WO2008128058A1 - New gallium bisaminothiolate complexes for myocardial imaging - Google Patents

New gallium bisaminothiolate complexes for myocardial imaging Download PDF

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WO2008128058A1
WO2008128058A1 PCT/US2008/060054 US2008060054W WO2008128058A1 WO 2008128058 A1 WO2008128058 A1 WO 2008128058A1 US 2008060054 W US2008060054 W US 2008060054W WO 2008128058 A1 WO2008128058 A1 WO 2008128058A1
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alkyl
alkoxy
complex
compound
gallium
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PCT/US2008/060054
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French (fr)
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Hank F. Kung
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The Trustees Of The University Of Pennsylvania
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/30—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention is directed to novel ligands and radioisotopic complexes useful as imaging agents for positron emission tomography (PET).
  • PET positron emission tomography
  • One aspect is related to novel gallium complexes having excellent myocardial uptake and retention, due to the lipid-solubility and cationic nature of such novel complexes.
  • the present invention is directed to novel radioisotopic complexes for positron emission tomography (PET) and, more specifically, to novel gallium complexes with enhanced lipid- solubility which possess utility as myocardial imaging agents.
  • PET positron emission tomography
  • PET is a technique whereby a three-dimensional reconstruction of in vivo radionuclide distribution is possible, providing images that map and quantitate tissue activity levels.
  • the demand for new and novel positron-emitting radiopharmaceuticals continues to increase as more institutions acquire instrumentation for PET imaging.
  • Gallium-67 and Gallium-68 there are two gallium radioisotopes: Gallium-67 and Gallium-68. Both possess nuclear properties that make them attractive for use in nuclear medicine.
  • the first, Gallium-67 is cyclotron-produced from Zn-68, has a half life of 78 hours and is commercially available as gallium chloride and gallium citrate.
  • the second, Gallium-68 has the distinction of being one of the few short-lived positron emitting radionuclides available from a parent/daughter generator system, 68 Ge/ 68 Ga.
  • Such generator systems for producing positron emitting isotope without an on-site cyclotron have been reported (Ehrhardt GJ, Welch MJ., J Nucl Med.
  • solid oxides such as, TiO 2 , ZrO 2 or SiO 2
  • a tin dioxide/1 N HCl generator also provided a sterile solution of Gallium-68 in ionic form, ready for use in the preparation of many radiopharmaceuticals see Loc'h C, Maziere B, Comar D. A new generator for ionic gallium-68. J Nucl Med. 1980;21 : 171-3.
  • the criteria for an ideal 68 Ge/ 68 Ga generator system include: 1) high efficient separation of 68 Ga from the column; 2) minimum amount of "parent breakthrough" - low level Of 68 Ge in the eluent; 3) stability of the column over time. All of the reported 68 Ga/ 68 Ge generator systems meet the basic criteria listed above; however, one major unmet need in the field of nuclear medicine is the lack of FDA approved commercial 68 Ge/ 68 Ga generator system for human use, which limits the potential for developing 68 Ga labeled radiopharmaceuticals for PET imaging see Breeman WA, Verbruggen AM.
  • the (68)Ge/(68)Ga generator has high potential, but when can we use (68)Gallium-labelled tracers in clinical routine? Eur J Nucl Med MoI Imaging. 2007.
  • Gallium complexes OfN 2 S 2 bisaminoethanethiolate,
  • Kung HF Liu B-L, Mankoff D, Kung M-P, Billings JJ, Francesconi LC, Alavi A.
  • a new myocardial imaging agent synthesis, characterization, and biodistribution of gallium-68-B AT-TECH. J Nucl Med. 1990;31 :1635-40, Francesconi LC, Liu B-L, Billings JJ, Carroll PJ, Graczyk G, Kung HF.
  • Synthesis, characterization and solid state structure of a neutral gallium(III) amino thiolate complex a potential radiopharmaceutical for PET imaging.
