium, radium, bismuth, and lead isotopes. Such instability results in dissociation of the radionuclide from the macrocycle, and this results in a lack of selectivity to targeted tissue, which also results in toxicity to non-targeted tissue. [00199] The present technology provides new macrocyclic complexes that are substantially more stable than those of the conventional art. Thus, these new complexes can advantageously target cancer cells more effectively, with substantially less toxicity to non-targeted tissue than complexes of the art. Moreover, the new complexes can advantageously be produced at room temperature, in contrast to DOTA-type complexes, which generally require elevated temperatures (e.g., at least 80 °C) for complexation with the radionuclide. The present technology also may employ alpha-emitting radionuclides instead of beta radionuclides. Alpha- emitting radionuclides are of much higher energy, and thus substantially more potent, than beta- emitting radionuclides. [00200] In an aspect, a compound of any one of Formula I, Formula II, Formula III, and Formlua IV is provided
Figure imgf000036_0001
or a pharmaceutically acceptable salt and/or solvate thereof, wherein
Figure imgf000036_0002
R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. [00201] In a related aspect, a compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formula IVA is provided
Figure imgf000039_0001
(IIIA) (IVA) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the compound; A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w-R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), - SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, - NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. In any embodiment disclosed herein, it may be that M1 is independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium-177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium- 226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+). [00202] In a further related aspect, the present technology provides a targeting compound useful in, e.g., useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), where the targeting compound is of any one of Formula V, Formula VI, Formula VII, and Formula VIII
Figure imgf000043_0001
or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the targeting compound; A5, A6, A7, and A8 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or X1 L3 R22 Z1 is independently at each occurrence OH or NH–L4–R24; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –L5–R26; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; L3, L4 , and L5 are independently at each occurrence a bond or a linker group; and R22, R24, and R26 each independently at each occurrence comprise an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase- containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin. In any embodiment disclosed herein, M1 of the targeting compound may independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium- 177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+). [00203] Representative R22, R24, and R26 groups include those antibodies listed in Table A as well as antigen-binding fragments of such antibodies and any equivalent embodiments, as would be known to those of ordinary skill in the art.
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
2 Also designated Ch14.18. 3 Also designated HuMaB4D5-8. 4 Also designated H4H7798N.
Figure imgf000049_0001
Figure imgf000050_0002
*Note: the disclosures of the each of the patents and patent publications listed in Table A are incorporated herein by reference. [00204] In any embodiment disclosed herein, it may be that the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof. Exemplary PSMA binding peptides include, but are not limited to, those according to the following structure
Figure imgf000050_0001
where nn is 0, 1, or 2, and P1, P2, and P3 are each independently H, methyl, benzyl, 4- methoxybenzyl, or tert-butyl. In any embodiment herein, it may be that each of P1, P2, and P3 are H. [00205] Somatostatin, illustrated in Scheme A, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein. There are five known somatostatin receptors, all being G protein-coupled seven transmembrane receptors: SST1 (SSTR1); SST2 (SSTR2); SST3 (SSTR3); SST4 (SSTR4); and SST5 (SSTR5). Exemplary somatostatin receptor agonists include somatostatin itself, lanreotide, octreotate, octreotide, pasireotide, and vapreotide. Scheme A.
Figure imgf000051_0001
[00206] Many neuroendocrine tumors express SSTR2 and the other somatostatin receptors. Long acting somatostatin agonists (e.g., Octreotide, Lanreotide) are used to stimulate the SSTR2 receptors, and thus to inhibit further tumor proliferation. See, Zatelli MC, et al., (Apr 2007). "Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds". European Journal of Endocrinology / European Federation of Endocrine Societies.156 Suppl 1: S29–35. Octreotide is an octapeptide that mimics natural somatostatin but has a significantly longer half-life in vivo. Octreotide is used for the treatment of growth hormone producing tumors (acromegaly and gigantism), when surgery is contraindicated, pituitary tumors that secrete thyroid stimulating hormone (thyrotropinoma), diarrhea and flushing episodes associated with carcinoid syndrome, and diarrhea in people with vasoactive intestinal peptide-secreting tumors (VIPomas). Lanreotide is used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. Pasireotide is a somatostatin analog with an increased affinity to SSTR5 compared to other somatostatin agonists and is approved for treatment of Cushing's disease and acromegaly. Vapreotide is is used in the treatment of esophageal variceal bleeding in patients with cirrhotic liver disease and AIDS related diarrhea. [00207] Bombesin is a peptide originally isolated from the skin of the European fire-bellied toad (Bombina bombina). In addition to stimulating gastrin release from G cells, bombesin activates at least three different G-protein-coupled receptors: BBR1, BBR2, and BBR3, where such activity includes agonism of such receptors in the brain. Bombesin is also a tumor marker for small cell carcinoma of lung, gastric cancer, pancreatic cancer, and neuroblastoma. Bombesin receptor agonists include, but are not limited to, BBR-1 agonists, BBR-2 agonists, and BBR-3 agonists. [00208] Seprase (or Fibroblast Activation Protein (FAP), such as Fibroblast Activation Protein-alpha (FAP-alpha)) is an integral membrane serine peptidase. In addition to gelatinase activity, seprase has a dual function in tumour progression. Seprase promotes cell invasiveness towards the ECM and also supports tumour growth and proliferation. Seprase binding compounds include seprase inhibitors. [00209] In a further related aspect, a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any embodiment dislclosed herein of any one of Formula I, Formula II, Formula III, Formula IA, Formula IIA, and Formula IIIA (or pharmaceutically acceptable salt and/or solvate thereof), with an antibody, antibody fragment, or binding peptide. In any embodiment disclosed herein, it may be that the antibody includes belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab. In any embodiment disclosed herein, it may be that the antibody fragment includes an antigen-binding fragment of belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, C t b Et i b I b di t disclosed herein, it may be that the binding peptide includes a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof. [00210] Targeting compounds may be prepared by a process that includes reacting with R22- W1 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes –X1-W2 group, where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R21 refers to the portion of the compound other than the –X1-W2 group (this R21 portion referred to as “macrocycle R21”). As such, R22 may be conjugated to macrocycle R21 by reaction of complementary chemical functional groups W1 and W2 to form linker L3. For example, R22-W1 may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen- binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof). W1 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where W2 may be selected to selectively react with W1 in order to provide L3 of the targeting compound.
Table B.
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
5 1 0 9 8-3 7 8 3 9 0. o N . t k D 2 . 0 9 4 1-9 6 0 4-3 5 8 4
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
[00211] Targeting compounds may be prepared by a process that includes reacting with R24- W1a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes a –W3 group, where Table C provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R23 refers to the portion of the compound other than the –W3 group (this R23 portion is referred to as “macrocycle R23”). As such, R24 may be conjugated to macrocycle R23 by reaction of complementary chemical functional groups W3 and W4 to form linker L4. For example, R24-W4 may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen- binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof). W4 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table C, where W3 may be selected to selectively react with W4 in order to provide L4 of the target compound. Table C.
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
[00212] Targeting compounds may be prepared by a process that includes reacting with R26- W6 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes a –W5 group, where Table D provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R25 refers to the portion of the compound other than the –W5 group (this R25 portion is referred to as “macrocycle R25”). As such, R26 may be conjugated to macrocycle R25 by reaction of complementary chemical functional groups W5 and W6 to form linker L5. For example, R26-W6 may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen- binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof). W6 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table D, where W5 may be selected to selectively react with W6 in order to provide L5 of the target compound.
Table D.
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
[00213] A person of ordinary skill in the art will recognize that numerous chemical conjugation strategies provide ready access to targeting compounds of the present technology, whereby exposed amino acid residues on a protein (e.g., an antibody) undergo well-known reactions with reactive moieties on a prosthetic molecule. For example, amide coupling is a well-known route, where – as an example – lysine residues on the antibody surface react with terminal activated carboxylic acid esters to generate stable amide bonds. Amide coupling is typically mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are detailed elsewhere. (See generally Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV.606 (2009).) These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation and Linker Chemistries, 9 PROTEIN CELL 33, 36 (2018); see also, e.g., A.C. Lazar et al., Analysis of the Composition of Immunoconjugates Using Size- Exclusion Chromatography Coupled to Mass Spectrometry, 19 RAPID COMMUN. MASS SPECTROM.1806 (2005).) [00214] Additionally, a person of ordinary skill in the art will recognize that cysteine coupling reactions may be employed to conjugate prosthetic molecules with thiol-reactive termini to protein surfaces through exposed thiol side chains on cysteine residues on the protein (e.g., antibody) surface. (See generally Tsuchikama & An, supra, at 36–37; see also, e.g., Pierre Adumeau et al., Thiol-Reactive Bifunctional Chelators for the Creation of Site- Selectively Modified Radioimmunoconjugates with Improved Stability, 29 BIOCONJUGATE CHEM.1364 (2018).) Because cysteine residues readily form disulfide linkages with nearby cysteine residues under physiological conditions, rather than existing as free thiols, some cysteine coupling strategies may rely upon selective reduction of disulfides to generate a higher number of reactive free thiols. (See id.) Cysteine coupling techniques known in the art include, but are not limited to, cys alkylation reactions, cysteine rebridging reactions, and cys-aryl coupling using organometallic palladium reagents. (See, e.g., C.R. Behrens et al., Antibody-Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrates Improved Homogeneity and Other Pharmacological Properties Over Conventional Heterogeneous ADCs, 12 MOL. PHARM.3986 (2015); Vinogradova et al., Organometallic Palladium Reagents for Cysteine Bioconjugation, 526 NATURE 687 (2015); see also Tsuchikama, supra, at 37 (collecting examples).) [00215] Protein conjugation strategies using non-natural amino acid side chains are also well-known in the art. For example, “click chemistries” provide access to conjugated proteins, by rapid and selective chemical transformations under a diverse range of reaction conditions. Click chemistries are known to yield peptide conjugates with limited by-product formation, despite the presence of unprotected functional groups, in aqueous conditions. One important non-limiting example of a click reaction in the formation of conjugated peptides is the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC). (See Liyuan Liang & Didier Astruc, The Copper(I)-Catalysed Alkyne-Azide Cycloaddition (CuAAC) “Click” Reaction and Its Applications: An Overview, 255 COORD. CHEM. REV. 2933 (2011); see also, e.g., Herman S. Gill & Jan Marik, Preparation of 18F-labeled Peptides using the Copper(I)-Catalyzed Azide-Alkyne 1,3-Dipolar Cycloaddition, 6 NATURE PROTOCOLS 1718 (2011).) The CuAAC click reaction may be carried out in the presence of ligands to enhance reaction rates. Such ligands may include, for example, polydentate nitrogen donors, including amines (e.g., tris(triazolyl)methyl amines) and pyridines. (See Liang & Astruc, supra, at 2934 (collecting examples); P.L. Golas et al., 39 MACROMOLECULES 6451 (2006).) Other widely-utilized click reactions include, but are not limited to, thiol-ene, oxime, Diels-Alder, Michael addition, and pyridyl sulfide reactions. [00216] Copper-free (Cu-free) click methods are also known in the art for delivery of therapeutic and/or diagnostic agents, such as radionuclides (e.g., 18F), chemotherapeutic agents, dyes, contrast agents, fluorescent labels, chemiluminescent labels, or other labels, to protein surfaces. Cu-free click methods may permit stable covalent linkage between target molecules and prosthetic groups. Cu-free click chemistry may include reacting an antibody or antigen-binding fragment, which has been modified with a non-natural amino acid side chain that includes an activating moiety such as a cyclooctyne (e.g., dibenzocyclooctyne (DBCO)), a nitrone or an azide group, with a prosthetic group that presents a corresponding or complementary reactive moiety, such as an azide, nitrone or cyclooctyne (e.g., DBCO). (See, e.g., David. J. Donnelly et al., Synthesis and Biologic Evaluation of a Novel 18F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression, 59 J. NUCL. MED.529 (2018).) For example, where the targeting molecule comprises a cyclooctyne, the prosthetic group may include an azide, nitrone, or similar reactive moiety. Where the targeting molecule includes an azide or nitrone, the prosthetic group may present a complementary cyclooctyne, alkyne, or similar reactive moiety. Cu-free click reactions may be carried out at room temperature, in aqueous solution, in the presence of phosphate-buffered saline (PBS). The prosthetic group may be radiolabeled (e.g., with 18F) or may be conjugated to any alternative diagnostic and/or therapeutic agent (e.g., a chelating agent). (See id. at 531.) [00217] The compounds of any embodiment and aspect herein of the present technology may be a tripartite compound. However, such tripartite compounds are not restricted to compositions including Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA. Thus, in an aspect, a tripartite compound is provided that includes a first domain that has relatively low but still specific affinity for serum albumin (e.g., 0.5 to 50 x 10-6M), a second domain including a chelating moiety such as but not limited to those described herein, and a third domain that includes tumor targeting moiety (TTT) having relatively high affinity for a tumor antigen (e.g., 0.5 to 50 x 10-9M). The following exemplary peptide receptors, enzymes, cell adhesion molecules, tumor associated antigens, growth factor receptors and cluster of differentiation antigens are useful targets for constructing the TTT domain: somatostatin peptide receptor-2 (SSTR2), gastrin- releasing peptide receptor, seprase (FAP-alpha), incretin receptors, glucose-dependent insulinotropic polypeptide receptors , VIP-1, NPY, folate receptor, LHRH, and αvβ3, an overexpressed peptide receptor, a neuronal transporter (e.g., noradrenaline transporter (NET)), or other tumor associated proteins such as EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2,TF-antigen, endothelial specific markers, neuropeptide Y, uPAR, TAG-72, CCK analogs, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, GLP-1, CXCR4, Hepsin, TMPRSS2, caspaces, Alpha V beta six, cMET. Other such targets will be apparent to those of skill in the art, and compounds that bind these can be incorporated in the TTT to produce a tripartite radiotherapeutic compound. [00218] The following Formulas L-LIV provide exemplary general structures for tripartite compounds of the present technology. (L)
Figure imgf000075_0001
Figure imgf000076_0001
) where TTT is independently at each occurrence a binding domain for a somatostatin peptide receptor-2 (SSTR2), a gastrin-releasing peptide receptor, a seprase (FAP- alpha), an incretin receptor, a glucose-dependent insulinotropic polypeptide receptor, VIP-1, NPY, a folate receptor, LHRH, αvβ3, an overexpressed peptide receptor, a neuronal transporter (e.g., noradrenaline transporter (NET)), a receptor for a tumor associated protein (such as EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2,TF-antigen, endothelial specific markers, neuropeptide Y, uPAR, TAG-72, CCK analogs, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, GLP-1, CXCR4, Hepsin, TMPRSS2, caspaces, Alpha V beta six, cMET, or combination of any two or more thereof), or a cominbation of any two or more thereof, X501 is independently at each occurrence absent, O, S, or NH;. L501 is independently at each occurrence absent, -C(O)-, -C(O)-NR4-, -C(O)-NR5-C1- C12 alkylene-,-C1-C12 alkylene-C(O)-, -C(O)-NR6-C1-C12 alkylene-C(O)-, - arylene-, –O(CH2CH2O)r–CH2CH2C(O)–, –O(CH2CH2O)rr–CH2CH2C(O)– NH–, –O(CH2CH2O)rrr–CH2CH2–, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or a combination of any two or more thereof, where r is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, rr is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, rrr is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, and where R4, R5, and R6 are each independently H, alkyl, or aryl; Rad is independently at each occurrence a moiety capable of including a radionuclide, optionally further including a radionuclide; L502 is independently at each occurrence absent, -C(O)-, –(CH2CH2O)s– CH2CH2C(O)–, –(CH2CH2O)ss–CH2CH2C(O)–NH–, –(CH2CH2O)sss– CH2CH2–, an amino acid, –CH(CO2H)–(CH2)4–, –CH(CO2H)–(CH2)4–NH–, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, 19, or 20 amino acids, or a combination of any two or more thereof, where s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, or 19, ss is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, or 19, and sss is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, or 19; Alb is independently at each occurrence an albumin-binding moiety; p is independently at each occurrence 0, 1, 2, or 3; and q is independently at each occurrence 1 or 2. In any embodiment disclosed herein, the radionuclide may be 177Lu3+, 175Lu3+, 45Sc3+, 66Ga3+, 67Ga3+,68Ga3+, 69Ga3+,71Ga3+, 89Y3+,86Y3+, 89Zr4+, 90Y3+, 99mTc+1, 111In3+, 113In3+, 115In3+, 139La3+, 136Ce3+, 138Ce3+, 140Ce3+, 142Ce3+, 151Eu3+, 153Eu3+, 152Dy3+, 149Tb3+, 159Tb3+, 154Gd3+, 155Gd3+, 156Gd3+, 157Gd3+, 158Gd3+, 160Gd3+, 188Re+1, 186Re+1, 213Bi3+, 211At+, 217At+, 227Th4+, 226Th4+, 225Ac3+, 233Ra2+, 152Dy3+, 213Bi3+, 212Bi3+, 211Bi3+, 212Pb2+ ,212Pb4+, 255Fm3+, or uranium-230. For example, the the radionuclide may be an alpha-emitting radionuclide such as 213Bi3+, 211At+, 225Ac3+, 152Dy3+, 212Bi3+, 211Bi3+, 217At+, 227Th4+, 226Th4+, 233Ra2+, 212Pb2+ , or 212Pb4+. [00219] In any embodiment disclosed herein, it may be the tripartite compounds of Formulas L-LIV are of Formulas LV-LIX
Figure imgf000078_0001
Figure imgf000079_0001
where L503 is independently at each occurrence absent, -C(O)-, -C1-C12 alkylene-,-C1-C12 alkylene-C(O)-, -C1-C12 alkylene-NR10-, -arylene-, –(CH2CH2O)z–CH2CH2C(O)–, – (CH2CH2O)zz–CH2CH2C(O)–NH–, –(CH2CH2O)zzz–CH2CH2–, an amino acid, –CH(CO2H)– (CH2)4–, –CH(CO2H)–(CH2)4–NH–, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, 19, or 20 amino acids, or a combination of any two or more thereof, where z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, or 19, zz is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, or 19, and zzz is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, or 19; and CHEL is independently at each occurrence a covalently conjugated chelator (of any embodiment disclosed herein of compounds of the present technology) that optionally includes a chelated radionuclide. [00220] The albumin-binding moiety plays a role in modulating the rate of blood plasma clearance of the compounds in a subject, thereby increasing circulation time and compartmentalizing the cytotoxic action of cytotoxin-containing domain and/or imaging capability of the imaging agent-containing domain in the plasma space instead of normal organs and tissues that may express antigen. Without being bound by theory, this component of the structure is believed to interact reversibly with serum proteins, such as albumin and/or cellular elements. The affinity of this albumin-binding moiety for plasma or cellular components of the blood may be configured to affect the residence time of the compounds in the blood pool of a subject. In any embodiment herein, the albumin binding-moiety may be configured so that it binds reversibly or non-reversibly with albumin when in blood plasma. In any embodiment herein, the albumin binding-moiety may be selected such that the binding affinity of the compound with human serum albumin is about 5 µM to about 15 µM. [00221] By way of example, the albumin-binding moiety of any embodiment herein may include a short- chain fatty acid, medium-chain chain fatty acid, a long-chain fatty acid, myristic acid, a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanoic acid, a substituted or unsubstituted naphthalene acylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2-(4-iodophenyl)acetic acid, a substituted or unsubstituted 3-(4-iodophenyl)propionic acid, or a substituted or unsubstituted 4-(4-iodophenyl)butanoic acid. Certain representative examples of albumin- binding moieties that may be included in any embodiment herein include one or more of the following:
Figure imgf000080_0001
,
Figure imgf000081_0001
. [00222] In any embodiment herein, the tripartite compounds may include an albumin- binding moiety that is
Figure imgf000081_0002
Figure imgf000082_0001