  • radioisotopic complexes also depend on the biodistribution properties of the specific radiopharmaceutical agents.
  • high definition imaging of heart tissue requires not only efficient myocardial uptake of the radiopharmaceutical agent but, as well, retention of the radioactivity in the targeted issue.
  • the ideal radioisotopic complex will exhibit a biodistribution pattern which will provide higher concentrations of the radioisotopic complex in the targeted tissue relative to the blood levels and relative to its concentration in adjacent non-targeted tissues.
  • radioisotopic complex designed for imaging the heart are high myocardial tissue uptake, good heart/blood ratios, and prolonged retention of the radiopharmaceutical concentrations in the myocardial tissues relative to that in the blood and of other tissues/organs in the thoracic cavity.
  • Gallium bisaminoethanethiolate complexes have a plus one charge.
  • the stabilizing counterion dissociated to form a Gallium bisaminothiolate (GaBAT) a plus one charge ion. It is believed that the highly lipophilic plus one charged complexes become trapped in the myocardial tissue similar to those 99m Tc myocardial imaging agents ( 99m Tc-MIBI and Tetrafosamine).
  • One aspect of the present invention is related to novel radioisotopic complexes having suitable organ uptake and retention.
  • One aspect is directed to Gallium radioisotropic complexes of tricyclohexyl analogs of bisaminoethanethiolate having improved myocardial uptake and retention.
  • a need continues to exist in the art for radioactive metal complexes useful for imaging.
  • a need continues to exist in the art for imaging agents for myocardial perfusion studies using PET.
  • the present invention is directed to compounds of Formula I and radioisotopic complexes of Formula II, wherein bisaminothiolate tricyclohexyl ligands and Gallium-68 bisaminothiolate tricyclohexyl complexes are generated.
  • Such complexes are highly lipophilic, possessing two additional methylene moieties with a plus one charge, whereby the radioactive complex is trapped in the myocardial tissue at an with increased incident, hence enhancing it's myocardial perfusion and retention and subsequent efficacy as an imaging agent.
  • This invention therefore relates to compounds of Formula I:
  • each of A 1 , A 2 and A 3 are the same or different, and are optionally substituted cycloalkyl, R 1 through R 6 are independently hydrogen or alkyl, whilst R 7 and R 8 are independently hydrogen or alkyl; and R P is hydrogen or a sulfhydryl protecting group.
  • a 1 , A 2 and A 3 are the same or different, and are optionally substituted cycloalkyl.
  • R 1 through R 6 are independently hydrogen or alkyl and R 7 and R 8 are independently hydrogen or alkyl and M is a metal, where in some embodiments is M is a radioisotope.
  • a " is a monovalent counterion, wherein some embodiments the counterion is a halide.
  • the complexes are radioisotopic complexes and imaging agents, with increased lipophilicity and a + 1 cationic charge.
  • complexes of Formula II are lipid-soluble, and that the compounds exhibit high uptake in the heart as well as in the liver, providing further evidence that the radioisotopic complexes of the present invention should therefore be useful as tracers for myocardial perfusion imaging.
  • the complexes of the invention also offer the advantage of being available to institutions not having the use of an on-site cyclotron.
  • kits for formation of radiodiagnostic imaging agents comprising a compound of Formula I provided in a vial.
  • One or more excipients for forming a chlelate can also be provided.
  • kits for formation of radiodiagnostic imaging agents comprising a compound of Formula I provided in a vial.
  • excipients for forming a chlelate can also be provided.
  • kits for formation of radiodiagnostic imaging agents comprising a compound of Formula I provided in a vial.
  • excipients for forming a chlelate can also be provided.
  • Another aspect of the present invention is directed to methods of radioimaging comprising administering a chelate of Formula II to a subject and thereafter imaging.
  • a preferred aspect is directed to myocardial perfusion imaging, employing a radiogallium complex of Formula II, and imaging using PET.
  • FIG. 1 illustrates a preferred retro-synthetic route of compounds of Formula I from synthons of
  • FIG. 2 provides a scheme for a preferred synthetic route for synthesizing compounds of
  • FIG. 3 provides a scheme for a preferred synthetic route for synthesizing compounds of
  • FIG. 4 A depicts a TLC profile of a preferred embodiment of the present invention, complex
  • FIG. 4B provides the structure of a preferred embodiment of the present invention, complex
  • FIG. 4C provides the structure of preferred embodiment of the present invention, complex 67 / G- a-
  • FIG. 4D provides a comparison of the heart uptake of two embodiments of the present invention
  • FIG. 5 Autoradiography of a preferred embodiment of the present invention, 67 / Ga-B, in healthy Sprague Dawley rat heart (upper row) and in a Sprague Dawley rat which underwent a procedure to have the anterior branch of the left main coronary artery permanently ligated (lower row).
  • FIG.6 X-ray Crystal (Ortep diagram) of the a preferred embodiment of the present invention, complex 67 Ga-B
  • the present invention is directed to novel compounds useful for forming radioisotopic complexes, radioisotopic complexes, their use as imaging agents for positron emission tomography (PET) and, in certain embodiments, to novel gallium complexes with enhanced myocardial uptake and retention, due to the lipid-solubility and cationic nature of such novel complexes.
  • PET positron emission tomography
  • Radioisotopic complexes of Formula II are prepared from radioisotopes such as, for example, 68 Gallium or 67 Gallium, wherein the complexes formed are stable 1 charged cations.
  • the radioisotopic complexes of the present invention display enhanced lipophilicity and enhanced uptake in the heart and greater retention in said tissue, therefore such Gallium complexes will be useful as myocardial profusion imaging agents.
  • Such examples of radioisotopes are mentioned only by way of illustration and without implied limitation, 6 8 Gallium and 67 Gallium radioisotopes are preferred.
  • the present invention is directed to compounds of Formula I, or pharmaceutically acceptable salts thereof; wherein A 1 , A 2 and A 3 are the same or different cycloalkyl, wherein at least one of A 1 , A 2 or A 3 is substituted, R 1 through R 6 are independently hydrogen or alkyl and R 7 and R 8 are independently hydrogen or alkyl; and R P is hydrogen or sulfhydryl protecting group.
  • a 1 , A 2 and A 3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which is optionally substituted.
  • a 1 , A 2 and A 3 are independently selected from the group consisting of cyclopentyl, cyclohexyl or cycloheptyl, which are optionally substituted.
  • the compound A 1 , A 2 and A 3 are optionally mono, di or tri substituted with substituents that are independently amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_ 6 )alkyl, amino(Ci_ 6 )alkyl, hydroxy(Ci_ 6 )alkyl, halo(Ci_ 6 )alkyl, cyano(Ci_ 6 )alkyl, thio(Ci_ 6 )alkyl, carboxy(Ci_ 6 )alkyl, aryl(Ci_ 6 )alkyl, (Ci_ 6 )alkoxy(Ci_ 6 )alkyl, (C 2 _ 6 )alkeny
  • a 1 , A 2 and A 3 are cyclohexyl optionally substituted by hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18 fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy.
  • a 1 is unsubstituted.
  • a 2 is unsubstituted.
  • A is mono substituted at the 2 position or mono substituted at the 3 position.
  • A is mono substituted at the 4 position and substituted with a substituent that is methoxy, 3-fluoropropoxy, 3-hydroxypropoxy and X- ((CR a R b )2 ⁇ ) n , wherein X is halo or hydroxy and R a and R b are each independently hydrogen or C i_4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
  • R 1 through R 8 are independently hydrogen or (d_ 6 )alkyl. In some embodiments R 1 through R 8 are independently hydrogen, methyl, ethyl, propyl, a butyl, pentyl and hexyl, wherein the group may be straight chained or branched and in further embodiments R 1 through R 8 are each hydrogen. In some embodiments of the compound of Formula I, R p is hydrogen, methoxymethyl, methoxyexthoxyethyl, p- methoxybenzyl and benzyl. In some embodiments, each R p is hydrogen.