Y502, Y503, Y504, and Y505 are independently H, halo, or alkyl, X503, X504, X505, and X506 are each independently O or S, aa is independently at each occurrence 0, 1, or 2, bb is independently at each occurrence 0 or 1, cc is independently at each occurrence 0 or 1, and dd is independently at each occurrence 0, 1, 2, 3, or 4. In any embodiment herein, it may be that bb and cc cannot be the same value. In any embodiment herein, it may be that Y503 is I and each of Y501, Y502, Y503, Y504, and Y505 are each independently H. [00223] In any embodiment disclosed herein, it may be that the CHEL of the tripartite compounds is a chelator as provided in the compounds of Formula I, II, III, IA, IIA, or IIIA. For example, tripartite compound may be a targeting compound of Formula II where R22, R24, R26, and R28 are each independently
Figure imgf000082_0002
Figure imgf000083_0001
. [00224] In any embodiment disclosed herein, TTT may be
Figure imgf000084_0001
W501 is –C(O)–, –(CH2)ww–, or –(CH2)oo–NH2-C(O)–; mm is 0 or 1; ww is 1 or 2; oo is 1 or 2;and P501, P502, and P503 are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl. In any embodiment herein, it may be that each of P501, P502, and P503 are H. [00225] The tripartite compounds of the present technology include variations on any of the three domains: e.g., the domain including the chelator, the domain including the albumin- binding group, or the domain including the tumor targeting moiety. [00226] The present technology also provides compositions (e.g., pharmaceutical compositions) and medicaments comprising any of one of the embodiments of the compounds disclosed herein, any one of the embodiments of the targeting compounds disclosed herein, any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology disclosed herein, or any one of the embodiments of the tripartite compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively refered to as “pharmaceutically acceptable carrier” unless otherwise specified). The compositions may be used in the methods and treatments described herein. The pharmaceutical composition may include an effective amount of any embodiment of the compounds of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA. In an related aspect, a method of treating a subject is provided, wherein the method includes administering a targeting compound of the present technology to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of the present technology to the subject. In any embodiment disclosed herein, it may be that the subject suffers from cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”). In any embodiment herein, it may be the administering includes administering an effective amount of any embodiment of the compounds of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA. The subject may suffer from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase (FAP-alpha), or a combination of any two or more thereof and/or mammalian tissue overexpressing PSMA. The mammalian tissue of any embodiment disclosed herein may include one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer. In any embodiment disclosed herein, the subject may suffer from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. In any embodiment disclosed herein, the composition (e.g., pharmaceutical composition) and/or medicament may be formulated for parenteral administration. In any embodiment disclosed herein, the composition (e.g., pharmaceutical composition) and/or medicament may be formulated for intraveneous administration. In any embodiment disclosed herein, the administering step of the method may include parenteral administration. In any embodiment disclosed herein, the administering step of the method may include intraveneous administration. [00227] In any of the above embodiments, the effective amount may be determined in relation to a subject. “Effective amount” refers to the amount of a compound or composition required to produce a desired effect. One non-limiting example of an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use including, but not limited to, the treatment of e.g., one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. Another example of an effective amount includes amounts or dosages that are capable of reducing symptoms associated with e.g., one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer, such as, for example, reduction in proliferation and/or metastasis of prostate cancer, breast cancer, or bladder cancer.. The effective amount may be from about 0.01 μg to about 1 mg of the compound per gram of the composition, and preferably from about 0.1 μg to about 500 μg of the compound per gram of the composition. As used herein, a “subject” or “patient” is a mammal, such as a cat, dog, rodent or primate. Typically the subject is a human, and, preferably, a human suffering from or suspected of suffering from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. The term “subject” and “patient” can be used interchangeably. [00228] In any of the embodiments of the present technology described herein, the pharmaceutical composition may be packaged in unit dosage form. The unit dosage form is effective in treating one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. Generally, a unit dosage including a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology may vary from 1 × 10–4 g/kg to 1 g/kg, preferably, 1 × 10–3 g/kg to 1.0 g/kg. Dosage of a compound of the present technology may also vary from 0.01 mg/kg to 100 mg/kg or, preferably, from 0.1 mg/kg to 10 mg/kg. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges. suppositories. patches. nasal sprays, injectibles, implantable sustained-release formulations, rnucoadherent films, topical varnishes, lipid complexes, etc. [00229] The pharmaceutical compositions may be prepared by mixing one or more of the compounds, any one of the targeting compounds, or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology, or any embodiment of the tripartite compound of the present technology, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with cancer and/or a mammalian tissue overexpressing PSMA. The compounds and compositions described herein may be used to prepare formulations and medicaments that treat e.g., prostate cancer, breast cancer, or bladder cancer. Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions may be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injections. The following dosage forms are given by way of example and should not be construed as limiting the instant present technology. [00230] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art. [00231] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. [00232] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations. [00233] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. [00234] For injection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. [00235] Compounds of the present technology may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols are typically used for delivery of compounds of the present technology by inhalation. [00236] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. The instant compositions may also include, for example, micelles or liposomes, or some other encapsulated form. [00237] Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology. [00238] Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology. [00239] For the indicated condition, test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75–90%, or 95% or greater, reduction, in one or more symptom(s) caused by, or associated with, the disorder in the subject, compared to placebo–treated or other suitable control subjects. [00240] In another aspect, the present technology provides a method of treating cancer by administering an effective amount of the targeting composition of any embodiment disclosed herein to a subject having cancer. Since a cancer cell targeting agent can be selected to target any of a wide variety of cancers, the cancer considered herein for treatment is not limited. The cancer can be essentially any type of cancer. For example, antibodies or peptide vectors can be produced to target any of a wide variety of cancers. The targeting compositions described herein are typically administered by injection into the bloodstream, but other modes of administration, such as oral or topical administration, are also considered. In some embodiments, the targeting composition may be administered locally, at the site where the target cells are present, i.e., in a specific tissue, organ, or fluid (e.g., blood, cerebrospinal fluid, etc.). Any cancer that can be targeted through the bloodstream is of particular consideration herein. Some examples of applicable body parts containing cancer cells include the breasts, lungs, stomach, intestines, prostate, ovaries, cervix, pancreas, kidney, liver, skin, lymphs, bones, bladder, uterus, colon, rectum, and brain. The cancer can also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors). The cancer may also be a form of leukemia. In some embodiments, the cancer is a triple negative breast cancer. [00241] As is well known in the art, the dosage of the active ingredient(s) generally depends on the disorder or condition being treated, the extent of the disorder or condition, the method of administration, size of the patient, and potential side effects. In different embodiments, depending on these and other factors, a suitable dosage of the targeting composition may be precisely, at least, above, up to, or less than, for example, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or 1500 mg, or a dosage within a range bounded by any of the foregoing exemplary dosages. Furthermore, the composition can be administered in the indicated amount by any suitable schedule, e.g., once, twice, or three times a day or on alternate days for a total treatment time of one, two, three, four, or five days, or one, two, three, or four weeks, or one, two, three, four, five, or six months, or within a time frame therebetween. Alternatively, or in addition, the composition can be administered until a desired change in the disorder or condition is realized, or when a preventative effect is believed to be provided. [00242] The examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, or tautomeric forms thereof. The examples herein are also presented in order to more fully illustrate the preferred aspects of the present technology. The examples should in no way be construed as limiting the scope of the present technology, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects or embodiments of the present technology described above. The variations, aspects or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects or embodiments of the present technology. EXAMPLES Example 1: Exemplary Ligand Synthesis [00243] The synthesis of py-macrodipa (Scheme 1) involves the assembly of the macrocyclic core through a reductive animation reaction15 and the subsequent installation of the two picolinate pendant arms. The identity and purity of the intermediates and final product were ascertained by NMR spectroscopy, mass spectrometry, and analytical HPLC (FIGs.6−24). The macrodipa ligand was obtained via the published procedure.9 Scheme 1.
Figure imgf000092_0001
Scheme 1 (cont.).
Figure imgf000093_0001
[00244] Py-macrodiphospho [00245] The ligand py-macrodiphospho was synthesized indicated in Scheme 2.
Scheme 2.
Figure imgf000094_0001
[00246] Compounds 1 and 2 were obtained following literature procedures (Liebigs Ann. Chem.1990, 129–143; Inorg. Chem.2018, 57, 6095–6106). [00247] Synthesis of 3: Compound 1.3TFA (0.15 g, 0.24 mmol) and Na2CO3 (0.17, 1.60 mmol) were suspended in a solution of dry MeCN (8 mL), and a drying tube was equipped on the condenser. This mixture was heated at 75 °C for 30 min, after which compound 2 (0.16 g, 0.61 mmol) was added. This mixture was then heated at 75 °C for 4 d. Afterwards, the suspension was filtered, and the filtrate was concentrated to dryness under reduced pressure. This crude material was then dissolved in H2O containing 10% MeOH and 0.1% TFA (1.5 mL). Following filtration, this solution was injected into the preparative HPLC system to purify the product. HPLC gradient: 0−5 min, 90% H2O/MeOH; 5−40 min, 90% → 0% H2O/MeOH. Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield 2 as a colorless oil (0.11 g). Based on the peak integrations in the 1H spectra (FIG.130)and 19F NMR spectra (not shown) of this compound relative to an internal standard of fluorobenzene, 3 was estimated to be a 4TFA salt. The entirety of this material was used in the next step. [00248] Synthesis of py-macrodiphospho: Compound 3 (0.11 g, directly from the prior step) was dissolved in 4 M HCl (3 mL) and heated at 80 °C for 48 h. The solution was then concentrated under reduced pressure to obtain a white solid. To ensure the complete removal of the TFA coming from 3, 4 M HCl (3 mL) was added, and the resulting solution was concentrated to dryness under reduced pressure. The residue was then dissolved in H2O (3 mL) and lyophilized to yield the xHCl .yH2O salt of py-macrodiphoshpho as a white solid (0.05 g), the 1H spectra of which is provided in FIG.131. [00249] Hf(IV)-py-macrodipa. [00250] A preliminary Hf(IV)-py-macrodipa synthesis involved mixing HfCl4 and
Figure imgf000095_0001
NaOH, and allowing to stir overnight. A chromatogram (FIG.24) was obtained, evidencing complex formation. [00251] Ln3+ Complexes Stability Constants [00252] Metal complex stability constants provide a quantitative measure of the thermodynamic affinity of ligands for metal ions. The magnitudes of these stability constants for different ligands have been useful for assessing their values in different metal chelation applications.16 In order to test out our hypotheses, we determined the protonation constants (Ki) of py-macrodipa and macrodipa ligands (data not provided) and the stability constants (KLnL, Table 1) for Ln3+–py-macrodipa and Ln3+–macrodipa complexes, via either potentiometric titrations or UV−Vis spectrophotometric titrations. These quantities are defined as in eqs 1–2, with the concentrations of all species at chemical equilibrium. L notates an uncomplexed ligand at its fully deprotonated state. Ki = [HiL] / [H+][Hi−1L] (1) KLnL = [LnL] / [Ln3+][LnL] (2) Table 1. Stability Constants of the Ln3+ Complexes Formed with py-macrodipa, macrodipa, and macropa a
Figure imgf000096_0001
0.1 M KCl, this work. The values in the parentheses are one standard deviation of the last significant figure. b0.1 M KCl. For La3+−Lu3+, ref 9; for Sc3+, this work. c0.1 M KCl, ref 8. [00253] FIG.1 plots log KLnL values against the Ln3+ 6-coordinate ionic radius14 for py- macrodipa and macrodipa. Similar to macrodipa, py-macrodipa shows a “dual preference” to Ln3+ ions: a greater affinity to the large and small Ln3+ than the middle ones, which strongly suggests that the concept of conformational toggle is preserved in the py-macrodipa system. Remarkably, py-macrodipa shows a great improvement in its affinity to Ln3+ ions compared to macrodipa, with an about 2-log-unit increase in KLnL for large Ln3+ and about 1-log-unit rise for small Ln3+. [00254] Ligand py-macrodipa shows comparable affinity to the largest Ln3+ ions as does macropa; at the same time, it retains high affinity to the smallest Ln3+ ions for which macropa barely works. [00255] Complex Structures—NMR Spectroscopy [00256] To verify the presence of conformational toggle between Conformations A and B in py-macrodipa, we characterized the solution structures of Ln3+−py-macrodipa complexes with La3+ , Lu3+, and Sc3+ because of their diamagnetisms. Y3+, a diamagnetic Ln3+ analogue,12 was also included in this NMR study. Moreover, its 90-pm ionic radius14 aligns well with the minimum affinity among all Ln3+ complexes (FIG.1), which could provide more perceptions on the equilibrium between the two conformations. The 1H (FIG.2) and 13C{1H}(data not provided) NMR spectra of these four complexes were acquired in D2O at pD = 7. [00257] FIG.2 shows stacked 1H NMR spectra of these complexes. La3+, Y3+, Lu3+, and Sc3+ show a monotonic decrease in their ionic radius, spanning widely from 103.2 pm to 74.5 pm.14 A gradual change of the complex conformation is observed when the Ln3+ gets smaller: La3+−py-macrodipa is present as the 2-fold symmetric Conformation A, Y3+−py-macrodipa shows a mixture of both (molar ratio A:B = 3.6:1), and Lu3+, Sc3+ complexes exist as in the asymmetric Conformation B. We have previously obtained the 1H and 13C{1H} spectra for La3+−, Y3+−, and Lu3+−macrodipa complexes,9 the observation from which is highly comparable to the La3+−, Y3+−, and Lu3+−py-macrodipa spectra. For a more thorough comparison between these two ligands, we acquired the 1H and 13C{1H} spectra of Sc3+−macrodipa complex in this work (data not provided), which clearly show a Conformer B, complying with our expectation. In summary, upon the inclusion of a pyridyl moiety, py- macrodipa retains the “macrodipa-like” conformational toggle to accommodate Ln3+ with different sizes. Large Ln3+ resides in a symmetric Conformation A, and an asymmetric Conformation B is preferred when the Ln3+ gets small. [00258] Complex Structures—X-ray Crystallography [00259] X-ray crystallography is a characterization method extensively leveraged in coordination chemistry and capable of helping visualize the complexes.17 To gain more intuitive insights on the structures of Ln3+−py-macrodipa complexes, we characterized three representative Ln3+ complexes in the series, La3+, Lu3+, and Sc3+, by X-ray crystallography. Their crystal structures are depicted in FIG.3. [00260] These crystal structures are consistent to what has been deduced from the NMR spectroscopy data. La3+−py-macrodipa complex shows a 10-coodinate Conformation A with a slightly distorted C2 symmetry; whereas the Lu3+− and Sc3+−py-macrodipa complexes reside in an 8-coordinate Conformation B without any apparent symmetry elements. The Lu3+ and Sc3+ are highly comparable except for a notable difference. In the Sc3+ structure, an inner-sphere water molecule from solvent acts as a donor atom, giving rise to a complex hydration number q = 1. In contrast, one of the ethereal oxygens on the macrocycle takes this coordination site in the Lu3+ structure instead, giving q = 0. For the ease of discussion, we annotate this q = 0 and q = 1 conformations as Conformations B0 and B1, respectively. [00261] This subtle conformational difference is possibly correlated to their crystallization conditions. Lu3+ crystal was grown via vapor diffusion of Et2O into a MeOH solution, under which condition the H2O source is limited; Sc3+ crystal was obtained from an aqueous solution instead, a condition that favors H2O coordination. Moreover, Lu3+−macrodipa structure represents a Conformation B1, the crystals of which were afforded in an aqueous solution as well.9 In addition, Gagné recently surveyed bond lengths (r) of Ln3+ ions bonded to oxygen and obtained a r(Lu−O) = 2.342 ± 0.103 Å for 8-coordinate Lu3+ complexes.18 At a close inspection on the [Lu(py-macrodipa)]+ structure, the distance between Lu3+ center and ethereal oxygen donor O1, r(Lu−O) = 2.509 Å, is substantially longer than expected, which indicates O1 is a loose and weak binder. Based on these findings, we anticipate that in aqueous solution, the context of nuclear medicine, Conformation B1 is more accessible than Conformation B0. [00262] In short, these solid-state structures further support the mechanism of this conformational toggle between Conformations A and B in Ln3+−py-macrodipa system, which changes upon the size of the metal ion it binds. However, some complexity in Conformation B was observed in the solid state, where the presence or absence of a bound H2O is somewhat ambiguous. This issue will be further addressed by our computational work. [00263] DFT Calculations [00264] To (i) understand what factors dictate this conformational toggle in py-macrodipa ligand system and (ii) seek for the reasons why Ln3+−py-macrodipa complexes are thermodynamically more stable than Ln3+−macrodipa complexes systematically, we carried out DFT calculation with Gaussian 0919 on the Ln3+−py-macrodipa system (Ln = La−Lu, Sc), using the same computational conditions we previously implemented for Ln3+−macrodipa (Ln = La−Lu) complexes9 for a consistency and ease of comparison. Specifically, ωB97XD/6-31G(d,p) level of theory20–22 was employed, large-core relativistic effective core potential (LCRECP)23 was assigned on Ln3+ ions (Ln = La−Lu), and SMD solvation model24,25 was applied to account for solvation effects from the aqueous environment. For a better comparison, Sc3+-macrodipa complex was also computationally investigated in this work. [00265] In order to understand the conformational toggle in a computational manner, Conformers A and B for all Ln3+−py-macrodipa complexes were optimized and their standard free energies (G°) were calculated. As observed in the crystallographic data, Conformations B0 and B1 are likely for Conformation B, and thus they both were calculated. Depending on if Conformer B exists as B0 or B1, the conformational switch between Conformers A and B in the aqueous solution can be written as either Eq 3 or 4, where the standard free energy change of these two reactions are annotated as ΔG°(A,B0) and ΔG°(A,B1), respectively. [Ln(py-macrodipa)]+ (Conformation A, aq) ⇌ [Ln(py-macrodipa)]+ (Conformation B0, aq) (3) [Ln(py-macrodipa)]+ (Conformation A, aq) + H2O (l)⇌ [Ln(py-macrodipa)]+ (Conformation B1, aq) (4) [00266] FIG.4A summarizes computed ΔG°(A,B0) and ΔG°(A,B1) values across all Ln3+, both of which reveal that large Ln3+ favors Conformation A and small Ln3+ prefers Conformation B, complying well with the experimental observations. Additionally, as indicated by the more negative ΔG°(A,B1) values, Conformation B1 is systematically favored over B0 in aqueous solution, by ~30 kJ .mol-1. Since DFT calculation suggests Conformation B1 is more accessible than B0 in aqueous solution, we focus the following calculations particularly on Conformation B1. [00267] We successfully analyzed the conformational toggle in the Ln3+−macrodipa (Ln = La−Lu) system by deconvoluting the free energy change from Conformation A to Conformation B, ΔG° (equivalent to ΔG°(A,B1) in this work), into three contributors: relative strain energy (ΔΔGS°), relative binding energy (ΔΔGB°), and relative solvation energy (ΔΔGsolv°).9 “Relative” means the energy change moving from Conformation A to B1. Herein, we apply the same strategy to analyze what factors dictate this conformational toggle in the Ln3+−py-macrodipa system. These quantities were computed and summarized in FIG. 4B. [00268] For a better comparison, we plot corresponding values of the Ln3+−macrodipa system9 in FIG.4C, in which Sc3+−macrodipa was also calculated in this work and included. These values from Ln3+−macrodipa are more straightforward to interpret, with all three factors show monotonic change across the Ln3+ series. The magnitude of ΔΔGsolv° is significantly smaller than the other two, and the result of conformational change is more of an interplay between ΔΔGS° and ΔΔGB°. ΔΔGB° is positive for all Ln3+ except for Sc3+, which can be attributed to the fact that Conformation A provides two more donor atoms than does Conformation B1, thus binding the Ln3+ stronger in general. However, Sc3+ is too small to interact effectively with Conformation A, causing a negative ΔΔGB°. The decrease of ΔΔGB° across all Ln3+ indicates that Confomation A is more suitable for large Ln3+. ΔΔGS° is negative for all Ln3+, suggesting Conformation B1 endures less strain. As it gets more negative across all Ln3+, Conformation B is more well suited for small Ln3+. [00269] Nonetheless, Ln3+−py-macrodipa