  • the present invention is also directed to the production of metal chelates whereby in some embodiments, a metal chelate is produced by mixing a compound of Formula I with a metal salt.
  • the metal salt is a salt of a metal that is Technetium-99m, Rhenium-188, Cobalt-57, cold Gallium, Gallium-68, Gallium-67, Indium-111, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201.
  • the metal is gallium.
  • the metal chelate is stabilized by counterion that is halide, sulfate, nitrate, carboxylate or phosphate. In some embodiments said counterion is halide.
  • the present invention is also directed to complexes of Formula II or pharmaceutically acceptable salts thereof; wherein A 1 , A 2 and A 3 are the same or different cycloalkyl, wherein at least one of A 1 , A 2 or A 3 is substituted, R 1 through R 6 are independently hydrogen or alkyl and R 7 and R 8 are independently hydrogen or alkyl, and M is a metal
  • a 1 A 2 and A 3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which are optionally substituted.
  • a 1 , A 2 and A 3 are independently cyclopentyl, cyclohexyl or cycloheptyl, which are optionally substituted. In some embodiments A 1 , A 2 and A 3 are optionally mono, di or tri substituted with substituents that are amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_ 6 )alkyl, amino(Ci_ 6 )alkyl, hydroxy(Ci_ 6 )alkyl, halo(Ci_ 6 )alkyl, cyano(Ci_ 6 )alkyl, thio(Ci_ 6 )alkyl, carboxy(Ci_ 6 )alkyl, aryl(Ci_ 6 )alkyl, (Ci_ 6 )alkoxy(Ci_ 6 )alkyl, (C 2 .
  • a 1 , A 2 and A 3 are cyclohexyl optionally substituted by hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18 fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy.
  • a 1 is unsubstituted
  • a 2 is unsubstituted.
  • a 3 is mono substituted at the 2 position, in some embodiments A 3 is mono substituted at the 3 position.
  • a 3 is mono substituted at the 4 position and in some embodiments A 3 is substituted with a substituent selected from the group comprising a methoxy, a 3-fluoropropoxy, 3-hydroxypropoxy and X- ((CR a R b ) 2 ⁇ ) n , wherein X is halo or hydroxy and R a and R b are each independently hydrogen or C i_4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
  • R 1 through R 8 are independently hydrogen or (Ci_ 6 )alkyl. In some embodiments R 1 through R 8 are independently hydrogen, methyl, ethyl, propyl, a butyl, pentyl or hexyl, wherein the group may be straight chained or branched. In some embodiments R 1 through R 8 are each hydrogen.
  • M is a metal that is Technetium-99m, Rhenium-188, Cobalt-57, Gallium-68, Gallium-67, cold Gallium, Indium-I l l, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201.
  • M is Gallium-68, in some embodiments M is Gallium-67 and in some embodiments M is cold Gallium whilst A is substituted with a radioactive 18-Fluoropropoxy to produce a radioactive complex.
  • complexes of Formula II are stabilized by a counterion A " , that is halide, sulfate, nitrate, carboxylate or phosphate.I
  • the counterion is halide.
  • the present invention is also directed to radioactive imaging kits comprising a first vial of a compound of Formula I, and second vial of a salt of a radioactive metal, wherein the contents of the first vial and the contents of the second vial are mixed to form a radioisotopic complex suitable for use as an imagining agent.
  • the methods of imaging comprise administering the radioisotopic complex to a subject and thereafter imaging said subject.
  • the method of imaging will comprise myocardial perfusion imaging, comprising administering the radioisotopic complex of Formula II to a subject; thereafter imaging the heart of said subject.
  • said subject will in be human and in some embodiments said subject will be mammalian.
  • Complexes of Formula II of the present invention have a formal cationic charge of +1.
  • N 2 S 2 bisaminothiolate
  • Figure 1 depicts how the final N 2 S 2 ligand, Structure 1, can be achieved from Structures, II and III.