system is more sophisticated, and the trends are not as clear as for Ln3+−macrodipa. Similarly, ΔΔGB° is positive for all Ln3+ except Sc3+, but ΔΔGB° tends to show a maximum level-off between Nd3+ and Ho3+. This result indicates the rigidity of the pyridine moiety somewhat restrains the ligand structure: Conformation A is best-suited to bind some certain Ln3+ and its advantage over Conformation B1 fades off when the Ln3+ gets either too large or too small. Different from Ln3+−macrodipa system where ΔΔGS° favors Conformation B1 for all Ln3+, ΔΔGS° is positive for Ln3+−py-macrodipa complexes of the largest Ln3+ ions (La3+−Pr3+), indicating Conformation A is favored by ligand strain for these ions. This observation can be attributed to the preorganizartion effect from the pyridine unit. The presence of rigid pyridine forces the free ligand structure to be partially close to the complex geometry for the very large Ln3+, and thus reduce the strain energy needed during the complex formation. ΔΔGsolv° shows a much smaller magnitude compared to the other two factors and fluctuates around naught for all Ln3+. It is thus the least significant factor that influences this conformational toggle. In short, in Ln3+−py-macrodipa system, the interplay of these three parameters, with ΔΔGB° and ΔΔGS° having greater influeneces, dictate this conformational toggle. For large Ln3+, both ΔΔGB° and ΔΔGS favors the Conformation A. When moving to smaller Ln3+, they tend to get more negative and thus Conformation B1 gradually becomes the suitable conformation. [00270] In addition, we sought to find out why Ln3+−py-macrodipa complexes are substantially more stable than Ln3+−macrodipa complexes. Absolute binding energies (ΔGB°) afford the most straightforward clue (data not provided). ΔGB° values for Ln3+−py-macrodipa complexes are systematically more favorable than those of Ln3+−macrodipa complexes, no matter what the conformation is. This observation suggests that the pyridyl donor is a stronger binder to Ln3+ than is the ethereal oxygen donor. [00271] We next tried to compare the absolute strain energies (ΔGS°) for these two ligand systems. However, a challenge to compute these values is that the global free energy minimum for the free ligand is needed. This is difficult to model as free ligands are structurally flexible and many energetically similar conformations are possible. Therefore, we optimized the free ligand starting from the complex geometries of both Conformations A and B1, letting them relax to their corresponding local minima. It turned out that the free energies of these two local minima are very close in energy, for both ligand systems (data not provided). Thus, we make an approximation herein, assuming these two local minima are reasonable representatives to the free ligand global minimum. As such, ΔGS° is the free energy difference between the strained ligand in a complex in either Conformation A or B1 and its corresponding optimized local minimum. Calculated ΔGS° values (data not provided) are plotted in FIG.5 for a more intuitive inspection. In comparing Confomation A between the two ligand systems, macrodipa strains itself much more than py-macrodipa when forming the complex, by 31−66 kJ .mol-1. However, for Conformation B1, py-macrodipa needs more strain energy to form the complex, but by a less extent, 4−30 kJ .mol-1. We attribute this observation to the rigidification from the pyridine moiety. By including this pyridine unit on py-macrodipa, the preorganization effect helps the formation of Confomer A but Confomer B1 is somewhat impeded by its rigidity. [00272] Lastly, we inspect the difference in the absolute solvation energy (ΔGsolv°). ΔGsolv° for both systems are comparable for both conformations, always showing a <15 kJ .mol-1 difference (data not provided). Thus, the influence from solvation is fairly insignificant, compared to the above-mentioned effects from binding and strain. [00273] In short, our computational results provide useful insights on why Ln3+−py- macrodipa complexes are thermodynamically more stable than Ln3+−macrodipa complexes. With a stronger pyridyl nitrogen donor, the metal−ligand binding interaction is effectively enhanced for py-macrodipa. Moreover, the geometry restraint brought by the pyridine unit in py-macrodipa strongly favors the reorientation to Conformation A, but hindering Conformation B1 to some extent. Considering that large and small Ln3+ reside in Confomation A and B1 respectively, this observation could address why the KLnL improvement for large Ln3+ (~2 log units) are more substantial than for small Ln3+ (~1 log unit). [00274] DTPA Transchelation Challenge. [00275] In the context of nuclear medicine, the kinetic stability of Ln3+ complexes are of critical importance since the release of the Ln3+ ion is not allowed due to the various toxicological effects caused by uncomplexed rare-earth ions.26 Therefore, the kinetic stabilities of Ln3+−py-macrodipa and Ln3+−macrodipa complexes were also investigated with a representative subset of rare-earth ions, in addition to their thermodynamic stabilities. Specifically, we monitored the transchelation reaction of these Ln3+ complexes by UV−Vis spectroscopy, with the presence of 100-fold excessive DTPA at pH = 7.4 and RT (22 °C). DTPA is a ligand possessing higher thermodynamic affinity to Ln3+,27,28 and thus the Ln3+ loss of Ln3+−py-macrodipa or Ln3+−macrodipa complexes is thermodynamically favored under this condition. This reaction follows pseudo-first-order kinetics, and the half-live (t1/2) of this process is a good measure of the complex kinetic stability. These t1/2 values are listed in Table 2. Table 2. Half-lives of Ln3+−py-macrodipa and Ln3+−macrodipa Complexes when Challenged with 100 Equivalents of DTPA.a
Figure imgf000102_0001
[00276] For both ligand systems, the kinetic stability of their Ln3+ complexes complies with the thermodynamic stability, representing a “high−low−high” trend across the series. It should otherwise be clarified that the thermodynamic stability does not necessarily match its kinetic stability in general. In this specific case, this observation can be addressed by the fact that neither of the two conformations is well-suited for middle Ln3+ ions, and thus their complexes are more labile than Ln3+−py-macrodipa of larger and smaller Ln3+. [00277] A noteworthy result is that the dissociation of Er3+−py-macrodipa complex follows a biexponential function, which could be attributed to the concurrence of both Conformations A and B before the DTPA addition. The 1H NMR spectrum of Y3+−py- macrodipa (FIG.2) support this justification: it clearly shows a mixture of both conformers, and Er3+ has a comparable ionic radius (91 pm) to that of Y3+ (90 pm).14 [00278] The kinetic stability of Ln3+−macrodipa complexes is not desirable, with none of them lasts for over half an hour. But notably, py-macrodipa complexes is substantially improved compared to the macrodipa complexes. In particular, as indicated by their long t1/2 values, both the largest La3+ and smallest Sc3+ complexes show remarkable kinetic stabilities, a prerequisite for applications in nuclear medicine. Under such a hard condition, these complex t1/2 values are substantially longer than the half-lives of their corresponding medicinally relevant radioisotopes like 132La (t1/2 = 4.6 h), 135La (t1/2 = 18.9 h), and 44Sc (t1/2 = 4.0 h).29,30 The extended kinetic stability of La3+− and Sc3+−py-macrodipa show the candidacy of py-macrodipa to be used in chelating radioactive La3+ and Sc3+. [00279] References of Example 1: (1) Blower, P. J. A nuclear chocolate box: the periodic table of nuclear medicine. Dalt. Trans.2015, 44, 4819–4844. (2) Boros, E.; Packard, A. B. Radioactive Transition Metals for Imaging and Therapy. Chem. Rev.2019, 119, 870–901. (3) Kostelnik, T. I.; Orvig, C. Radioactive Main Group and Rare Earth Metals for Imaging and Therapy. Chem. Rev.2019, 119, 902–956. (4) Price, E. W.; Orvig, C. Matching Chelators to Radiometals for Radiopharmaceuticals. Chem. Soc. Rev.2014, 43, 260–290. (5) Stasiuk, G. J.; Long, N. J. The Ubiquitous DOTA and its Derivatives: the Impact of 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid on Biomedical Imaging. Chem. Commun.2013, 49, 2732–2746. (6) Aluicio-Sarduy, E.; Thiele, N. A.; Martin, K. E.; Vaughn, B. A.; Devaraj, J.; Olson, A. P.; Barnhart, T. E.; Wilson, J. J.; Boros, E.; Engle, J. W. Establishing Radiolanthanum Chemistry for Targeted Nuclear Medicine Applications. Chem. – A Eur. J. 2020, 26, 1238– 1242. (7) Thiele, N. A.; Brown, V.; Kelly, J. M.; Amor-Coarasa, A.; Jermilova, U.; MacMillan, S. N.; Nikolopoulou, A.; Ponnala, S.; Ramogida, C. F.; Robertson, A. K. H.; Rodríguez- Rodríguez, C.; Schaffer, P.; Williams, C.; Babich, J. W.; Radchenko, V.; Wilson, J. J. An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy. Angew. Chem. Int. Ed.2017, 56, 14712–14717. (8) Roca-Sabio, A.; Mato-Iglesias, M.; Esteban-Gómez, D.; Tóth, E.; de Blas, A.; Platas- Iglesias, C.; Rodríguez-Blas, T. Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides. J. Am. Chem. Soc.2009, 131, 3331–3341. (9) Hu, A.; MacMillan, S. N.; Wilson, J. J. Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern for the Lanthanide Ions. J. Am. Chem. Soc.2020, 142, 13500–13506. (10) Li, L.; Jaraquemada-Peláez, M. de G.; Kuo, H.-T.; Merkens, H.; Choudhary, N.; Gitschtaler, K.; Jermilova, U.; Colpo, N.; Uribe-Munoz, C.; Radchenko, V.; Schaffer, P.; Lin, K.-S.; Bénard, F.; Orvig, C. Functionally Versatile and Highly Stable Chelator for 111In and 177Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting. Bioconjugate Chem. 2019, 30, 1539–1553. (11) Hu, A.; Keresztes, I.; MacMillan, S. N.; Yang, Y.; Ding, E.; Zipfel, W. R.; DiStasio, R. A.; Babich, J. W.; Wilson, J. J. Oxyaapa: A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides. Inorg. Chem.2020, 59, 5116–5132. (12) Cotton, S. A. Scandium, Yttrium & the Lanthanides: Inorganic & Coordination Chemistry. Encyclopedia of Inorganic Chemistry.2006. (13) Seitz, M.; Oliver, A. G.; Raymond, K. N. The Lanthanide Contraction Revisited. J. Am. Chem. Soc.2007, 129, 11153–11160. (14) Shannon, R. D. Revised Effective Ionic Radii and Systematic Studies of Interatomic Distances in Halides and Chalcogenides. Acta Crystallogr. Sect. A 1976, 32, 751–767. (15) Lüning, U.; Baumstark, R.; Peters, K.; von Schnering, H. G. Concave Reagents, 3. Synthesis, Basicity, and Conformation of New Concave Pyridines. Liebigs Ann. der Chemie 1990, 1990, 129–143. (16) Martell, A. E.; Hancock, R. D. Metal Complexes in Aqueous Solutions; Plenum Press: New York, 1996. (17) Girolami, G. S. X‑Ray Crystallography; University Science Books: Mill Valley, CA, 2015. (18) Gagné, O. C. Bond-length distributions for ions bonded to oxygen: results for the lanthanides and actinides and discussion of the {\it f}-block contraction. Acta Crystallogr. Sect. B 2018, 74, 49–62. (19) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; … Fox, D. J. Gaussian 09, Revision D.01. Gaussian Inc.: Wallingford, CT 2009. (20) Chai, J.-D.; Head-Gordon, M. Long-Range Corrected Hybrid Density Functionals with Damped Atom–Atom Dispersion Corrections. Phys. Chem. Chem. Phys.2008, 10, 6615–6620. (21) Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self-Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. J. Chem. Phys.1972, 56, 2257–2261. (22) Hariharan, P. C.; Pople, J. A. The Influence of Polarization Functions on Molecular Orbital Hydrogenation Energies. Theor. Chim. Acta 1973, 28, 213–222. (23) Dolg, M.; Stoll, H.; Savin, A.; Preuss, H. Energy-Adjusted Pseudopotentials for the Rare Earth Elements. Theor. Chim. Acta 1989, 75, 173–194. (24) Marenich, A. V; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378–6396. (25) Regueiro-Figueroa, M.; Esteban-Gómez, D.; de Blas, A.; Rodríguez-Blas, T.; Platas- Iglesias, C. Understanding Stability Trends along the Lanthanide Series. Chem. – A Eur. J. 2014, 20, 3974–3981. (26) Rim, K. T.; Koo, K. H.; Park, J. S. Toxicological Evaluations of Rare Earths and Their Health Impacts to Workers: A Literature Review. Saf. Health Work 2013, 4, 12–26. (27) Grimes, T. S.; Nash, K. L. Acid Dissociation Constants and Rare Earth Stability Constants for DTPA. J. Solution Chem.2014, 43, 298–313. (28) Pniok, M.; Kubíček, V.; Havlíčková, J.; Kotek, J.; Sabatie-Gogová, A.; Plutnar, J.; Huclier-Markai, S.; Hermann, P. Thermodynamic and Kinetic Study of Scandium(III) Complexes of DTPA and DOTA: A Step Toward Scandium Radiopharmaceuticals. Chem. – A Eur. J.2014, 20, 7944–7955. (29) Abel, E. P.; Clause, H. K.; Fonslet, J.; Nickles, R. J.; Severin, G. W. The Half-lives of 132La and 135La. Phys. Rev. C 2018, 97, 34312. (30) García-Toraño, E.; Peyrés, V.; Roteta, M.; Sánchez-Cabezudo, A. I.; Romero, E.; Martínez Ortega, A. Standardisation and precise determination of the half-life of 44Sc. Appl. Radiat. Isot.2016, 109, 314–318. Example 2: Further Exemplary Chelators [00280] Ligand synthesis [00281] The syntheses of macrodipa and macrotripa follow Schemes 100-S1 and 100-S2, respectively. Compound 1, 4, 6, 7, 8.3HBr, and 6-chloromethylpyridine-2-carboxylic methyl ester were prepared as described in the literature.1–3 Deionized H2O (≥ 18 MΩ .cm) was obtained from an Elga Purelab Flex 2 water purification system. Organic solvents were of ACS grade or higher. All other reagents were purchased from commercial sources and used without further purification. [00282] High-performance liquid chromatography (HPLC) consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC-20AT (analytical) pump, and an SPD-20AV UV−Vis detector monitoring at 270 nm (Shimadzu, Japan). Semipreparative purification was performed using an Epic Polar preparative column, 120 Å, 10 μm, 25 cm × 20 mm (ES Industries, West Berlin, NJ) at a flow rate of 14 mL/min. Analytical chromatography was carried out using an Ultra Aqueous C18 column, 100 Å, 5 μm, 250 mm × 4.6 mm (Restek, Bellefonte, PA) at a flow rate of 1.0 mL/min. All HPLC methods employed use a binary mobile phase (H 2 O and MeOH, 0.1% TFA added for both solvents) gradient. Preparative HPLC runs were carried out with the following methods. Method P1: 0−10 min, 90% H2O/MeOH; 10−25 min, 90% → 0% H2O/MeOH; Method P2: 0−15 min, 90% H 2 O/ MeOH ; 15−25 min, 90% → 0% H 2 O/MeOH. Method P3: 0−5 min, 90% H 2 O/MeOH; 5−30 min, 90% → 0% H2O/MeOH. All analytical HPLC runs were carried out with the same method: 0−5 min, 90% H2O/MeOH; 5−25 min, 90% → 0% H2O/MeOH. [00283] 1H and 13C{1H} NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 and 125.68 MHz for 1H and 13C observations, respectively. All these NMR experiments were carried out at 25 °C. High- resolution mass spectra (HRMS) were acquired on a Thermo Scientific Exactive Orbitrap mass spectrometer with a heated electrospray (HESI) ion source.
Scheme 3. Synthetic Route to macrodipa
Figure imgf000107_0001
Scheme 4. Synthetic route to macrotripa
Figure imgf000108_0001
[00284] Synthesis of 3. Compounds 1 (2.24 g, 5.43 mmol) and 2 (2.60 g, 5.17 mmol) were dissolved in MeCN (110 mL). Cs 2 CO 3 (5.06 g, 15.5 mmol) was added and this mixture was then heated at 75 °C for 30 h. Afterwards, the MeCN was removed under reduced pressure, and CH 2 Cl 2 (20 mL) was added to the remaining residue. The resulting suspension was centrifuged, and the supernatant was collected by decantation. The remaining pellet was rinsed with CH 2 Cl 2 (2 × 15 mL) and centrifuged. All supernatants were combined and concentrated under reduced pressure to obtain a yellow oily residue. This crude residue was then purified by column chromatography (silica gel, 1:1 hexane/ethyl acetate) to yield the product as a white solid (1.56 g, 53%). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.68 (d, J = 8.0 Hz, 4H, Ph), 7.29 (d, J = 8.0 Hz, 4H, Ph), 3.64 (dt, J = 11.3, 5.9 Hz, 8H, –CH2–), 3.58 (m, 8H, –CH2–), 3.33 (m, 8H, –CH2–), 2.42 (s, 6H, –CH3).13C{1H} NMR (126 MHz, CDCl3) δ: 143.3, 136.5, 129.7, 127.2, 71.0, 70.8, 70.6, 70.1, 49.9, 49.4, 21.5. ESI-HRMS m/z: 593.1985; calcd for [C 26 H 38 N 2 O 8 S 2 + Na]+: 593.1962. [00285] Synthesis of 5. To a mixture of 4 (0.32 g, 1.22 mmol), 6-chloromethylpyridine-2- carboxylic methyl ester (0.85 g, 4.58 mmol) and Na 2 CO 3 (0.39 g, 3.68 mmol), dry MeCN (20 mL) was added. This suspension was then heated to 80 °C for 40 hours with a drying tube equipped on the condenser. Afterwards, the suspension was filtered off and the goldish- yellow filtrate was concentrated to dryness under reduced pressure to give crude 5 as a yellow solid, which was used in the next step without further purification. ESI-HRMS m/z: 561.2944; calcd for [C 28 H 40 N 4 O 8 + H]+: 561.2919. [00286] Synthesis of macrodipa. The above crude material of 5 was dissolved in 6 M HCl (7.5 mL) and heated at 80 °C for 18 h. The solution was then concentrated under reduced pressure to give a yellow oily residue. This material is dissolved in 10% MeOH/H 2 O containing 0.1% TFA (3 mL). It was then filtered and injected into the preparative HPLC system with a gradient elution following Method P1. Pure fractions were combined and concentrated under reduced pressure to an oil. In order to convert the product to a non- hygroscopic HCl salt, it was dissolved in 6 M HCl (4 mL) and concentrated under reduced pressure, which was repeated for three times. Afterwards, the residue was dissolved in H 2 O (3 mL) and lyophilized to yield the 4HCl .3H2O salt of macrodipa as a pale-yellow solid (0.50g, 56% over 2 steps from 4). 1H NMR (500 MHz, D 2 O, pD ≈ 8) δ: 7.84 (m, 4H, py), 7.47 (d, 2H, J = 7.1 Hz, py), 3.88 (s, 4H, –NCH2py–), 3.71 (m, 4H, –CH2–), 3.65 (m, 8H, –CH2–), 3.50 (t, 4H, J = 5.2 Hz, –CH2–), 2.86 (s, –CH2–). 13C{1H} NMR (126 MHz, D2O, pD ≈ 8) δ: 173.4, 156.8, 153.8, 138.9, 126.4, 123.1, 70.0, 69.6, 67.8, 67.7, 59.9, 54.5, 53.5. ESI- HRMS m/z: 267.1331; calcd for [ C26H36N4O8 + 2H]2+: 267.1339. Elemental analysis: found %: C 42.31, H 6.52, N 7.57; calcd % for C33H42N6O9 .4HCl .3H2O: C 42.63, H 6.33, N 7.65. Analytical HPLC: t R = 16.84 min. [00287] Synthesis of 9. To a mixture of 8.3HBr (0.70 g, 1.39 mmol), 6- chloromethylpyridine-2-carboxylic methyl ester (0.83 g, 4.47 mmol) and Na 2 CO 3 (1.18 g, 11.1 mmol), dry MeCN (35 mL) was added. This suspension was then heated to 80 °C for 24 hours with a drying tube equipped on the condenser. Afterwards, the suspension was filtered off and the greenish-yellow filtrate was concentrated to dryness under reduced pressure to give crude 9 as a yellow solid, which was used in the next step without further purification. ESI-HRMS m/z: 355.1813; calcd for [C 36 H 48 N 6 O 9 + 2H]2+: 355.1814. [00288] Synthesis of macrotripa. The above crude material of 9 was dissolved in 6 M HCl (8.5 mL) and heated at 80 °C for 18 h. The solution was then concentrated under reduced pressure to a yellow oily residue. This material is dissolved in 10% MeOH/H 2 O containing 0.1% TFA (4 mL). It was then filtered and injected into the preparative HPLC system with a gradient elution following Method P2. Pure fractions were combined and concentrated under reduced pressure to an oil. In order to convert the product to non-hygroscopic HCl salt, it was dissolved in 6 M HCl (6 mL) and concentrated under reduced pressure, which was repeated for three times. Afterwards, the residue was dissolved in H2O (3 mL) and lyophilized to yield the 5HCl .2H2O salt of macrotripa as a white solid (0.73 g, 59% over 2 steps from 8.3HBr).1H NMR (500 MHz, D2O, pD = 6–7) δ: 7.87 (m, 6H, py), 7.57 (d, 3H, J = 7.0 Hz, py), 4.24 (s, 6H, –NCH2py–), 3.73 (s, 12H, –NCH2CH2O–), 3.19 (s, 12H, –NCH2CH2O–).13C{1H} NMR (126 MHz, D2O, pD = 6–7) δ: 173.2, 154.1, 153.0, 139.3, 126.9, 123.8, 66.0, 58.3, 54.6. ESI-HRMS m/z: 334.1585; calcd for [C 33 H 42 N 6 O 9 + 2H]2+: 334.1580. Elemental analysis: found %: C 44.93, H 5.85, N 9.45; calcd % for C33H42N6O9 .5HCl .2H2O: C 44.78, H 5.81, N 9.50. Analytical HPLC: t R = 16.10 min. [00289] Potentiometric Titrations [00290] Potentiometric titrations were carried out using a Metrohm Titrando 888 titrator equipped with a Ross Orion combination electrode (8103BN, ThermoFisher Scientific) and a Metrohm 806 exchange unit with an automatic burette (10 mL). This titration system was controlled by Tiamo (ver.2.5) software. The titration vessel was fitted into a removable glass cell (≈ 70 mL) and thermostated at 25.0 °C (pK w = 13.78)4 using a Thermomix 1442D circulating water bath. CO 2 was excluded from the vessel prior to and during the titrations by an argon flow, which was passed through an aqueous 30 wt% KOH solution. Carbonate-free KOH (0.1 M) was prepared by dissolving KOH pellets (semiconductor grade, 99.99% trace metals basis, Sigma-Aldrich) in freshly boiled water and was standardized by potentiometric titration against potassium hydrogen phthalate. Hydrochloric acid (0.1 M, J.T. Baker) was standardized against Tris (base form). Titration solutions were maintained at a constant ionic strength of 0.1 M with KCl (BioUltra, ≥ 99.5%, Sigma-Aldrich) and were equilibrated for 15 minutes prior to the addition of titrant. The electrode was calibrated before each titration by titrating a solution of standardized HCl with standardized KOH, and the data were analyzed using the program Glee5 (ver.3.0.21) to obtain the standard electrode potential and slope factor. [00291] Ligand stock solutions were made by dissolving the solid ligand in H 2 O, and their exact concentrations were determined based on the end points of the potentiometric titration curves obtained during the protonation constant determinations. The concentrations determined from titration curves matched the concentrations calculated from the ligand masses, where the MWs of the ligands were estimated from the elemental analysis results. Ln 3+ stock solutions were made by dissolving the corresponding LnCl 3 hydrate salts (99.9% purity or higher) in standardized HCl (0.1 M). The exact concentrations were determined by complexometric titrations 6 with a standardized Na2H2EDTA solution (Alfa Aesar ). The complexometric titrations were performed at pH = 5.4 maintained by a HOAc-NaOAc buffer, and the end point was indicated by xylenol orange. [00292] Protonation constant or stability constant determinations were carried out by titrating an acidic solution containing free ligand or both ligand and metal with standardized KOH. For protonation constant determinations, the ligand concentration was 1 mM. For stability constant determinations, both the ligand and metal ion concentrations were around 1 mM. The total analyte volumes were 15–20 mL. Up to 3 min (protonation constant determinations) or 5 min (stability constant determinations) were given as equilibration times before recording the solution pH after the addition of an aliquot of base. The solutions were inspected throughout the titrations for signs of Ln(OH) 3 precipitation. Data points of the titration curves were excluded from analysis if any precipitate was observed. These titration data were refined with Hyperquad 20137 software to determine protonation and stability constants. The data points within the pH range of 2.5–11.3 were used for analysis. At least seven independent titrations for protonation constant measurements and three titrations for stability constant measurements were carried out for each L and LnL system. Table 3 lists protonation constants of macrodipa, macrotripa, OxyMepa, and macropa. FIGs. 41-70 provide representative protonation constant detminations by potentiometric titrations. [00293] Table 3. Protonation constants of macrodipa, macrotripa, OxyMepa, and macropa.
Figure imgf000112_0001
[00294] NMR Study on Complex Solution Structures [00295] The 1D 1H and 2D NMR spectra of the La3+ and Lu3+ complexes were acquired on a 600 MHz Varian INOVA spectrometer equipped with a 5-mm HCN inverse probehead operating at 599.50 MHz for 1H observation and 150.76 MHz for 13C decoupling. The 1D 1H NMR spectra of the Y3+ complexes and all the 13C{1H} NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 MHz for 1H observation and 125.68 MHz for 13C observation. 2D experiments were performed using the standard Varian pulse sequences HSQCAD, gHMBCAD, gCOSY and ROESYAD as provided in VnmrJ (ver. 3.2). All these NMR experiments were carried out at 25 °C. 1H NMR spectra of La3+, Lu3+, and Y3+ complexes were referenced to residual internal HDO solvent peak at 4.77 ppm (25 °C), which was calculated according to the literature equation that accounts for the temperature dependence of the HDO chemical shift.10 The 13C and 2D NMR spectra were referenced indirectly to the corresponding 1H spectra using the “absolute reference” function provided in MestReNova (Mestrelab Research S.L.). All 1H and 13C signals were assigned for La3+, Lu3+ complexes based on the 2D spectra, except C1–C12 and the hydrogens on these carbons. These signals are difficult to unambiguously distinguish due to their highly similar chemical environments. [00296] Table 4 provides peak assignments of NMR spectra on La-macrodipa complex. Table 4. Peak assignments of NMR spectra on La-macrodipa complex
Figure imgf000113_0001
[00297] Table 5 provides peak assignments of NMR spectra on Lu-macrodipa complex. Table 5. Peak assignments of NMR spectra on Lu-macrodipa complex.
Figure imgf000114_0001
[00298] Table 6 provides peak assignments of NMR spectra on La-macrotripa complex. Table 6. Peak assignments of NMR spectra on La-macrotripa complex.
Figure imgf000115_0001
[00299] Table 7 provides peak assignments of NMR spectra on Lu-macrotripa complex. Table 7. Peak assignments of NMR spectra on Lu-macrotripa complex.
Figure imgf000116_0001
[00300] X-Ray Crystallography [00301] X-ray quality crystals of La-macrodipa complex were obtained via the following procedure. Caution! Perchlorate salts should be handled as potentially explosive compounds. Do not apply vacuum or remove these crystals from the mother liquor. macrodipa .4HCl .3H2O (27.9 mg, 0.038 mmol) was suspended in i-PrOH (500 μL). Triethylamine (31.6 μL, 0.228 mmol) was added to this suspension, and it was then heated to 75 °C for 30 min, causing full dissolution of the ligand. La(ClO4)3.6H2O (23.9 mg, 0.044 mmol) was dissolved in i-PrOH (500 μL), and this solution was dropwise added into the reaction mixture. A precipitate formed immediately. This suspension was stirred at 75 °C for another 2 h. Afterwards, this suspension was allowed to cool to RT and then transferred into a 2-mL centrifuge tube. It was centrifuged, and the supernatant was removed. The white pellet was resuspended in i-PrOH and isolated by centrifugation twice, to wash away impurities. The remaining pellet was used for crystal growth. Slow diffusion of Et2O into a DMF solution of this material at RT afforded X-ray quality crystals of the [La(macrodipa)][ClO4] .DMF over about 2 months. [00302] X-ray quality crystals of the Lu-macrodipa complex were obtained via the following procedure. macrodipa .4HCl .3H2O (22.2 mg, 0.030 mmol) and LuCl3.6H2O (12.8 mg, 0.033 mmol) were dissolved in 500 μL of H2O. The pH of this solution was adjusted to 4–5 with 1 M NaOH (~145 μL), added while stirring. This mixture was allowed to stir for 30 min. Solid KPF6 (9.0 mg, 0.049 mmol) was then added, leading to the formation of a white precipitate within several minutes. This suspension was allowed to stir for another 30 min and then transferred into a 2-mL centrifuge tube. It was centrifuged, and the supernatant was removed. The pellet was resuspended in H2O and isolated by centrifugation twice, to dissolve water-soluble impurities. Because the pellet had some solubility in H2O, each washing step led to a loss of mass. Thus, the supernatants afforded by the 3 centrifugations were collected separately. Slow evaporation of the supernatant obtained from the second centrifugation overnight at RT afforded X-ray quality crystals of [Lu(macrodipa)(OH2)][PF6] .3H2O. [00303] X-ray quality crystals of the La-macrotripa complex were obtained via the following procedure. macrotripa .5HCl .2H2O (31.0 mg, 0.035 mmol) and LaCl3.7H2O (14.9 mg, 0.040 mmol) were dissolved in 500 μL of H2O. The pH of this solution was adjusted to ~6 with 1 M NaOH (~250 μL), added while stirring. After 10 min, saturated aqueous solution of NaBPh4 (150 μL) was added, leading to the formation of a white precipitate within several minutes. This suspension was allowed to stir for another 10 min and then transferred into a 2- mL centrifuge tube. It was centrifuged, and the supernatant was removed. The pellet was resuspended in H2O and isolated by centrifugation twice, to dissolve water-soluble impurities. The remaining pellet was transferred into a scintillation vial as a suspension in H2O, and then lyophilized to give a white solid (42.8 mg). Slow diffusion of Et2O into a MeCN solution of this material at 4 °C afforded X-ray quality crystals of [La(macrotripa)][BPh4] .Et2O .MeCN over about 4 months. [00304] Crystals of the Lu-macrotripa complex were obtained via the following procedure. Macrotripa .5HCl .2H2O (32.0 mg, 0.036 mmol) and LuCl3.6H2O (15.7 mg, 0.040 mmol) were dissolved in 800 μL of H2O. The pH of this solution was adjusted to ~6 with 1 M NaOH (~240 μL), added while stirring. After 30 min, the reaction mixture was filtered and injected into the preparative HPLC system with a gradient elution following Method P3 (no TFA was added into the HPLC solvents). Pure fractions were combined and most of the solvent was removed under reduced pressure (~3 mL left). It was then lyophilized to yield a white solid (12.9 mg). Slow diffusion of Et2O into an EtOH solution of this material at −20 °C afforded small, poor-quality crystals of the Lu-macrotripa complex over about 2 weeks. [00305] Low-temperature X-ray diffraction data were collected on a Rigaku XtaLAB Synergy diffractometer coupled to a Rigaku Hypix detector with Cu Kα radiation (λ = 1.54184 Å), from a PhotonJet micro-focus X-ray source at 100 K. The diffraction images were processed and scaled using the CrysAlisPro11 software. The structures were solved through intrinsic phasing using SHELXT12 and refined against F2 on all data by full-matrix least squares with SHELXL13 following established refinement strategies.14 All non- hydrogen atoms were refined anisotropically. All hydrogen atoms bound to carbon were included in the model at geometrically calculated positions and refined using a riding model. Hydrogen atoms bound to oxygen were located in the difference Fourier synthesis and subsequently refined semi-freely with the help of distance restraints. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the Ueq value of the atoms they are linked to (1.5 times for methyl groups). The La- macrodipa dataset contains disordered solvent molecules of H2O that were included in the unit cell but could not be satisfactorily modeled. Therefore, those solvents were treated as diffuse contributions to the overall scattering without specific atom positions using the solvent mask routine in Olex2.15 The Lu-macrodipa stucture was refined as a two-component non-merohedral twin, BASF 0.4739(5). CCDC 2003601−2003603 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: +441223 336033. Table 8 provides X-ray crystal data and structure refinement details for La- macrodipa ([La(macrodipa)][ClO4] .DMF), Lu-macrodipa ([Lu(macrodipa)(OH2)][PF6] . 3H2O) and La-macrotripa ([La(macrotripa)][BPh4] .Et2O .MeCN) complexes. Table 8. X-ray crystal data and structure refinement details for La-macrodipa ([La(macrodipa)][ClO4] .DMF), Lu-macrodipa ([Lu(macrodipa)(OH2)][PF6] .3H2O) and La-macrotripa ([La(macrotripa)][BPh4] .Et2O .MeCN) complexes.
Figure imgf000119_0001
[00306] FIG.120 shows 1H NMR spectrum (500 MHz, D2O, pD ≈ 6, 25 °C) of [La(macrodipa)][ClO4] crystals. FIG.121 shows 1H NMR spectrum (500 MHz, CD3OD, 25 °C) of [Lu(macrodipa)(OH2)][PF6] crystals. FIG.122 shows 1H NMR spectrum (500 MHz, DMSO-d6, 25 °C) of [La(Hmacrotripa)][BPh4] crystals. FIG.123 shows 1H NMR spectrum (500 MHz, D2O, pD = 6–7, 25 °C) of [Lu(macrotripa)(OH2)] crystals. FIG.124 shows ESI-HRMS of La-macrodipa complex. MeCN was used as the mobile phase. FIG.125 shows ESI-HRMS of Lu-macrodipa complex. MeCN was used as the mobile phase. FIG.126 shows ESI-HRMS of La-macrotripa complex. MeCN was used as the mobile phase. FIG. 127 shows ESI-HRMS of Lu-macrotripa complex. MeCN was used as the mobile phase. [00307] DFT Calculations [00308] DFT calculations were executed using Gaussian 09.16 The geometries of complexes were optimized using the range-separated ωB97XD functional.17,18 The 6- 31G(d,p) basis set19,20 was used for light atoms (C, H, N, O), whereas the large-core relativistic effective core potential (LCRECP) and the associated (7s6p5d)/[5s4p3d] basis set21 was assigned to the lanthanide atoms. The LCRECP calculation includes (46 + 4fn) electrons in the core of the lanthanide, leaving the outermost 5s, 5p, 5d, and 6s electrons explicitly dealt with, and thus all calculations were performed in the pseudosinglet state. The use of the LCRECP for other Ln3+ complexes has been validated by previous studies22–24 and is justified by the fact that 4f orbitals do not have a significant contribution to bonding. In addition, frequency calculations were carried out on optimized geometries to confirm, via the absence of imaginary frequencies, that these structures are local minima on the potential energy surface. Zero-point energies were also afforded by the frequency calculations. The effect of the aqueous environment was considered using the polarizable continuum model (PCM) by a single-point calculation on the optimized structures. In particular, the SMD solvation model25 and the parameterized PCM radii of Ln3+ ions24 were applied in our computations. The initial geometries of complexes were taken from the crystal structures, and the La3+ or Lu3+ center was replaced with other Ln3+ ions when applicable. [00309] Data analysis. In order to further understand the unusual Ln3+-selectivity pattern of macrodipa, we performed DFT calculations on Ln-macrodipa complexes in both Conformation A and B. Their free energies in aqueous solution (G°(A, aq) and G°(B, aq)) are listed in Table 9. Table 9. Free energies in aqueous solution (G°(aq), kJ ^mol-1) of DFT-optimized Ln- macrodipa complexes (Conformation A and B) and H2O at 298 K. ΔG° = G°(B, aq) − G°(A, aq) − G°(H2O, l), Eq S1
Figure imgf000121_0001
Considering a bound H2O molecule is present in Conf B, G°(H2O, l) was also computed. To compare the relative energy difference of Conf A and Conf B (ΔG°), we applied the following reaction equation:
Figure imgf000121_0002
[00310] The terms G°(B, aq), G°(A, aq), and G°(H2O, l) were determined directly from the DFT calculations with corrections to the solvation models required for standard state conditions (see Eqs S21–S23). From now on, we use LA or LB to present the macrodipa ligand with a Conf A geometry or a Conf B geometry for simplicity. Thus, Eq S1 is rewritten in a simpler way as [00311] The ΔG° value for this conformation switch can be expressed as the sum of three different free energy contributions: relative ligand strain energy (ΔΔGS°), relative binding energy (ΔΔGB°), and relative solvation energy (ΔΔGsolv°) between Conf A and Conf B. Ligand strain energy ΔGS° is the standard free energy required to change the free ligand from a fully relaxed conformation to the conformation that is attained when found in the Ln3+ complex in the gas phase. Binding energy ΔGB° is the standard free energy for the binding process of a Ln3+ ion to the ligand in the prearranged conformation in the gas phase. Solvation energy ΔGsolv° is the standard free energy associated with moving the complexes from the gas phase into aqueous solution. The formula derivation is represented as below. [00312] The formation reaction of Ln-macrodipa complex in Conf A, [LnLA]+(aq), can be written as Ln3+(aq) + LA2−(aq) → [LnLA]+(aq); ΔG°(A) = G°(A, aq) − G°(Ln, aq) − G°(LA, aq). (S2)
[00313] We can express Eq S2 with following equations (S2 = S3 + S4 – S5 − S6 + S7): L2−(g) → LA2−(g); ΔGS°(A) = G°(LA, g) − G°(L, g). (S3) Ln3+(g) + LA2−(g) → [LnLA]+(g); ΔGB°(A) = G°(A, g) − G°(LA, g). (S4) Ln3+(g) → Ln3+(aq); ΔGS°(Ln) = G°(Ln, aq) − G°(Ln, g). (S5) L2−(g) → L2−(aq); ΔGS°(L) = G°(L, aq) − G°(L, g). (S6) [LnLA]+(g) → [LnLA]+(aq); ΔGsolv°(A) = G°(A, aq) − G°(A, g). (S7) [00314] Eq S3 shows the ligand conformational rearrangement from the initial conformation L(g) in the complex formation, and the free energy change in this process is the ligand strain energy for Conf A, ΔGS°(A). Eq S4 shows the metal-ligand binding process in the complex formation, and the free energy change for this process is the binding energy for Conf A, ΔGB°(A). Eqs S5−7 are the solvation processes for involved species. The solvation energies for Ln, L, and LnLA are noted as ΔGS°(Ln), ΔGS°(L), and ΔGS°(A), respectively. With Hess’s law, ΔG°(A) is expressed as ΔG°(A) = ΔGS°(A) + ΔGB°(A) − ΔGsolv°(Ln) − ΔGsolv°(L) + ΔGsolv°(A). (S8) [00315] The formation reaction of Ln-macrodipa complex in Conf B, [LnLB(OH + 2)] (aq), can be written as [00316] Ln3+(aq) + L 2−(aq) +H O(l) → [LnL (OH )]+(aq); ΔG°(B) = G°(B, aq) − G°(Ln, aq) − G°(LB, aq) − G°(H2O, l). (S9) [00317] Similarly, we can express Eq S9 with following equations (S9 = S10 + S11 − S5 − S6 – S12 + S13): [00318] Analogously, ΔGS°(B) is the ligand strain energy for Conf B. ΔGB°(B) is the binding energy for Conf B ΔGsolv°(Ln) ΔGsolv°(L), ΔGsolv°(H2O), and ΔGsolv°(B) are the solvation energies for Ln, L, H2O, and LnLB(OH2). With Hess’s law, ΔG°(B) is expressed as ΔG°(B) = ΔGS°(B) + ΔGB°(B) – ΔGsolv°(Ln) – ΔGsolv°(L) – ΔGsolv°(H2O) + ΔGS°(B). (S14) [00319] Note that reaction S1 = S9 – S2. With Hess’s law, we can obtain an expression of ΔG° as ΔG° = ΔG°(B) – ΔG°(A) = [ΔGS°(B) – ΔGS°(A)] + [ΔGb°(B) – ΔGb°(A)] + [ΔGsolv°(B) – ΔGsolv°(A) – ΔGsolv°(H2O)] (S15) [00320] These three terms in Eq S15 are defined as relative ligand strain energy ΔΔGS° = ΔGS°(B) – ΔGS°(A); (S16) relative binding energy ΔΔGB° = ΔGB°(B) – ΔGB°(A); (S17) relative solvation energy ΔΔGsolv° = ΔGsolv°(B) – ΔGsolv°(A) – ΔGsolv°(H2O). (S18) [00321] Therefore, Eq S15 can be simplified to Eq S19. It shows the competition between Conf A and Conf B are accounted for by three contributions: ΔΔGS°, ΔΔGB°, and ΔΔGsolv°. ΔG° = ΔΔGS° + ΔΔGB° + ΔΔGsolv°. (S19) [00322] With Eqs S3 and S10, ΔΔGS° can be obtained by Eq S20. In this case, the unknown G°(L, g) is canceled out. ΔΔGS° = ΔGS°(B) – ΔGS°(A) = G°(LB, g) − G°(LA, g). (S20) [00323] The values of G°(LA, g) and G°(LB, g) were calculated by determining the standard free energies of the ligands in their respective metal-binding conformations. [00324] Note that all equations above are discussed in the standard states (°). All computations were carried out at 298 K and 1 atm, which is the standard state for gases, and thus no further correction is needed for gaseous species. However, when calculating the solvation energies (Eqs S7, S12, S13), corrections are needed to afford the standard-state free energies. The standard states for [LnLA]+(aq) and [LnLB(OH + 2)] (aq) are 298 K and 1 M, whereas for H2O(l) its standard state is 298 K and 55.5 M (the molarity of pure water). A pressure of 1 atm corresponds to a molarity of 1/24.5 M at 298 K as derived from the ideal gas law. ΔGsolv is used to note the energy afforded by SMD method. Therefore, the solvation energies for Eq S7, S12, S13 in the standard states are ΔGsolv°(A) = ΔGsolv(A) + RT ln (1 M/1 atm) = ΔGsolv(A) + RT ln 24.5 = ΔGsolv(A) + 7.9 kJ ^mol-1; (S21) ΔGsolv°(B) = ΔGsolv(B) + RT ln (1 M/1 atm) = ΔGsolv(B) + RT ln 24.5 = ΔGsolv(B) + 7.9 kJ ^mol-1; (S22) ΔGsolv°(H2O) = ΔGsolv(H2O) + RT ln (55.5 M/1 atm) = ΔGsolv(H2O) + RT ln 1360 = ΔGsolv(H -1 2O) + 17.9 kJ ^mol . (S23) [00325] As a result, Eq S18 can be written as ΔΔGsolv° = ΔGsolv(B) – ΔGsolv(A) – ΔGsolv(H2O) – 17.9 kJ/mol. (S24)
[00326] The effects from these three factors were analyzed for all Ln-macrodipa complexes. Computed ΔΔGS°, ΔΔGB°, and ΔΔGsolv° values are listed in Tables 10-12. Table 10. Relative ligand strain energies (ΔΔGS°, kJ .mol-1) for Ln-macrodipa complexes. ΔΔGS° = G°(LB, g) − G°(LA, g), Eq S20
Figure imgf000126_0001
Table 11. Relative binding energies (ΔΔGB°, kJ .mol-1) for Ln-macrodipa complexes. ΔΔGB° = ΔGB°(B) – ΔGB°(A), Eq S17.
Figure imgf000127_0001
Table 12. Relative solvation energies (ΔΔG solv °, kJ ^mol-1) for Ln-macrodipa complexes. ΔΔG solv ° = ΔG solv (B) – ΔG solv (A) – ΔG solv (H 2 O) – 17.9 kJ/mol, Eq S24.