  • No-carrier-added [ 67 Ga] citrate (1 mCi/mL) is added to the N 2 S 2 ligand (1 mg) in 0.5 rnL of water.
  • the mixture is vortexed and heating at 75 0 C for 0.5 hr.
  • the percent labeling yield is measured by thin-layer chromatography (Silica gel plate, developing solvent: acetone: acetic acid 3:1, v/v) see FIG 4A.
  • the radiochemical purity (RCP) of [ 67 GaJBiaminothiolate-tricyclohexyl complex (FIG 4B) is determined to be > 90%. This material was used directly for animal studies. The effect of acidity and reaction time on the formation of this complex can also be determined by the same TLC technique.
  • Biodistribution studies were performed using utilizing Sprague Dawley rats. (Tables 1 and 2). Under isoflurane anesthesia, 0.2 ml of saline solution (containing 10-100 mCi of radioactive tracer) was injected into the femoral vein. The rats were sacrificed at the time indicated by cardiac excision while under anesthesia. Organs of interest were removed and weighed, and the radioactivity was counted. The percent dose per organ was calculated by comparing the tissue counts to counts of 1% of the initial dose (aliquots of the injected material diluted 100 times) measured at the same time.
  • the [ 67 Ga]biaminothiolate-tricyclohexyl (Ga-B) complex was also compared to other myocardial perfusion imaging complexes including the [ 67 Ga]biaminothiolato-tetraethyl-cyclohexyl (Ga-A) complex of the prior invention (FIG 4C). It can be seen from FIG 5 that in vivo bio-distribution of this novel 67 Gallium-complex which are tested in normal rats exhibited excellent heart uptake and retention with a heart uptake compared to 1.68 % dose/organ (Ga-A) after 2 minutes and a retention of 0.9, compared to 0.26 % dose/organ for Gallium-A after 60 minutes.
  • GaJBiaminothiolate- tricyclohexyl (Ga-B) complex suggests that this agent, as well as related complexes within the scope of Formula II should provide an enhanced myocardial perfusion imaging in comparison to the less lipophilic complexes.
  • Complexes of the present invention also indicate that the highly lipophilic plus one charged complexes are trapped in the myocardial tissue in a similar fashion to 99m Tc myocardial imaging agents as presented in Tables 3, and 4 for the bio-distribution in Sprague Dawley rats after an IV injection of [Tc-99m] sestaMIBI via the femoral vein.

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Abstract

The present invention is directed to compounds of Formula I: and pharmaceutically acceptable salts thereof; wherein A1, A2 and A3 are the same or different cycloalkyl, wherein at least one of A1, A2 or A3 is substituted. R1 through R6 are independently hydrogen or alkyl, R7 and R8 are independently hydrogen or alkyl and RP is hydrogen or sulfhydryl protecting group. This invention is also directed to complexes, wherein said compounds chelate radioactive metal ions, such as Gallium. The complexes of the rpesent invention are useful as myocardial perfusion imaging agents.

Description

NEW GALLIUM BISAMINOTHIOLATE COMPLEXES FOR MYOCARDIAL
IMAGING
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application No. 60/907,703, filed Aprill3, 2007, the entirety of which is incorporated herein by reference.
GOVERNMENT RIGHTS
Part of the work performed during development of this invention utilized U.S. Government funds. The U.S. Government has certain rights in this invention.
FIELD OF THE INVENTION
The present invention is directed to novel ligands and radioisotopic complexes useful as imaging agents for positron emission tomography (PET). One aspect is related to novel gallium complexes having excellent myocardial uptake and retention, due to the lipid-solubility and cationic nature of such novel complexes.
BACKGROUND OF THE INVENTION
The present invention is directed to novel radioisotopic complexes for positron emission tomography (PET) and, more specifically, to novel gallium complexes with enhanced lipid- solubility which possess utility as myocardial imaging agents. Positron emission tomography (PET) is a technique whereby a three-dimensional reconstruction of in vivo radionuclide distribution is possible, providing images that map and quantitate tissue activity levels. The demand for new and novel positron-emitting radiopharmaceuticals continues to increase as more institutions acquire instrumentation for PET imaging.