Figure imgf000128_0001
[00327] References of Example 2 (1) Griffin, J. L. W.; Coveney, P. V; Whiting, A.; Davey, R. Design and Synthesis of Macrocyclic Ligands for Specific Interaction with Crystalline Ettringite and Demonstration of a Viable Mechanism for the Setting of Cement. J. Chem. Soc., Perkin Trans. 21999, 1973– 1981. (2) Lukyanenko, N. G.; Basok, S. S.; Filonova, L. K. Macroheterocycles. Part 44. Facile Synthesis of Azacrown Ethers and Cryptands in a Two-Phase System. J. Chem. Soc., Perkin Trans. 11988, 3141–3147. (3) Mato-Iglesias, M.; Roca-Sabio, A.; Pálinkás, Z.; Esteban-Gómez, D.; Platas-Iglesias, C.; Tóth, É.; de Blas, A.; Rodríguez-Blas, T. Lanthanide Complexes Based on a 1,7-Diaza- 12- crown-4 Platform Containing Picolinate Pendants: A New Structural Entry for the Design of Magnetic Resonance Imaging Contrast Agents. Inorg. Chem. 2008, 47, 7840–7851. (4) Sweeton, F. H.; Mesmer, R. E.; Baes, C. F. Acidity Measurements at Elevated Temperatures. VII. Dissociation of Water. J. Solution Chem.1974, 3, 191–214. (5) Gans, P.; O’Sullivan, B. GLEE, a New Computer Program for Glass Electrode Calibration. Talanta 2000, 51, 33–37. (6) Wuhan University. Analytical Chemistry I, 5th ed.; Higher Education Press: Beijing, 2006. (7) Gans, P.; Sabatini, A.; Vacca, A. Investigation of Equilibria in Solution. Determination of Equilibrium Constants with the HYPERQUAD Suite of Programs. Talanta 1996, 43, 1739– 1753. (8) Hu, A.; Keresztes, I.; MacMillan, S. N.; Yang, Y.; Ding, E.; Zipfel, W. R.; DiStasio, R. A., Jr.; Babich, J. W.; Wilson, J. J. Oxyaapa: A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides. Inorg. Chem.2020, 59, 5116–5132. (9) Roca-Sabio, A.; Mato-Iglesias, M.; Esteban-Gómez, D.; Tóth, É.; de Blas, A.; Platas- Iglesias, C.; Rodríguez-Blas, T. Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides. J. Am. Chem. Soc.2009, 131, 3331–3341. (10) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities. J. Org. Chem.1997, 62, 7512–7515. (11) CrysAlisPro; Rigaku OD: The Woodlands, TX, 2015. (12) Sheldrick, G. M. SHELXT – Integrated Space-Group and Crystal-Structure Determination. Acta Crystallogr., Sect. A: Found. Adv.2015, 71, 3–8. (13) Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr.2008, 64, 112–122. (14) Müller, P. Practical Suggestions for Better Crystal Structures. Crystallogr. Rev.2009, 15, 57–83. (15) Dolomanov, O. V; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr.2009, 42, 339–341. (16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J; Ishida, M.; Nakajima, T.; Honda, Y; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr., Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand J; Raghavachari K; Rendell A; Burant J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009. (17) Chai, J.-D.; Head-Gordon, M. Systematic Optimization of Long-Range Corrected Hybrid Density Functionals. J. Chem. Phys.2008, 128, 084106. (18) Chai, J.-D.; Head-Gordon, M. Long-Range Corrected Hybrid Density Functionals with Damped Atom–Atom Dispersion Corrections. Phys. Chem. Chem. Phys.2008, 10, 6615– 6620. (19) Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self-Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. J. Chem. Phys.1972, 56, 2257–2261. (20) Hariharan, P. C.; Pople, J. A. The Influence of Polarization Functions on Molecular Orbital Hydrogenation Energies. Theor. Chim. Acta 1973, 28, 213–222. (21) Dolg, M.; Stoll, H.; Savin, A.; Preuss, H. Energy-Adjusted Pseudopotentials for the Rare Earth Elements. Theor. Chim. Acta 1989, 75, 173–194. (22) Maron, L.; Eisenstein, O. Do f Electrons Play a Role in the Lanthanide−Ligand Bonds? A DFT Study of Ln(NR 2 ) 3 ; R = H, SiH 3 . J. Phys. Chem. A 2000, 104, 7140–7143. (23) Eisenstein, O.; Maron, L. DFT Studies of Some Structures and Reactions of Lanthanides Complexes. J. Organomet. Chem.2002, 647, 190–197. (24) Regueiro-Figueroa, M.; Esteban-Gómez, D.; de Blas, A.; Rodríguez-Blas, T.; Platas- Iglesias, C. Understanding Stability Trends along the Lanthanide Series. Chem. - Eur. J. 2014, 20, 3974–3981. (25) Marenich, A. V; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378–6396. Example 3: Exemplary Results [00328] Three types of selectivity patterns have been identified previously (FIG.25). The most common trend shows a systematic increase in KLnL across the lanthanide series (type I). This type I behavior is observed for many well-known ligands including EDTA12, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA),13 and diethylenetriaminepentaacetic acid (DTPA) [00329] The syntheses of macrodipa and macrotripa involved the assembly of the tosyl- protected 18-crown-6 macrocycles, deprotection of the tosyl groups, and subsequent alkylation of the picolinate donor arms. They were characterized by NMR spectroscopy, mass spectrometry, and HPLC (FIGs. 31-40). [00330] Potentiometric titrations were performed to determine their protonation constants (Ki, Table 14, FIGs. 41-70). To probe the thermody- namic affinities of these ligands for Ln3+ ions, we conducted potentiometric titrations to obtain their stability constants (KLnL and KLnHL, Table 13). These protonation and stability constants are defined in eqs 1−3, with the concentrations of all species at chemical equilibrium.
Figure imgf000131_0001
Table 13. Stability Constants of the Lanthanide Complexes Formed with Macrodipa, Macrotripa, OxyMepa, Macropa, EDTA, and
OBETA
Figure imgf000132_0001
Table 14. Protonation constant of macrodipa, macrotripa, OxyMepa, and macropa.
Figure imgf000133_0001
[00331] FIG.26 shows a plot of log KLnL versus the Ln3+ ionic radius28 for both macrodipa and macrotripa, which reveals them to be the first known ligands that exhibit type IV selectivity. In comparing the log KLnL values between Ln3+-macrodipa and Ln3+- macrotripa systems, they are similar for early lanthanides, La3+−Gd3+. Ln3+-macrodipa reaches a minimum for Dy3+ and Ho3+, whereas for macrotripa the minimum occurs earlier in the series, between Gd3+ and Tb3+. For late lanthanides, the macrotripa complexes are significantly more stable than those of macrodipa. [00332] The log KLnHL values, which represent the protonation of LnL complex, are also noteworthy. These values were not found for Ln3+-macrodipa complexes but were observed for Ln3+-macro- tripa complexes. Comparing the chemical structures of macro- dipa and macrotripa and their complexes (vide infra), it can be reasonably inferred that this protonation event occurs on the third picolinate arm in macrotripa. The KLnHL values of the macrotripa complexes remain steady from La3+ to Pr3+, but then increase abruptly from Nd3+ to Tb3+, before leveling off from Dy3+ to Lu3+. The sudden change in log KLnHL implies that a conformational change may be present for Ln3+-macrotripa complexs when crossing the Ln3+ series. [00333] To gain insight on the type IV selectivity of macrodipa and macrotripa, we analyzed their complexes of the largest and smallest lanthanides, La3+ and Lu3+, by NMR spectroscopy. These diamagnetic La3+ and Lu3+ complexes were characterized by 1H, 13C{1H}, and 2D (HSQC, HMBC, COSY, ROESY) NMR spectroscopy in D2O at pD=7 (FIG.27 and FIGs.71-110 ). The 1H NMR spectra of all four complexes indicate that a single species is present in solution. However, significant differences are apparent in comparing the La3+ and Lu3+ complexes. For example, the La3+-macrodipa complex is 2-fold symmetric, indicated by one-half the number of 1H and 13C resonances relative to the asymmetric Lu3+-macrodipa complex. [00334] Additionally, the hydrogen resonances from the methylene groups linking the crown and picolinate donors (H-13, H-20 for macrodipa, and H-13, H-20, H-27 for macrotripa; Scheme 6), which are informative due to their proximities to the picolinate donors, are significantly different between the La3+ and Lu3+ complexes. For example, the peaks for the diastereotopic H-27′ and H-27″ in the La3+-macrotripa case are well- separated, whereas for Lu3+-macrotripa they have near-identical chemical shifts. Collectively, these NMR data suggest that there is a significant conformational difference between the La3+ and Lu3+ complexes of these ligands. Scheme 6. Structures of Ligands Discussed
Figure imgf000135_0001
Figure imgf000135_0002
[00335] To further explore these different conformations, we characterized these complexes by X-ray crystallography. Crystal structures of [La(macrodipa)]+, [Lu(macrodipa)(OH2)]+, and [La(macrotripa)]+ are shown in FIG. 28. A weakly diffracting and partially twinned crystal of [Lu(macrotripa)(OH2)] was also obtained, but the connectivity information was reliably ascertained (FIG. 119). Confirming the NMR spectroscopic data, the La3+ complexes attain a significantly different conformation than do the Lu3+ complexes. In both La3+ structures, this ion is encapsulated into the 18- membered macrocyclic core, which interacts with all of its six donor atoms. Moreover, the pendent picolinate groups bind to La3+ from two opposite faces of the macrocycle, resulting in 10-coordinate complexes. The third picolinate donor of macrotripa does not participate in coordination. Consistent with its NMR spectra, [La(macrodipa)]+ attains a slightly distorted C2 symmetry. By contrast, both Lu3+ structures show significantly different coordination environments. Specifically, only two tertiary nitrogens and one ethereal oxygen from the macrocycle act as donors. The coordination sphere is completed with the four donor atoms from two picolinate groups and an inner-sphere water molecule, yielding 8-coordinate Lu3+ centers. In [Lu- (macrotripa)(OH2)], the third unbound picolinate donor is positioned to interact with the bound water molecule through hydrogen bonding. Except for the macrocycle, these Lu3+ structures are highly comparable to those found for the acyclic ligand OxyMepa,27 which displays type I selectivity, indicating that the complete 18-crown-6 macrocycles of macrodipa and macrotripa are critical for their unique Ln3+-selectivity profiles. [00336] As a further validation on the proposed intramolecular hydrogen bond in [Lu(macrotripa)(OH2)], we optimized its structure (FIG.128) using validated DFT methods (vide infra) and carried out a topological analysis of the electron density using the quantum theory of atoms in molecules (QTAIM).29 Specifically, we found all bond critical points (BCP) with the Multiwfn30 program (FIG.129). A BCP was located between a hydrogen atom of the coordinated water molecule and the oxygen atom of the pendent picolinate group. At this BCP, the magnitude of its local electron density (ρ) is 0.079 au, and the Laplacian of the electron density 2
Figure imgf000136_0001
is 0.16 au. The positive value for ∇ ρ reflects a closed-shell hydrogen bond, and the magnitude of ρ suggests that this interaction is strong, comparable to that found between OH− and H2O.31−33 This analysis supports the proposed intramolecular hydrogen- bonding interaction present in [Lu(macrotripa)(OH2)]. [00337] On the basis of the NMR and X-ray crystallographic data, it is clear that macrodipa and macrotripa attain distinct conforma- tions depending on whether they bind large or small Ln3+ ions (FIG.30). Large ions, like La3+, attain Conformation A, in which the ion is fully encapsulated by the macrocycle, whereas small ions, like Lu3+, sit in Conformation B, held by only part of the macrocycle. The ability of these ligands to drastically alter their conformations to match the sizes of metal ions accounts for the type IV selectivity pattern. The structures may also explain the difference in thermodynamic stability of macrodipa and macrotripa for the late, but not early, Ln3+ (FIG.26). Both ligands give rise to identical coordination spheres for the large early lanthanides, like La3+, and therefore exhibit only minor differences in their thermodynamic stabilities. However, for the small late lanthanides, like Lu3+, the inner coordination spheres are nearly identical between macrodipa and macrotripa, but the outer sphere differs due to the hydrogen-bonding interaction with the coordinated water molecule. Thus, the differences in thermodynamic stability between the macrodipa and macrotripa complexes of the late lanthanides are most likely a consequence of the hydrogen bonding of the pendent picolinate donor arm. This result highlights how modifying the outer coordination sphere of lanthanide complexes fine-tunes their thermodynamic properties. [00338] As a further test of this conformational toggle, we investigated the complexes of Y3+, a diamagnetic Ln3+ analogue with an ionic radius comparable to that of Ho3+,7,28 by NMR spectroscopy. The 1H and 13C{1H} NMR spectra of Y3+-macrodipa and Y3+- macrotripa were acquired in D2O at pD=7 (FIGs.111-118). Both Conformations A and B are detected for Y3+-macrodipa, in a molar ratio of 1:15. For the Y3+-macrotripa complex, only Conformation B is observed. The 90-pm ionic radius of Y3+ places its macrodipa complex near the local minimum of log KLnL, but its macrotripa complex is placed rather far from the minimum (FIG.26). Thus, these NMR data show that the conformational switch occurs for complexes of ions with their radii near the minimum of stability; larger and smaller ions show preferences for Conformations A and B, respectively. [00339] DFT has been extensively used to investigate the properties of Ln3+ coordination compounds.34−36 In this study, we took advantage of this powerful tool to help understand the origin of the type IV selectivity pattern of these ligands. We focused exclusively on the Ln3+-macrodipa system. These complexes lack the third noncoordinated picolinate arm of the Ln3+-macrotripa and therefore provide a straightforward system to model the inner coordination spheres of these complexes. DFT calcu- lations were executed using Gaussian 0937 with the ωB97XD functional.38,39 This functional, which is long-range corrected and includes dispersion corrections, has been shown to give accurate geometries of Ln3+ complexes.40 Because of the importance of relativistic effects in Ln3+ ions,41 we used the large-core relativistic effective core potential (LCRECP) by Dolg42 to account for these effects in a computationally efficient manner. For light atoms, the 6-31G(d,p) basis set43,44 was applied. The SMD solvation model45,46 was implemented to take the solvent effects into consideration. The ΔG° for the conformational equilibrium: was calculated for Ln3+-macrodipa complexes. The ΔG° (FIG. 29) is positive for light Ln3+ and negative for heavy Ln3+. This observation is consistent with the experimental results with La3+- macrodipa and Lu3+-macrodipa complexes attaining Conforma- tions A and B, respectively. Additionally, ΔG° changes its sign between Gd3+ and Tb3+, which indicates the switch of favored conformation. This crossover suggests that the type IV behavior of macrodipa is a consequence of the significant conformational changes that occur when binding Ln3+ ions of different sizes. [00340] Furthermore, ΔG° for this conformational change can be broken into three contributors. Specifically, it can be expressed as the sum of the relative ligand strain energies (ΔΔGS°), relative metal−ligand binding energies (ΔΔGB°), and relative solvation energies (ΔΔGsolv°) between Conformations A and B. As shown in FIG. 29, ΔΔGsolv° is positive for all Ln3+ complexes, which reveals that Conformer A and the noncoordinated water ligand are better solvated in aqueous solution than is Conformer B. Likewise, ΔΔGB° is positive for all Ln3+, which indicates that Conformation A is better suited to neutralize the electrostatic charges of these ions than is Conformation B. This observation can be rationalized by the fact that Conformation A interacts with the Ln3+ with two more donor atoms. However, ΔΔGB° decreases as the Ln3+ gets smaller, which suggests that Conformation A is less effective at binding the smaller ions. By contrast, ΔΔGS° is negative across the entire series, which shows that Conformation B requires less ligand strain than does Conformation A. Among the three values, ΔΔGS° shows the most significant changes as a function of the Ln3+ ionic radius, and it becomes more negative for smaller ions. Importantly, the strain energy is the only exothermic term for the switch from Conformation A to B, and thus it is the driving factor in the conformational switch of macrodipa. This result suggests that modifications of this ligand scaffold to alter the strain energy term could lead to a significant shift in the Ln3+-stability pattern for this ligand class. [00341] References of Example 3 (1) Cheisson, T.; Schelter, E. J. Rare Earth Elements: Mendeleev’s Bane, Modern Marvels. Science 2019, 363, 489−493. (2) Woodruff, D. N.; Winpenny, R. E. P.; Layfield, R. A. Lanthanide Single-Molecule Magnets. Chem. Rev.2013, 113, 5110−5148. (3) Dos santos-García, A. J.; Alario-Franco, M. Á.; Saéz-Puche, R. The Rare Earth Elements: Superconducting Materials. Encyclopedia of Inorganic and Bioinorganic Chemistry; John Wiley & Sons, Ltd.: Chichester, UK, 2012. (4) Pellissier, H. Recent Developments in Enantioselective Lanthanide-Catalyzed transformations. Coord. Chem. Rev.2017, 336, 96−151. (5) Qin, X.; Liu, X.; Huang, W.; Bettinelli, M.; Liu, X. Lanthanide- Activated Phosphors Based on 4f-5d Optical Transitions: Theoretical and Experimental Aspects. Chem. Rev.2017, 117, 4488−4527. (6) Teo, R. D.; Termini, J.; Gray, H. B. Lanthanides: Applications in Cancer Diagnosis and Therapy. J. Med. Chem.2016, 59, 6012−6024. (7) Cotton, S. A. Scandium, Yttrium & the Lanthanides: Inorganic & Coordination Chemistry. Encyclopedia of Inorganic Chemistry; John Wiley & Sons, Ltd.: Chichester, UK, 2006. (8) Huang, C.; Bian, Z. Introduction. In Rare Earth Coordination Chemistry: Fundamentals and Applications; Huang, C., Ed.; John Wiley & Sons (Asia) Pte Ltd.: Singapore, 2010; pp 1−39. (9) Seitz, M.; Oliver, A. G.; Raymond, K. N. The Lanthanide Contraction Revisited. J. Am. Chem. Soc. 2007, 129, 11153−11160. (10) Peters, J. A.; Djanashvili, K.; Geraldes, C. F. G. C.; Platas-Iglesias, C. The Chemical Consequences of the Gradual Decrease of the Ionic Radius along the Ln-Series. Coord. Chem. Rev.2020, 406, 213146. (11) Piguet, C.; Bünzli, J.-C. G. Mono- and Polymetallic Lanthanide- Containing Functional Assemblies: A Field between Tradition and Novelty. Chem. Soc. Rev.1999, 28, 347−358. (12) Martell, A. E.; Smith, R. M. Critical Stability Constants; Plenum Press: New York, 1974; Vol.1. (13) Cacheris, W. P.; Nickle, S. K.; Sherry, A. D. Thermodynamic study of Lanthanide Complexes of 1,4,7-Triazacyclononane-N,N′,N″- triacetic Acid and 1,4,7,10- Tetraazacyclododecane-N,N′,N″,N‴-tetra- acetic Acid. Inorg. Chem.1987, 26, 958−960. (14) Moeller, T.; Thompson, L. C. Observations on the Rare Earths LXXV: The Stabilities of Diethylenetriaminepentaacetic Acid Chelates. J. Inorg. Nucl. Chem.1962, 24, 499−510. (15) Grimes, T. S.; Nash, K. L. Acid Dissociation Constants and Rare Earth Stability Constants for DTPA. J. Solution Chem.2014, 43, 298− 313. (16) Baranyai, Z.; Botta, M.; Fekete, M.; Giovenzana, G. B.; Negri, R.; Tei, L.; Platas-Iglesias, C. Lower Ligand Denticity Leading to Improved Thermodynamic and Kinetic Stability of the Gd3+ Complex: The Strange Case of OBETA. Chem. - Eur. J.2012, 18, 7680−7685. (17) Negri, R.; Baranyai, Z.; Tei, L.; Giovenzana, G. B.; Platas-Iglesias, C.; Benýei, A. C.; Bodnar,́ J.; Vagńer, A.; Botta, M. Lower Denticity Leading to Higher Stability: Structural and Solution Studies of Ln(III)−OBETA Complexes. Inorg. Chem. 2014, 53, 12499−12511. (18) Voss, D. A., Jr.; Farquhar, E. R.; Horrocks, W. D., Jr.; Morrow, J. R. Lanthanide(III) Complexes of Amide Derivatives of DOTA Exhibit an Unusual Variation in Stability across the Lanthanide Series. Inorg. Chim. Acta 2004, 357, 859−863. (19) Roca-Sabio, A.; Mato-Iglesias, M.; Esteban-Gomeź, D.; Toth́, É.; de Blas, A.; Platas- Iglesias, C.; Rodríguez-Blas, T. Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides. J. Am. Chem. Soc.2009, 131, 3331−3341. (20) Chang, C. A.; Rowland, M. E. Metal Complex Formation with 1,10-Diaza-4,7,13,16-tetraoxacyclooctadecane-N,N′-diacetic Acid. An Approach to Potential Lanthanide Ion Selective Reagents. Inorg. Chem.1983, 22, 3866−3869. (21) Thiele, N. A.; Brown, V.; Kelly, J. M.; Amor-Coarasa, A.; Jermilova, U.; MacMillan, S. N.; Nikolopoulou, A.; Ponnala, S.; Ramogida, C. F.; Robertson, A. K. H.; Rodríguez- Rodríguez, C.; Schaffer, P.; Williams, C., Jr.; Babich, J. W.; Radchenko, V.; Wilson, J. J. An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy. Angew. Chem., Int. Ed.2017, 56, 14712− 14717. (22) Thiele, N. A.; MacMillan, S. N.; Wilson, J. J. Rapid Dissolution of BaSO4 by Macropa, an 18-Membered Macrocycle with High Affinity for Ba2+. J. Am. Chem. Soc.2018, 140, 17071−17078. (23) Thiele, N. A.; Woods, J. J.; Wilson, J. J. Implementing f-Block Metal Ions in Medicine: Tuning the Size Selectivity of Expanded Macrocycles. Inorg. Chem.2019, 58, 10483−10500. (24) Aluicio-Sarduy, E.; Thiele, N. A.; Martin, K. E.; Vaughn, B. A.; Devaraj, J.; Olson, A. P.; Barnhart, T. E.; Wilson, J. J.; Boros, E.; Engle, J. W. Establishing Radiolanthanum Chemistry for Targeted Nuclear Medicine Applications. Chem. - Eur. J.2020, 26, 1238−1242. (25) Chen, D.; Squattrito, P. J.; Martell, A. E.; Clearfield, A. Synthesis and Crystal Structure of a Nine-Coordinate Gadolinium(III) Complex of 1,7,13-Triaza-4,10,16- trioxacyclooctadecane-N,N′,N″-triacetic Acid. Inorg. Chem.1990, 29, 4366−4368. (26) Delgado, R.; Sun, Y.; Motekaitis, R. J.; Martell, A. E. Stabilities of Divalent and Trivalent Metal Ion Complexes of Macrocyclic Triazatri- acetic Acids. Inorg. Chem.1993, 32, 3320−3326. (27) Hu, A.; Keresztes, I.; MacMillan, S. N.; Yang, Y.; Ding, E.; Zipfel, W. R.; DiStasio, R. A., Jr.; Babich, J. W.; Wilson, J. J. Oxyaapa: A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides. Inorg. Chem.2020, 59, 5116−5132. (28) Shannon, R. D. Revised Effective Ionic Radii and Systematic Studies of Interatomic Distances in Halides and Chalcogenides. Acta Crystallogr., Sect. A: Found. Adv.1976, 32, 751−767. (29) Bader, R. F. W. Atoms in Molecules − A Quantum Theory; Oxford University Press: Oxford, 1990. (30) Lu, T.; Chen, F. Multiwfn: A Multifunctional Wavefunction Analyzer. J. Comput. Chem.2012, 33, 580−592. (31) Bader, R. F. W. A Quantum Theory of Molecular Structure and Its Applications. Chem. Rev.1991, 91, 893−928. (32) Grabowski, S. J.; Robinson, T. L.; Leszczynski, J. Strong Dihydrogen Bonds - ab initio and Atoms in Molecules Study. Chem. Phys. Lett.2004, 386, 44−48. (33) Parthasarathi, R.; Subramanian, V.; Sathyamurthy, N. Hydrogen Bonding without Borders: An Atoms-in-Molecules Perspective. J. Phys. Chem. A 2006, 110, 3349−3351. (34) Tsipis, A. C. DFT Flavor of Coordination Chemistry. Coord. Chem. Rev.2014, 272, 1−29. (35) Platas-Iglesias, C.; Roca-Sabio, A.; Regueiro-Figueroa, M.; Esteban-Gomeź, D.; de Blas, A.; Rodriguez-Blas, T. Applications of Density Functional Theory (DFT) to Investigate the Structural, Spectroscopic and Magnetic Properties of Lanthanide(III) Complexes. Curr. Inorg. Chem.2011, 1, 91−116. (36) Platas-Iglesias, C. The Solution Structure and Dynamics of MRI Probes Based on Lanthanide(III) DOTA as Investigated by DFT and NMR Spectroscopy. Eur. J. Inorg. Chem. 2012, 2012, 2023−2033. (37) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009. (38) Chai, J.-D.; Head-Gordon, M. Systematic Optimization of Long- Range Corrected Hybrid Density Functionals. J. Chem. Phys.2008, 128, 084106. (39) Chai, J.-D.; Head-Gordon, M. Long-Range Corrected Hybrid Density Functionals with Damped Atom-Atom Dispersion Correc- tions. Phys. Chem. Chem. Phys.2008, 10, 6615−6620. (40) Roca-Sabio, A.; Regueiro-Figueroa, M.; Esteban-Goḿez, D.; de Blas, A.; Rodríguez- Blas, T.; Platas-Iglesias, C. Density Functional Dependence of Molecular Geometries in Lanthanide(III) Complexes Relevant to Bioanalytical and Biomedical Applications. Comput. Theor. Chem.2012, 999, 93−104. (41) Barysz, M.; Ishikawa, Y. Relativistic Methods for Chemists; Springer Science+Business Media B.V.: Dordrecht, 2010. (42) Dolg, M.; Stoll, H.; Savin, A.; Preuss, H. Energy-Adjusted Pseudopotentials for the Rare Earth Elements. Theor. Chim. Acta 1989, 75, 173−194. (43) Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self-Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. J. Chem. Phys.1972, 56, 2257−2261. (44) Hariharan, P. C.; Pople, J. A. The Influence of Polarization Functions on Molecular Orbital Hydrogenation Energies. Theor. Chim. Acta 1973, 28, 213−222. (45) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378−6396. (46) Regueiro-Figueroa, M.; Esteban-Gómez, D.; de Blas, A.; Rodríguez-Blas, T.; Platas- Iglesias, C. Understanding Stability Trends along the Lanthanide Series. Chem. - Eur. J.2014, 20, 3974−3981. Example 4 [00342] In this example, macrodipa and py-macrodipa were evaluated for their ability to complex 225Ac3+ and 213Bi3+. Radiolabeling studies were conducted, revealing the efficient incorporation of both 225Ac3+ and 213Bi3+ by py-macrodipa that matches or surpasses the well- known chelators macropa and DOTA. Incubation in human serum at 37 °C showed that ~90% of the 225Ac3+−py-macrodipa complex dissociates after 1 d. The Bi3+−py-macrodipa complex possesses remarkable kinetic inertness in an EDTA transchelation challenge study, surpassing that of Bi3+−macropa. [00343] Production of 225Ac and 213Bi Radionuclides: 225Ac was produced from irradiated thorium (232Th(p,x)225/227Ac†), herein referred to as 225/227Ac† where the “†” symbol denotes “first-pass 225Ac”, where separation of 225/227Ac† from irradiated thorium was performed as described in Robertson, A. K. H.; McNeil, B. L.; Yang, H.; Gendron, D.; Perron, R.; Radchenko, V.; Zeisler, S.; Causey, P.; Schaffer, P.232Th-Spallation-Produced 225Ac with Reduced 227Ac Content. Inorg. Chem.2020, 59, 12156–12165. Isolation of 213Bi from 225Ac was performed using an analogous approach to previously reported methods for clinically proven generator systems. See Ma, D.; McDevitt, M. R.; Finn, R. D.; Scheinberg, D. A. Breakthrough of 225Ac and Its Radionuclide Daughters from an 225Ac/213Bi Generator: Development of New Methods, Quantitative Characterization, and Implications for Clinical Use. Appl. Radiat. Isot.2001, 55, 667–678; McDevitt, M. R.; Finn, R. D.; Sgouros, G.; Ma, D.; Scheinberg, D. A. An 225Ac/213Bi Generator System for Therapeutic Clinical Applications: Construction and Operation. Appl. Radiat. Isot.1999, 50, 895–904. AGMP-50 cation exchange resin (50 mg) was packed into a 1 mL reservoir, equipped with polyethylene frits and pre-equilibrated with 4 M HNO3 (2 mL). Approximately 6.5 MBq of 225/227Ac† in 4 M HNO3 (620 μL) was loaded onto the column. After washing the column with 4 M HNO3 (2 mL), 213Bi was eluted with freshly prepared 0.2 M NaI/0.1 M HCl solution (300−600 µL), wherein the bulk of the activity was eluted in the first 150 µL. Subsequent elutions (with or without 2 mL of 1 mM HCl prewash of the generator) proceeded no earlier than 3 hours after the last elution, therefore optimizing the ratio of 213Bi to the amount of other radionuclide impurities such as 209Pb and 209Bi. The generator was sealed between each elution to minimize evaporation from the resin.213Bi activity and radionuclidic purity was determined using a High Purity Germanium (HPGe) detector (Mirion Technologies (Canberra) Inc.) with Genie 2000 software by measurement of gamma emission line of 213Bi (t1/2 = 45.6 min, 440 keV, 25.9% abundance) and 221Fr (t1/2 = 4.9 min, 218 keV, 11.6% abundance). [00344] Radiolabeling Studies: [00345] Stock solutions (1 × 10−2 and 1 × 10−3 M) of macrodipa, py-macrodipa, macropa, and DOTA were made with ultra-pure deionized water. Serial dilutions were used to prepare initial ligand solutions of 10−4 M, 10−5 M, 10−6 M, 10−7 M with ultra-pure water. Concentration-dependent radiolabeling studies for 225/227Ac† were performed by the addition of 225/227Ac† (10 µL, 20–40 kBq) to a solution containing ligand sock (10 µL; or deionized water for negative controls) in NH4OAc buffer (0.5 M, pH 5.5, 6 and/or 7). ^ macropa – 0.5 M NH4OAc pH 6 ^ macrodipa – 0.5 M NH4OAc pH 5.5 or 7 ^ py-macrodipa – 0.5 M NH4OAc pH 5.5 or 7 ^ DOTA – 0.5 M NH4OAc pH 5.5 [00346] Concentration-dependent radiolabeling studies for 213Bi were performed by the addition of [213Bi]BiI4 −/[213Bi]BiI5 2− (30−300 kBq) to a solution containing ligand sock (10 µL; or deionized water for negative controls) in 2-(N-morpholino)ethanesulfonic acid (MES) buffer (80 µL; 0.5 M, pH 5.5−6). All 213Bi3+ radiolabeling studies were carried out within 5 min post-elution of the 225Ac/213Bi generator. [00347] The 225Ac3+ and 213Bi3+ reaction mixtures were gently agitated using a vortex mixer and the pH confirmed to be between 5−7 by spotting a portion (1−2 µL) of reaction mixture. For 213Bi3+ reactions, the radiochemical yield (RCY) was analyzed after 6−8 minutes at RT or elevated temperatures by spotting an aliquot (5−7 µL) on the bottom of instant thin layer chromatography plates (iTLCs). For 225Ac3+ reactions, the radiochemical yield (RCY) was analyzed after 5 and/or 60 minutes RT or elevated temperatures by spot. TLC imaging was performed using an AR-2000 imaging scanner equipped with PD-10 gas, and analysis of RCYs was carried out using WinScan software (ver.3.14). iTLC plate systems are as followed: ^ Method A ^ macrodipa, py-macrodipa, macropa, and DOTA – paper backed iTLC- silicic acid (iTLC-SA, Agilent Technologies), with EDTA (50 mM, pH 5.5) as mobile phase. Free 213Bi migrates with the solvent front (Rf = 1) while 213Bi3+−ligand complexes will remain at the baseline (Rf = 0). ^ Method B
Figure imgf000145_0001
macrodipa and py-macrodipa – paper backed iTLC-silicic acid (iTLC- SA, Agilent Technologies), with EDTA (50 mM, pH 7) as mobile phase. Free 225Ac3+ migrates with the solvent front (Rf = 1) while 225Ac3+−ligand complexes will remain at the baseline (Rf = 0). ^ Method C
Figure imgf000145_0002
macropa and DOTA – aluminum backed silica TLC plates (TLC-SG, silica gel 60, F254, MERCK, Germany), with citrate buffer (0.4 M, pH 4.0). Free 225Ac migrates with the solvent front (Rf = 1) while 225Ac3+−ligand complexes will remain at the baseline (Rf = 0). Table 15. Summary of radiochemical yields (RCYs, %) on 225Ac3+ with macrodipa, py-macrodipa, macropa, and DOTA, at different ligand concentrations (60 min reaction time).
Figure imgf000145_0003
Table 16. Summary of radiochemical yields (RCYs, %) on 213Bi3+ with macrodipa, py-macrodipa, macropa, and DOTA, at different ligand concentrations (pH 5.5−6, 6−8 min reaction time). The macropa and DOTA data are from Fiszbein, D. J.; Brown, V.; Thiele, N. A.; Woods, J. J.; Wharton, L.; MacMillan, S. N.; Radchenko, V.; Ramogida, C. F.; Wilson, J. J. Tuning the Kinetic Inertness of Bi3+ Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for 213Bi Targeted Alpha Therapy. Inorg. Chem.2021, 60, 9199–9211.
Figure imgf000146_0002
[00348] For both 225Ac3+ and 213Bi3+, py-macrodipa is able to achieve significantly higher radiochemical yields than its analogue macrodipa and the conventional chelator DOTA, which also required high temperatures for radiolabeling. Radiochemical yields of approximately 75% and 65% are obtained when using low py-macrodipa concentrations of 10−6 M and 10−8 M for 225Ac3+ and 213Bi3+, respectively. With respect to 225Ac3+ chelation, py- macrodipa was slightly less effective than macropa, but was better at radiolabeling 213Bi3+. [00349] Human Serum Challenge: The stability of 225Ac3+−py-macrodipa and 225Ac3+−macropa complexes were evaluated in the presence of human serum over a 5-day period. After confirming a RCY of >99% (100 kBq of 225/227Ac†), an aliquot (30 µL) the reaction mixture (final ligand concentration of 1 × 10-5 M, pH 7.0) was incubated with 90 µL of human serum (3:1 human serum:reaction mixture) at 37 °C. At various time points, aliquots (5−10 µL) were spotted on the iTLC plates using Method B described in “Radiolabeling Studies” section above. Table 17. Intact complex percentage (%) after incubation in human serum.
Figure imgf000146_0001
[00350] EDTA Transchelation Studies: UV–Vis spectra were recorded on a Shimadzu UV-1900 UV−Vis spectrometer with a 1-cm quartz cuvette. A stock solution of EDTA (150 mM) was prepared in H2O, and its pH was adjusted to 5.0 with NMe4OH. The concentrations of macrodipa and py-macrodipa were determined by potentiometric titrations, as described in our prior work. Hu, A.; MacMillan, S. N.; Wilson, J. J. Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern for the Lanthanide Ions. J. Am. Chem. Soc.2020, 142, 13500–13506; Hu, A.; Aluicio-Sarduy, E.; Brown, V.; MacMillan, S. N.; Becker, K. V; Barnhart, T. E.; Radchenko, V.; Ramogida, C. F.; Engle, J. W.; Wilson, J. J. Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes. J. Am. Chem. Soc.2021, 143, 10429–10440; and Hu, A.; Keresztes, I.; MacMillan, S. N.; Yang, Y.; Ding, E.; Zipfel, W. R.; DiStasio, R. A., Jr.; Babich, J. W.; Wilson, J. J. Oxyaapa: A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides. Inorg. Chem.2020, 59, 5116–5132. A standardized ICP-MS Bi3+ standard solution (ARISTAR®, VWR Chemicals BDH®) were used. The ligand (0.3 μmol) and metal (0.3 μmol) were mixed in a cuvette and diluted to 2980 μL with 0.1 M HOAc/NMe4OAc buffer (pH 5.0) to form the complex in situ. After allowing the solution to equilibrate for 15 min, 20 μL of the EDTA stock solution was added, giving a final complex and EDTA concentrations of 100 μM and 1 mM, respectively. Upon addition of EDTA, the reaction was monitored immediately by UV–Vis spectroscopy at 25 °C, for up to 5 weeks. The absorbance at 284 nm were plotted as a function of time. The half-lives (t1/2) for these first-order processes were obtained by fitting the Abs versus t data into an exponential model. Three independent replicates were performed for each Bi3+-ligand system. [00351] The results (provided in Table 18 below) show that Bi3+−macrodipa is kinetically labile to this transchelation challenge, whereas the kinetic inertness of Bi3+–py-macrodipa is remarkably enhanced with a half-life of 13 days. Table 18. Half-lives (t1/2) of Bi3+ Complexes when Challenged with 10 Equivalents of EDTA.a
Figure imgf000147_0001
Figure imgf000148_0001
Example 5 [00352] The chelator dipy-macrodipa was synthesized via the five-step procedure shown in Scheme 8. The benzyl-protected macrocyclic backbone 2 was constructed in two steps commencing from commercially available 2,6-Bis(bromomethyl)pyridine and 2- benzylaminoethanol. The benzyl groups were then removed by reduction with H2 over a Pd/C catalyst to yield the desired dipyridyl macrocycle 3. Subsequent installation of the two picolinate pendent arms via alkylation and acidic deprotection afforded dipy-macrodipa. The identity and purity of the intermediates and final product were verified by NMR spectroscopy, mass spectrometry, and analytical HPLC.
Scheme 8. Synthetic Route to dipy-macrodipa.
Figure imgf000149_0001
[00353] Deionized H2O (≥ 18 MΩ .cm) was obtained from an Elga Purelab Flex 2 water purification system. Organic solvents were of ACS grade or higher. All other reagents were purchased from commercial sources and used without further purification. The chelator dipy- macrodipa were synthesized following Scheme x.6-Bromomethylpyridine-2-carboxylic methyl ester was prepared as previously described. [00354] High-performance liquid chromatography (HPLC) consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC-20AT (analytical) pump, and an SPD-20AV UV−Vis detector monitoring at 270 nm (Shimadzu, Japan). Semipreparative purification was performed using an Epic Polar preparative column, 120 Å, 10 μm, 25 cm × 20 mm (ES Industries, West Berlin, NJ) at a flow rate of 14 mL/min. Analytical chromatography was carried out using an Ultra Aqueous C18 column, 100 Å, 5 μm, 250 mm × 4.6 mm (Restek, Bellefonte, PA) at a flow rate of 1.0 mL/min. All HPLC methods employed use a binary mobile phase (H2O and MeOH, 0.1% TFA added for both solvents) gradient. Preparative HPLC runs were carried out with the following methods. Method P1: 0−20 min, 95% H2O/MeOH; 20−25 min, 95% → 0% H2O/MeOH; Method P2: 0−10 min, 90% H2O/MeOH; 10−50 min, 90% → 0% H2O/MeOH. All analytical HPLC runs were carried out with the same method: 0−5 min, 90% H2O/MeOH; 5−25 min, 90% → 0% H2O/MeOH. [00355] NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 and 125.68 MHz for 1H and 13C observations, respectively. All NMR experiments were carried out at 25 °C. 1H NMR spectra acquired in D2O were referenced to residual internal HDO solvent peak at 4.77 ppm (25 °C), which was calculated according to the literature equation that accounts for the temperature dependence of the HDO chemical shift. The 13C{1H} NMR spectra were referenced indirectly to the corresponding 1H spectra using the “absolute reference” function provided in MestReNova (Mestrelab Research S.L.). High-resolution mass spectra (HRMS) were acquired on a Thermo Scientific Exactive Orbitrap mass spectrometer with a heated electrospray (HESI) ion source. [00356] Synthesis of 3. Crude 2 was dissolved in H2O containing 20% MeOH and 0.1% TFA (1.5 mL). Following filtration, this solution was injected into the preparative HPLC system to purify the product (Method P1). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield 3 as a white solid (0.61 g). Based on the peak integrations in the 1H and 19F NMR spectra of this compound relative to an internal standard of fluorobenzene, 3 was estimated to be a 0.3TFA salt.1H NMR (500 MHz, D2O, pD ≈ 12) δ: 7.86 (t, 1H, J = 7.7 Hz, py), 7.78 (t, 1H, J = 7.7 Hz, py), 7.41 (d, 2H, J = 7.7 Hz, py), 7.29 (d, 2H, J = 7.7 Hz, py), 4.56 (s, 4H, –CH2–), 3.77 (s, 4H, –CH2–), 3.74 (t, 4H, J = 4.8 Hz, – CH2–), 2.82 (t, 4H, J = 4.8 Hz, –CH2–).13C{1H} NMR (126 MHz, D2O, pD ≈ 12) δ: 158.5, 156.6, 139.6, 139.3, 124.2, 123.0, 73.2, 69.5, 53.4, 47.7. ESI-HRMS m/z: 329.1947; calcd for [C18H24N4O2 + H]+: 329.1972. Analytical HPLC: tR = 13.03 min. [00357] Synthesis of 4. To a mixture of 3.0.3TFA (0.38 g, 1.05 mmol), 6- bromomethylpyridine-2-carboxylic methyl ester (0.45 g, 1.95 mmol), and Na2CO3 (0.56 g, 5.28 mmol), dry MeCN (30 mL) was added. This suspension was then heated at 45 °C for 46 hours with a drying tube equipped on the condenser. Afterwards, the suspension was filtered, and the filtrate was concentrated to dryness under reduced pressure, giving a light yellow oil. This crude material was then dissolved in H2O containing 20% MeOH and 0.1% TFA (1.5 mL). Following filtration, this solution was injected into the preparative HPLC system to purify the product (Method P2). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield 4 as a colorless oil (0.61 g). Based on the peak integrations in the 1H and 19F NMR spectra of this compound relative to an internal standard of fluorobenzene, 4 was estimated to be a 4TFA salt. The entirety of this material was used in the next step.1H NMR (500 MHz, CD3OD) δ: 8.10 (dd, 2H, J = 7.8, 1.0 Hz, py), 8.05 (t, 1H, J = 7.8 Hz, py), 8.00 (d, 2H, J = 7.8 Hz, py), 7.83 (d, 2H, J = 7.8 Hz, py), 7.69 (dd, 2H, J = 7.8, 1.0 Hz, py), 7.64 (d, 2H, J = 7.8 Hz, py), 7.33 (d, 2H, J = 7.8 Hz, py), 4.92 (s, 4H, – CH2–), 4.82 (s, 4H, –CH2–), 4.68 (s, 4H, –CH2–), 4.06 (t, 4H, J = 4.8 Hz, –CH2–), 3.92 (s, 6H, –CH3), 3.75 (t, 4H, J = 4.8 Hz, –CH2–).13C{1H} NMR (126 MHz, CD3OD) δ: 166.2, 157.6, 152.2, 152.0, 148.7, 140.9, 140.6, 140.3, 129.4, 126.6, 126.2, 124.1, 74.0, 65.2, 59.2, 57.6, 56.0, 53.6. ESI-HRMS m/z: 627.2875; calcd for [C34H38N6O6 + H]+: 627.2926. Analytical HPLC: tR = 19.67 min. [00358] Synthesis of dipy-macrodipa. Compound 4 (0.61 g, directly from the prior step) was dissolved in 4 M HCl (4.5 mL) and heated at 80 °C for 20 h. The solution was then concentrated under reduced pressure to obtain a white solid. To ensure the complete removal of the TFA coming from 4, 4 M HCl (4.5 mL) was added, and the resulting solution was concentrated to dryness under reduced pressure. The residue was then dissolved in H2O (3 mL) and lyophilized to yield the 4HCl .3.5H2O salt of dipy-macrodipa as a white solid (0.47 g, 55% yield from 3).1H NMR (500 MHz, D2O, pD ≈ 8) δ: 7.77 (t, 1H, J = 7.7 Hz, py), 7.68 (m, 4H, py), 7.48 (t, 1H, J = 7.7 Hz, py), 7.34 (m, 4H, py), 7.27 (d, 2H, J = 7.7 Hz, py), 7.06 (d, 2H, J = 7.7 Hz, py), 4.52 (s, 4H, –CH2–), 3.86 (s, 4H, –CH2–), 3.78 (s, 4H, –CH2–), 3.64 (s, 4H, –CH2–), 2.89 (s, 4H, –CH2–).13C{1H} NMR (126 MHz, D2O, pD ≈ 8) δ: 173.3, 157.0, 156.7, 153.7, 139.2, 138.6, 126.3, 123.7, 123.0, 73.0, 67.6, 60.8, 60.2, 54.6. ESI- HRMS m/z: 599.2565; calcd for [C32H34N6O6 + H]+: 599.2613. Elemental analysis: found %: C 47.57, H 5.57, N 10.37; calcd % for C32H34N6O6 .4HCl .3.5H2O: C 47.23, H 5.60, N 10.49. Analytical HPLC: tR = 17.95 min. [00359] Potentiometric Titrations: [00360] Potentiometric titrations were carried out using a Metrohm Titrando 888 titrator equipped with a Ross Orion combination electrode (8103BN, ThermoFisher Scientific) and a Metrohm 806 exchange unit with an automatic burette (10 mL). This titration system was controlled by Tiamo (ver.2.5) software. The titration vessel was fitted into a removable glass cell (≈ 70 mL) and thermostated at 25.0 °C (pKw = 13.78) using a Thermomix 1442D circulating water bath. See Sweeton, F. H.; Mesmer, R. E.; Baes, C. F. Acidity Measurements at Elevated Temperatures. VII. Dissociation of Water. J. Solution Chem.1974, 3, 191–214. CO2 was excluded from the vessel prior to and during the titrations by an argon flow, which was passed through an aqueous 30 wt% KOH solution. Carbonate-free KOH (0.1 M, VWR Chemicals BDH®) was standardized by potentiometric titration against potassium hydrogen phthalate. HCl (0.1 M, J.T. Baker®) was standardized by potentiometric titration against Tris (base form). Titration solutions were maintained at a constant ionic strength of 0.1 M with KCl (BioUltra, ≥ 99.5%, Sigma-Aldrich) and were equilibrated for 15 minutes prior to the addition of titrant. The electrode was calibrated before each titration by titrating a solution of standardized HCl with standardized KOH, and the data were analyzed using the program Glee (ver.3.0.21) to obtain the standard electrode potential and slope factor. See Gans, P.; O’Sullivan, B. GLEE, a New Computer Program for Glass Electrode Calibration. Talanta 2000, 51, 33–37. [00361] Ligand stock solutions were made by dissolving the solid ligand in H2O, and their exact concentrations were determined based on the end points of the potentiometric titration curves obtained during the protonation constant measurements. The concentrations determined from titration curves matched the concentrations calculated from the ligand masses using molecular weights obtained from elemental analysis results. Ln3+ stock solutions were made by dissolving the corresponding LnCl3 hydrate salts (99.9% purity or higher) in standardized HCl (0.1 M). The exact concentrations were determined by complexometric titrations with a standardized Na2H2EDTA solution (Alfa Aesar). See Wuhan University. Analytical Chemistry I, 5th ed.; Higher Education Press: Beijing, 2006. The complexometric titrations were performed at pH 5.4 maintained by a HOAc-NaOAc buffer, and the end point was indicated by xylenol orange. [00362] Protonation constant determination for dipy-macrodipa or stability constant determination for Ln3+−dipy-macrodipa (Ln = Eu−Lu) was carried out by titrating an acidic solution containing free ligand or both ligand and metal with standardized KOH. For protonation constant determinations, the ligand concentration was 1 mM. For stability constant determinations, both the ligand and metal ion concentrations were around 1 mM. The total analyte volumes were 15–20 mL. Up to 3 min (protonation constant determinations) or 5 min (stability constant determinations) were given as equilibration times before recording the solution pH after the addition of an aliquot of base. During the stability constant determinations, the solutions were inspected throughout the titrations for signs of Ln(OH)3 precipitation. Data points of the titration curves were excluded from analysis if any precipitate was observed. These titration data were refined with Hyperquad 2013 software (see Gans, P.; Sabatini, A.; Vacca, A. Investigation of Equilibria in Solution. Determination of Equilibrium Constants with the HYPERQUAD Suite of Programs. Talanta 1996, 43, 1739–1753) to afford protonation and stability constants, where data points within the pH range of 2.1–11.3 were used for analysis. Six independent titrations for protonation constant measurements and three titrations for stability constant measurements were carried out for each ligand and Ln3+-ligand system. Results are provided in Table 19 below. Table 19. Protonation Constants of dipy-macrodipa, py-macrodipa, macrodipa, macropa, and Stability Constants of Their Ln3+ Complexes.
Figure imgf000153_0001
Figure imgf000154_0001
a0.1 M KCl, this study. The values in the parentheses are one standard deviation of the last significant figure. b0.1 M KCl. from Hu, A.; Aluicio-Sarduy, E.; Brown, V.; MacMillan, S. N.; Becker, K. V; Barnhart, T. E.; Radchenko, V.; Ramogida, C. F.; Engle, J. W.; Wilson, J. J. Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes. J. Am. Chem. Soc. 2021, 143, 10429–10440. c0.1 M KCl from Hu, A.; MacMillan, S. N.; Wilson, J. J. Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern for the Lanthanide Ions. J. Am. Chem. Soc.2020, 142, 13500–13506. d0.1 M KCl from Roca- Sabio, A.; Mato-Iglesias, M.; Esteban-Gómez, D.; Tóth, É.; de Blas, A.; Platas- Iglesias, C.; Rodríguez-Blas, T. Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides. J. Am. Chem. Soc.2009, 131, 3331–3341. e0.1 M KCl from Thiele, N. A.; MacMillan, S. N.; Wilson, J. J. Rapid Dissolution of BaSO4 by Macropa, an 18-Membered Macrocycle with High Affinity for Ba2+. J. Am. Chem. Soc.2018, 140, 17071–17078. [00363] DTPA Transchelation Studies: [00364] UV–Vis spectra were recorded on a Shimadzu UV-1900 UV−Vis spectrometer with a 1-cm quartz cuvette. A stock solution of DTPA (200 mM) was prepared in H2O, and its pH was adjusted to 7.4 with NMe4OH. The concentrations of dipy-macrodipa and Ln3+ stock solutions were determined by potentiometric titrations, as described in Section X. The ligand (0.3 μmol) and metal (0.3 μmol) were mixed in a cuvette and diluted to 2850 μL with 0.1 M MOPS buffer (pH 7.4) to form the complex in situ. After allowing the solution to equilibrate for 5 min, 150 μL of the DTPA stock solution was added, giving a final complex and DTPA concentrations of 100 μM and 10 mM, respectively. Upon addition of DTPA, the reaction was monitored immediately by UV–Vis spectroscopy at RT, for up to 5 weeks. The absorbance at 282 nm were plotted as a function of time. The half-lives (t1/2) for these first- order processes were obtained by fitting the Abs versus t data into an exponential model. Three independent replicates were performed for each Ln3+−dipy-macrodipa system. The results are provided in Table 20 below. Table 20. Half-lives of Ln3+−dipy-macrodipa, Ln3+−py-macrodipa, and
Figure imgf000155_0001
Example 6 [00365] Synthesis of py-macrodipa-NCS [00366] Deionized H2O (≥ 18 MΩ .cm) was obtained from an Elga Purelab Flex 2 water purification system. Organic solvents were of ACS grade or higher. All other reagents were purchased from commercial sources and used without further purification. (4- (benzyloxy)pyridine-2,6-diyl)dimethanol and 6-bromomethylpyridine-2-carboxylic methyl ester was prepared as previously described. See Li, L.; de Guadalupe Jaraquemada-Peláez, M.; Aluicio-Sarduy, E.; Wang, X.; Barnhart, T. E.; Cai, W.; Radchenko, V.; Schaffer, P.; Engle, J. W.; Orvig, C. Coordination chemistry of [Y(pypa)]− and comparison immuno-PET imaging of [44Sc]Sc- and [86Y]Y-pypa-phenyl-TRC105. Dalt. Trans.2020, 49, 5547–5562; Hu, A.; Aluicio-Sarduy, E.; Brown, V.; MacMillan, S. N.; Becker, K. V; Barnhart, T. E.; Radchenko, V.; Ramogida, C. F.; Engle, J. W.; Wilson, J. J. Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes. J. Am. Chem. Soc.2021, 143, 10429–10440. High-performance liquid chromatography (HPLC) consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC- 20AT (analytical) pump, and an SPD-20AV UV−Vis detector monitoring at 270 nm (Shimadzu, Japan). Semipreparative purification was performed using an Epic Polar preparative column, 120 Å, 10 μm, 25 cm × 20 mm (ES Industries, West Berlin, NJ) at a flow rate of 14 mL/min. Analytical chromatography was carried out using an Ultra Aqueous C18 column, 100 Å, 5 μm, 250 mm × 4.6 mm (Restek, Bellefonte, PA) at a flow rate of 1.0 mL/min. All HPLC methods employed use a binary mobile phase (H2O/MeOH or H2O/MeCN, 0.1% TFA added for all solvents) gradient. NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 and 125.68 MHz for 1H and 13C observations, respectively. All NMR experiments were carried out at 25 °C. High-resolution mass spectra (HRMS) were acquired on a Thermo Scientific Exactive Orbitrap mass spectrometer with a heated electrospray (HESI) ion source. [00367] Synthesis of Compound A:
Figure imgf000156_0001
To a solution of (4-(benzyloxy)pyridine-2,6-diyl)dimethanol (1.29 g, 5.26 mmol) in dry p- dioxane (30 mL), SeO2 (1.28 g, 11.54 mmol) was added, and this suspension was heated at 95 °C for 2.5 h. Afterwards, the reaction mixture was allowed to cool to RT and then filtered. This filtrate was concentrated to dryness under reduced pressure, giving a pink solid. This material was then rinsed with 3 × 5 mL of CH2Cl2, and these three portions of CH2Cl2 suspension were filtered and combined. The combined filtrate was concentrated under reduced pressure and dried under vacuum overnight, affording A as a pale-orange solid (1.15 g, 91%).1H NMR (500 MHz, CDCl3) δ: 10.11 (s, 2H, –CHO), 7.72 (s, 2H, py), 7.45–7.36 (m, 5H, Ph), 5.25 (s, 2H, –OCH2Ph–).13C{1H} NMR (126 MHz, CDCl3) δ: 192.3, 166.7, 154.8, 134.5, 128.9, 128.8, 127.7, 111.8, 71.0. ESI-HRMS m/z: 242.0815; calcd for [C14H11NO3 + H]+: 242.0812. [00368] Synthesis of Compound B:
Figure imgf000157_0001
Dry MeOH (10 mL) was added to a flask containing A (0.56 g, 2.32 mmol) and CaCl2.2H2O (0.36 g, 2.45 mmol), and a solution of 1,11-diamino-3,6,9-trioxaundecane (0.46 g, 2.39 mmol) in dry MeOH (3 mL) was then dropwise added with stirring. This mixture was stirred at room temperature for 15 min, and then heated at 60 °C for 2.5 h, with a drying tube equipped on the condenser. Afterwards, the reaction mixture was cooled to 0 °C with an ice bath, and NaBH4 (0.44 g, 11.63 mmol) was slowly added with vigorous stirring. The reaction mixture was stirred at RT overnight. H2O (12 mL) was then added, and the mixture was stirred for another 1.5 h. The MeOH of this mixture was removed under reduced pressure, and the leftover liquid was extracted with 8 × 30 mL of CH2Cl2. The combined extractants were dried over Na2SO4, concentrated to dryness under reduced pressure, and dried under vacuum overnight to afford B (0.80 g, 89%) as a pale-yellow oil. This product had a >95% purity and was used in the next step without further purification.1H NMR (500 MHz, CDCl3) δ: 7.41–7.32 (m, 5H, Ph), 6.66 (s, 2H, py), 5.08 (s, 2H, –OCH2Ph–), 3.81 (s, 4H, –NCH2py–), 3.67 (m, 8H, –CH2–), 3.62 (m, 4H, –CH2–), 2.83 (t, 4H, J = 4.8 Hz, –CH2–).13C{1H} NMR (126 MHz, CDCl3) δ: 165.5, 160.2, 135.8, 128.7, 128.3, 127.5, 107.5, 70.6, 70.4, 70.3, 69.8, 55.0, 49.1. ESI-HRMS m/z: 402.2389; calcd for [C22H31N3O4 + H]+: 402.2387. [00369] Synthesis of Compound C:
Figure imgf000158_0001
To a mixture of B (0.76 g, 1.89 mmol), 6-bromomethylpyridine-2-carboxylic methyl ester (0.83 g, 3.61 mmol), and Na2CO3 (0.77 g, 7.26 mmol), dry MeCN (30 mL) was added. This suspension was then heated at 45 °C for 44 hours with a drying tube equipped on the condenser. Afterwards, the suspension was allowed to cool to RT and filtered. The resulting filtrate (~30 mL), which contains C, was directly used in the next step. ESI-HRMS m/z: 402.2389; calcd for [C22H31N3O4 + H]+: 402.2387. [00370] Synthesis of Compound D:
Figure imgf000158_0002
To the above-mentioned filtrate containing C, 10% Pd/C (0.25 g) was added, and the mixture was stirred under H2 atmosphere at RT. The reaction progress was monitored by analytical HPLC, and sometimes more 10% Pd/C was added when the reaction became slow. After the reaction was complete (which usually took about 5 d), the suspension was filtered, and the filtrate was concentrated to dryness under reduced pressure, giving a yellow oil. This crude material was then dissolved in H2O containing 10% MeOH and 0.1% TFA (3 mL). Following filtration, this solution was injected into the preparative HPLC system to purify the product (Method: 0–10 min, 90% H2O/MeOH; 10–45 min, 90% → 0% H2O/MeOH). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield the 3.5TFA salt of D as a white solid (0.67 g, 35% from B).1H NMR (500 MHz, D2O, pD ≈ 2) δ: 8.07 (dd, 2H, J = 7.8, 1.0 Hz, py), 7.48 (t, 2H, J = 7.8 Hz, py), 7.27 (dd, 2H, J = 7.8, 1.0 Hz, py), 6.85 (s, 2H, py), 4.65 (m, 8H, –NCH2py–), 3.98 (t, 4H, J = 4.9 Hz, –CH2–), 3.91 (s, 6H, – CH3), 3.75 (m, 8H, –CH2–), 3.67 (s, 4H, –CH2–).13C{1H} NMR (126 MHz, D2O, pD ≈ 2) δ: 166.7, 166.6, 152.0, 150.5, 147.3, 140.2, 129.4, 126.4, 113.2, 70.2, 70.1, 64.4, 58.5, 58.4, 56.2, 53.9. ESI-HRMS m/z: 610.2874; calcd for [C31H39N5O8 + H]+: 610.2871. Elemental analysis: found %: C 45.64, H 4.54, N 7.20; calcd % for C31H39N5O8S .3.5CF3COOH: C 45.25, H 4.25, N 6.94. Analytical HPLC: tR = 18.89 min (Method: 0–5 min, 90% H2O/MeOH; 5–25 min, 90% → 0% H2O/MeOH). [00371] Sythnesis of Compound E:
Figure imgf000159_0001
To a mixture of D•3.5TFA (1 equiv) and Cs2CO3 (4.5 equiv), dry CH3CN (10 mL) was added. With a drying tube equipped on the condenser, this mixture was heated at 70 °C for 30 min, after which 4-((tert-butoxycarbonyl)amino)phenethyl 4-methylbenzenesulfonate (1.6 equiv) was added. This reaction mixture was then heated at 70 °C for 48 h. Afterwards, the suspension was filtered, and the filtrate was concentrated to dryness under reduced pressure, giving a yellow solid. This crude material, which contains the desired compound E, was directly used in the next step. ESI-HRMS m/z: 867.3696; calcd for [C44H56N6O10 + K]+: 867.3690.) [00372] Sythnesis of Compound F:
Figure imgf000160_0001
The entirety of the crude material from the prior step (i.e., that includes compound E) was dissolved in TFA (2 mL), and this mixture was heated at 60 °C for 22 h, during which the tert-butyloxycarbonyl (Boc) protecting group was removed. Afterwards, 6 M HCl (2 mL) was added, and the reaction mixture was heated at 60 °C for another 22 h, during which the two methyl esters on picolinate arms were hydrolyzed. The TFA/HCl/H2O was then removed under reduced pressure, and the resulting residue was dissolved in H2O containing 20% CH3OH and 0.1% TFA (3.0 mL). Following filtration, this solution was injected into the preparative HPLC system to purify the product (Method: 0–5 min, 90% H2O/CH3OH; 5–35 min, 90% → 0% H2O/CH3OH). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield the 4TFA salt of F as a white solid. 1H NMR (500 MHz, D2O, pD ≈ 2) δ: 7.86 (m, 4H, py), 7.58 (dd, 2H, J = 6.5, 2.3 Hz, py), 7.50 (m, 2H, py), 7.42 (m, 2H, py), 6.77 (s, 2H, py), 4.66 (s, 4H, –NCH2py–), 4.60 (s, 4H, –NCH2py–), 4.22 (t, 2H, J = 6.1 Hz, –CH2–), 4.00 (t, 4H, J = 4.9 Hz, –CH2–), 3.76 (m, 8H, –CH2–), 3.70 (t, 4H, J = 4.9 Hz, –CH2–), 3.14 (t, 2H, J = 6.1 Hz, –CH2–).13C{1H} NMR (126 MHz, D2O, pD ≈ 2) δ: 167.9, 167.2, 152.3, 150.4, 147.8, 140.3, 140.2, 131.3, 129.0, 128.9, 125.9, 123.7, 111.8. ESI- HRMS m/z: 701.3269; calcd for [C37H44N6O8 + H]+: 701.3293. Analytical HPLC: tR = 17.12 min. (Method: 0–5 min, 90% H2O/MeOH; 5–25 min, 90% → 0% H2O/MeOH). [00373] Synthesis of py-macropa-NCS:
Figure imgf000161_0001
To a mixture of Compound F•4TFA (0.094 g, 0.081 mmol) and Na2CO3 (0.107 g, 1.01 mmol), dry acetone (8 mL) was added. This suspension was heated at 50 °C for 30 min, after which CSCl2 (90 µL, ACROS Organics, 85%) was slowly added. The reaction mixture was then heated at reflux for 2 h and then concentrated under reduced pressure. This crude material solid was dissolved in H2O containing 10% MeCN and 0.1% TFA (1.5 mL). Following filtration, this solution was injected into the preparative HPLC system to purify the product (Method: 0–10 min, 90% H2O/MeCN; 10–40 min, 90% → 0% H2O/MeCN). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield the 3TFA salt of py-macrodipa-NCS as a nearly-white/pale-yellow solid (0.065 g, 74%).1H NMR (500 MHz, D2O, pD ≈ 2) δ: 7.88 (m, 4H, py), 7.27 (dd, 2H, J = 7.3, 1.5 Hz, py), 7.29 (m, 2H, Ph), 7.14 (m, 2H, Ph), 6.78 (s, 2H, py), 4.58 (m, 8H, –NCH2py–), 4.25 (t, 2H, J = 5.7 Hz, –CH2–), 3.98 (t, 4H, J = 4.6 Hz, –CH2–), 3.75 (m, 8H, –CH2–), 3.66 (t, 4H, J = 4.6 Hz, – CH2–), 3.05 (t, 2H, J = 5.7 Hz, –CH2–). 13C{1H} NMR (126 MHz, D2O, pD ≈ 2) δ: 168.0, 167.4, 152.3, 150.2, 148.0, 140.2, 138.7, 134.5, 131.0, 129.5, 129.1, 126.2, 126.0, 112.0, 70.2, 70.1, 69.7, 64.4, 58.8, 58.7, 56.5, 34.8. ESI-HRMS m/z: 743.2831; calcd for [C38H46N6O8S + H]+: 743.2858. Elemental analysis: found %: C 48.43, H 4.35, N 7.78; calcd % for C38H46N6O8S .3CF3COOH: C 48.71, H 4.18, N 7.75. Analytical HPLC: tR = 18.22 min (Method: 0–5 min, 90% H2O/MeCN; 5–25 min, 90% → 0% H2O/MeCN). [00374] Synthesis of py-macrodipa-PSMA
Figure imgf000162_0001
The Fmoc-trans-nap-Lys-urea-Glu-Wang resin (200 mg, 0.16 mmol) was prepared according to the solid phase approach. See Mosayebnia, M.; Rezaeianpour, S.; Rikhtechi, P.; Hajimahdi, Z.; Beiki, D.; Kobarfard, F.; Sabzevari, O.; Amini, M.; Abdi, K.; Shahhosseini, S. Novel and Efficient Method for Solid Phase Synthesis of Urea-Containing Peptides Targeting Prostate Specific Membrane Antigen (PSMA) in Comparison with Current Methods. Iran. J. Pharm. Res. IJPR 2018, 17, 917–926. Fmoc-β-L-alanine (199 mg, 0.64 mmole) was coupled to the resin using PyBOP (167 mg, 0.32 mmole) as coupling reagent in the presence of DIEA (112 µL, 0.64 mmol) within 12 h. After coupling, the resin was treated with mixture of 20% piperidine in DMF in order to remove Fmoc group. Finally, after washing and drying the Glu-urea-Lys-nap-trans-β-Ala (“β-Ala-PSMA-617”) was cleaved from the resin by treatment with a mixture of TFA/TIS/H2O (95%/2.5%/2.5%). After cleavage from the resin, the compound was precipitated and lyophilized. The crude product was then purified by reverse-phase semi-preparative HPLC. The bifunctional chelator py-macrodipa-NCS .3TFA (0.012 g, 0.011 mmol) and the targeting moiety β-Ala-PSMA-617 (0.008 g, 0.011 mmol) were dissolved in 200 μL and 800 μL of 0.1 M NaHCO3/Na2CO3 buffer (pH 9.0), respectively. These two solutions were mixed and then stirred for 3 days at RT. Afterwards, this reaction mixture is filtered and injected into the preparative HPLC system to purify the product (Method: 0–10 min, 90% H2O/MeCN; 10–40 min, 90% → 0% H2O/MeCN). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield py- macrodipa-PSMA as white fluffy solid (0.114 g). ESI-HRMS m/z: 1469.6419; calcd for [C74H92N12O18S + H]+: 1469.6446. Analytical HPLC: tR = 16.15 min (Method: 0–5 min, 90% H2O/MeCN; 5–25 min, 90% → 0% H2O/MeCN). [00375] Radiolabeling of py-macrodipa-PSMA to provide [135La]La–py-macrodipa- PSMA: Radio-HPLC analysis was carried out on the Shimadzu HPLC-20AR equipped with a binary gradient, pump, UV–Vis detector, autoinjector and a Laura radiodetector on a Phenomenex Luna (5 μm, 150 mm x 3 mm, 100 Å). (HPLC METHOD).132/135LaCl3 was obtained from the Engle Lab at University of Wisconsin-Madison. Py-macrodipa-PSMA (6 μL, 1 mM, 20% DMSO in 0.5 M NaOAc buffer, pH 5.5) was combined with 132/135La (537 μCi, 66 μL) and additional NaOAc buffer (320 μL, 20% DMSO in NaOAc). Quantitative radiolabeling was achieved in 20 min at room temperature and studies were performed without further purification. [00376] Ex Vivo Biodistribution of [135La]La–py-macrodipa-PSMA and Metabolite Analysis: All animal experiments were conducted according to the guidelines of the Institutional Animal Care and Use Committee (IACUC) at Stony Brook Medicine. Male Ncr mice (Taconic Biosciences, Rensselaer, NY) were inoculated subcutaneously with PSMA positive PC-3 PIP cells and PSMA negative PC-3 flu cells (1.0 x 106 each) suspended in Matrigel (1:2 DPBS: Matrigel), on the right and left shoulders respectively. When the tumors reached a suitable size, [132/135La]La–py-macrodipa-PSMA (25-34 μCi/0.93-1.26 MBq) and [132/135La]La–citrate (21-33 μCi/0.78-1.22 MBq) were injected via tail vein catheter. After 2 h, animals were sacrificed by cervical dislocation and selected tissues were collected and weighed. Activity of tissues was counted using a γ-counter (1470 PerkinElmer Wizard) and the radioactivity associated with each organ was expressed as % ID/g. To assess the amount of intact complex remaining, urine was directly injected to the radioHPLC and eluate was collected in 30 s increments from 0–20 min. Activity in each tube was quantified using a γ- counter and the counts were used to reconstruct the metabolite trace, which was then compared to the original radiolabeling trace. Results are provided in Table 21 below. Remarkably, py-macrodipa-PSMA successfully targets the 135La3+ dose to PSMA, as reflected by the substantial radioactivity accumulation in the PSMA+ tumors Table 21. Tabulated biodistribution data.
Figure imgf000164_0001
[00377] While certain embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments. [00378] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the present technology. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. [00379] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified. [00380] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. [00381] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth. [00382] All publications, provisional applications, patent applications, issued patents, and other documents (for example, journals, articles and/or textbooks) referred or cited to in this specification are herein incorporated by reference as if each individual publication, provisional application, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure. [00383] The present technology may include, but is not limited to, the features and combinations of features recited in the following lettered paragraphs, it being understood that the following paragraphs should not be interpreted as limiting the scope of the claims as appended hereto or mandating that all such features must necessarily be included in such claims: A. A compound of any one of Formula I, Formula II, Formula III, and Formula IV (I) (II) (III) (IV) or a pharmaceutically acceptable salt and/or solvate thereof, wherein A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.
B. The compound of Paragraph A, wherein the compound is of any one of Formula I-1, Formula II-1, and Formula III-1 (I-1) (II-1) (III-1) or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1 is or ; R2 is independently at each occurrence , , or ; one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, and Z8 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. C. The compound of Paragraph A or Paragraph B, where the compound is of Formula I-2
Figure imgf000173_0001
or a pharmaceutically acceptable salt and/or solvate thereof. D. A compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formula IVA (IA) (IIA) (IIIA) (IVA) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the compound; A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. E. The compound of Paragraph D, wherein the compound is of any one of Formula IA-1, Formula IIA-1, and Formula IIIA-1
Figure imgf000177_0001
ĨIIIA-1) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the compound; R1 is or ; R2 is independently at each occurrence , , or ; one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, and Z8 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. F. The compound of Paragraph D or Paragraph E, where the compound is of Formula IA-2
Figure imgf000180_0001
or a pharmaceutically acceptable salt and/or solvate thereof. G. The compound of any one of Paragraphs D-F, wherein M1 is independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium-177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+). H. A targeting compound of any one of Formula V, Formula VI, Formula VII, and Formula VIII (V) (VI) (VII) (VIII) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the targeting compound; A5, A6, A7, and A8 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–L3–R22; Z1 is independently at each occurrence OH or NH–L4–R24; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –L5–R26; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; L3, L4 , and L5 are independently at each occurrence a bond or a linker group; and R22, R24, and R26 each independently at each occurrence comprise an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin. I. The targeting compound of Paragraph H, wherein the targeting compound is of any one of Formula V-1, Formula VI-1, and Formula VII-1
Figure imgf000184_0001
or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the targeting compound;
Figure imgf000184_0002
R2 is independently at each occurrence
Figure imgf000184_0003
one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently
Figure imgf000186_0001
,
Figure imgf000186_0002
Z2, Z3, Z4, Z5, Z6, Z7, and Z8 are independently at each occurrence H or –X1–L3–R22; Z1 is independently at each occurrence OH or NH–L4–R24; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; L3, L4 , and L5 are independently at each occurrence a bond or a linker group; and R22, R24, and R26 each independently at each occurrence comprise an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin. J. The targeting compound of Paragraph H or Paragraph I, where the targeting compound is of Formula V-2
Figure imgf000186_0003
or a pharmaceutically acceptable salt and/or solvate thereof. K. The targeting compound of any one of Paragraphs H-J, wherein M1 is independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium-177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth- 213 (213Bi3+), lead-212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+). L. The targeting compound of any one of Paragraphs H-K, wherein R22, R24, and R26 each independently at each occurrence comprise belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, Etaracizumab, an antigen-binding fragment of any thereof, a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement of any thereof. M. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula I, Formula II, Formula III, and Formula IV or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide,
Figure imgf000187_0001
(III) (IV) wherein A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. N. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph M, wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of Formula I-1, Formula II-1, and Formula III-1
Figure imgf000191_0001
O. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph M or Paragraph N, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv- aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab. P. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs M-O, wherein the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof. Q. The modified antibody, modified antibody fragment, or modified binding peptideof any one of any one of Paragraphs M-P, wherein the compound of Formula I is of Formula I-2
Figure imgf000192_0001
or a pharmaceutically acceptable salt and/or solvate thereof. R. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula IA, Formula IIA, and Formula IIIA or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide,
Figure imgf000192_0002
(IIIA) (IVA) wherein M1 is a radionuclide chelated in the compound; A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently
Figure imgf000195_0001
,
Figure imgf000195_0002
Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. S. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph R, wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of any one of Formula IA-1, Formula IIA-1, and Formula IIIA-1
Figure imgf000196_0001
T. The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph R or Paragraph S, wherein M1 is independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium- 177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead- 212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium- 227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+). U. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-T, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv- aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab. V. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-U, wherein the binding peptide comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof. W. The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-V, wherein the compound of Formula IA is of Formula IA-2
Figure imgf000197_0001
or a pharmaceutically acceptable salt and/or solvate thereof. X. A composition comprising a pharmaceutically acceptable carrier and a compound of any one of Paragraphs A-L. Y. A composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of Paragraphs H-L or comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs M-W. Z. A pharmaceutical composition useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) in a subject, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of any one of Paragraphs H-L or a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs M-W. AA. The pharmaceutical composition of Paragraph Z, wherein the pharmaceutical composition comprises an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide. AB. The pharmaceutical composition of Paragraph Z or Paragraph AA, where the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof, and/or mammalian tissue overexpressing PSMA. AC. The pharmaceutical composition of any one of Paragraphs Z-AB, wherein the subject suffers from one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, AD. The pharmaceutical composition of any one of Paragraphs Z-AC, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. AE. The pharmaceutical composition of any one of Paragraphs Z-AD, wherein the pharmaceutical composition is formulated for intraveneous administration, optionally comprising sterilized water, Ringer's solution, or an isotonic aqueous saline solution. AF. The pharmaceutical composition of any one of Paragraphs Z-AE, wherein the effective amount of the compound is from about 0.01 μg to about 10 mg of the compound per gram of the pharmaceutical composition. AG. The pharmaceutical composition of any one of Paragraphs Z-AF, wherein the pharmaceutical composition is provided in an injectable dosage form. AH. A method of treating a subject, wherein the method comprises administering a targeting compound of any one of Paragraphs H-L to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one Paragraphs M-W. AI. The method of Paragraph AH, wherein the subject suffers from cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) AJ. The method of Paragraph AH or Paragraph AI, wherein the method comprises administering an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide AK. The method of any one of Paragraphs AH-AJ, wherein the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), when administered to a subject. AL. The method of any one of Paragraphs AH-AK, wherein the mammalian tissue comprises one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer. AM. The method of any one of Paragraphs AH-AL, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer. AN. The method of any one of Paragraphs AH-AM, wherein the administering comprises parenteral administration. AO. The method of any one of Paragraphs AH-AN, wherein the administering comprises intraveneous administration. AP. The method of any one of Paragraphs AH-AO, wherein the effective amount is from about 0.1 µg to about 50 µg per kilogram of subject mass. [00384] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

Claims

WHAT IS CLAIMED IS: 1. A compound of any one of Formula I, Formula II, Formula III, and Formula IV (I) (II) (III) (IV) or a pharmaceutically acceptable salt and/or solvate thereof, wherein A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.
2. The compound of claim 1, wherein the compound is of any one of Formula I-1, Formula II-1, and Formula III-1
Figure imgf000205_0001
or a pharmaceutically acceptable salt and/or solvate thereof. 3. The compound of claim 1, where the compound is of Formula I-2
Figure imgf000205_0002
or a pharmaceutically acceptable salt and/or solvate thereof. 4. A compound of any one of Formula IA, Formula IIA, Formula IIIA, and Formula IVA (IA) (IIA) (IIIA) (IVA) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the compound; A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2,
3,
4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.
5. The compound of claim 4, wherein the compound is of any one of Formula IA-1, Formula IIA-1, and Formula IIIA-1
Figure imgf000209_0001
Figure imgf000210_0001
or a pharmaceutically acceptable salt and/or solvate thereof.
6. The compound of claim 4, where the compound is of Formula IA-2
Figure imgf000210_0002
or a pharmaceutically acceptable salt and/or solvate thereof.
7. The compound of any one of claims 4-6, wherein M1 is independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium- 177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead- 212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium- 227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+).
8. A targeting compound of any one of Formula V, Formula VI, Formula VII, and Formula VIII (V) (VI) (VII) (VIII) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is a radionuclide chelated in the targeting compound; A5, A6, A7, and A8 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–L3–R22; Z1 is independently at each occurrence OH or NH–L4–R24; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –L5–R26; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; L3, L4 , and L5 are independently at each occurrence a bond or a linker group; and R22, R24, and R26 each independently at each occurrence comprise an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin.
9. The targeting compound of claim 8, wherein the targeting compound is of any one of Formula V-1, Formula VI-1, and Formula VII-1
Figure imgf000214_0001
or a pharmaceutically acceptable salt and/or solvate thereof.
10. The targeting compound of claim 8, where the targeting compound is of Formula V-2
Figure imgf000215_0001
or a pharmaceutically acceptable salt and/or solvate thereof.
11. The targeting compound of claim 8, wherein M1 is independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium- 177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead- 212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium- 227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+).
12. The targeting compound of claim 8, wherein R22, R24, and R26 each independently at each occurrence comprise belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, Etaracizumab, an antigen-binding fragment of any thereof, a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement of any thereof.
13. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula I, Formula II, Formula III, and Formula IV or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide, (I) (II) (III) (IV) wherein A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.
14. The modified antibody, modified antibody fragment, or modified binding peptide of claim 13, wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of Formula I-1, Formula II-1, and Formula III-1
Figure imgf000220_0001
15. The modified antibody, modified antibody fragment, or modified binding peptide of claim 13, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab.
16. The modified antibody, modified antibody fragment, or modified binding peptide of claim 13, wherein the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement thereof.
17. The modified antibody, modified antibody fragment, or modified binding peptideof any one of claim 13, wherein the compound of Formula I is of Formula I-2
Figure imgf000221_0001
or a pharmaceutically acceptable salt and/or solvate thereof.
18. A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula IA, Formula IIA, and Formula IIIA or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide,
Figure imgf000221_0002
wherein M1 is a radionuclide chelated in the compound; A1, A2, A3, and A4 are each independently or ; R1 is or ; R2 is independently at each occurrence , , or ; R3 and R4 are each independently H or Z13, or R3 and R4 together are butylene (e.g., -CH2CH2CH2CH2-); one of Y1 and Y2 is , , , or , and the other one of Y1 and Y2 is O; one of Y3 and Y4 is , , , or , and the other one of Y3 and Y4 is O; one of Y5 and Y6 is , , or , and the other one of Y5 and Y6 is O, or Y5 and Y6 are each independently , , , or ; one of Y7 and Y8 is , , or , and the other one of Y7 and Y8 is O, or Y7 and Y8 are each independently , , , or ; Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z10, Z11, Z12, and Z13 are independently at each occurrence H or –X1–W2; Z1 is independently at each occurrence OH or NH–W3; Z9 is independently at each occurrence H, -S(O)2OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X1–W2; α is independently at each occurrence 0 or 1; X1 is independently at each occurrence O, NH, or S; X2 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; X3 is independently at each occurrence OH, SH, NH2, N(CH3)H, or N(CH3)2; W2 and W3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W5 is independently at each occurrence OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2)w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH2CH2-(OCH2CH2)x-OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)yx-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH2CH2-(OCH2CH2)z-OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, - OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; and R’ is independently at each occurrence H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.
19. The modified antibody, modified antibody fragment, or modified binding peptide of claim 18, wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of any one of Formula IA-1, Formula IIA-1, and Formula IIIA-1
Figure imgf000225_0001
20. The modified antibody, modified antibody fragment, or modified binding peptide of claim 18, wherein M1 is independently at each occurrence actinium-225 (225Ac3+), lanthanum-132 (132La3+), lanthanum-135 (135La3+), lutetium-177 (177Lu3+), indium-111 (111In3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and/or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), uranium-230, scandium-44 (44Sc3+), scandium-47 (47Sc3+), gallium-67 (67Ga3+), or gallium-68 (68Ga3+).
21. The modified antibody, modified antibody fragment, or modified binding peptide of claim 18, wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab ozogamicin, Alemtuzumab, Cixutumumab, Girentuximab, Nimotuzumab, Catumaxomab, or Etaracizumab.
22. The modified antibody, modified antibody fragment, or modified binding peptide of claim 18, wherein the binding peptide comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragement thereof.
23. The modified antibody, modified antibody fragment, or modified binding peptide of claim 18, wherein the compound of Formula IA is of Formula IA-2
Figure imgf000226_0001
or a pharmaceutically acceptable salt and/or solvate thereof.
24. A composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-12.
25. A composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of claims 8-12 or comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 13-23.
26. A pharmaceutical composition useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) in a subject, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of any one of claims 8-12 or a modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 13-23.
27. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition comprises an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide.
28. The pharmaceutical composition of claim 26 or claim 27, where the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof, and/or mammalian tissue overexpressing PSMA.
29. The pharmaceutical composition of any one of claims 26-28, wherein the subject suffers from one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma,
30. The pharmaceutical composition of any one of claims 26-29, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
31. The pharmaceutical composition of any one of claims 26-30, wherein the pharmaceutical composition is formulated for intraveneous administration, optionally comprising sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
32. The pharmaceutical composition of any one of claims 26-31, wherein the effective amount of the compound is from about 0.01 μg to about 10 mg of the compound per gram of the pharmaceutical composition.
33. The pharmaceutical composition of any one of claims 26-32, wherein the pharmaceutical composition is provided in an injectable dosage form.
34. A method of treating a subject, wherein the method comprises administering a targeting compound of any one of claims 8-12 to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one of claims 13-23.
35. The method of claim 34, wherein the subject suffers from cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”)
36. The method of claim 34 or claim 35, wherein the method comprises administering an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide
37. The method of any one of claims 34-36, wherein the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), when administered to a subject.
38. The method of any one of claims 34-37, wherein the mammalian tissue comprises one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer.
39. The method of any one of claims 34-38, wherein the subject suffers from one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
40. The method of any one of claims 34-39, wherein the administering comprises parenteral administration.
41. The method of any one of claims 34-40, wherein the administering comprises intraveneous administration.
42. The method of any one of claims 34-41, wherein the effective amount is from about 0.1 µg to about 50 µg per kilogram of subject mass.
PCT/US2022/031196 2021-05-26 2022-05-26 Macrocycles and complexes with radionuclides useful in targeted radiotherapy of cancer WO2022251541A1 (en)

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