There are two gallium radioisotopes: Gallium-67 and Gallium-68. Both possess nuclear properties that make them attractive for use in nuclear medicine. The first, Gallium-67, is cyclotron-produced from Zn-68, has a half life of 78 hours and is commercially available as gallium chloride and gallium citrate. The second, Gallium-68, has the distinction of being one of the few short-lived positron emitting radionuclides available from a parent/daughter generator system, 68Ge/68Ga. Such generator systems for producing positron emitting isotope without an on-site cyclotron have been reported (Ehrhardt GJ, Welch MJ., J Nucl Med. 1978;19:925-9, Neirinckx RD, Davis MA. Potential column chromatography generators for ionic Gallium-68. 1. Inorganic substrates. J Nucl Med. 1979;20:1075-9, Loc'h C, Maziere B, Comar D. A new generator for ionic gallium-68. J Nucl Med. 1980;21 : 171-3 and Neirinckx RD, Davis MA. Potential column chromatography for ionic Gallium-68. II: Organic ion exchangers as chromatographic supports. J Nucl Med. 1980;21 :81-3). The unique features of this radionuclide generator system is the relatively long parent half- life (68Ge, T 1/2 = 270 d) and suitable daughter half-life (68Ga, T1/2 = 68 min). Separation of parent, 68Ge, from the desired daughter, 68Ga, is achieved using solid oxides (such as, TiO2, ZrO2 or SiO2) supported column chromatography. The column is eluted with a strong acid, under the strong acidic condition it leads to Ga(III) complexes avoiding the formation of gallium hydroxide as a solid precipitate. A tin dioxide/1 N HCl generator also provided a sterile solution of Gallium-68 in ionic form, ready for use in the preparation of many radiopharmaceuticals see Loc'h C, Maziere B, Comar D. A new generator for ionic gallium-68. J Nucl Med. 1980;21 : 171-3.
A similar column chromatography separation system using organic polymer (phenolic ion exchanger) coupled in series with a small anion exchange column (AG-I) was successfully employed for producing 68Ga for labeling see Schuhmacher J, Maier-Borst W. A new 68Ge/68Ga radioisotope generator system for production Of68Ga in dilute HCl. Int J Appl Radiat Isot. 1981;32:31-36. Alternatively, a new organic polymer (macroporous styrene-divinylbenzene copolymer) containing N-methylglucamine groups was reported for a new 68Ge/68Ga generator system as discussed in Nakayama M, Haratake M, Ono M, Koiso T, Harada K, Nakayama H, Yahara S, Ohmomo Y, Arano Y. A new 68Ge/68Ga generator system using an organic polymer containing N-methylglucamine groups as adsorbent for 68Ge. Int J Appl Radiat Isot. 2003;58:9- 14. The criteria for an ideal 68Ge/68Ga generator system include: 1) high efficient separation of 68Ga from the column; 2) minimum amount of "parent breakthrough" - low level Of68Ge in the eluent; 3) stability of the column over time. All of the reported 68Ga/68Ge generator systems meet the basic criteria listed above; however, one major unmet need in the field of nuclear medicine is the lack of FDA approved commercial 68Ge/68Ga generator system for human use, which limits the potential for developing 68Ga labeled radiopharmaceuticals for PET imaging see Breeman WA, Verbruggen AM. The (68)Ge/(68)Ga generator has high potential, but when can we use (68)Gallium-labelled tracers in clinical routine? Eur J Nucl Med MoI Imaging. 2007.
Recently, there has been renewed interest in using 68Ga for PET imaging for example Maecke HR, Hofmann M, Haberkorn U. (68)Gallium-labeled peptides in tumor imaging. J Nucl Med. 2005;46 Suppl 1 :172S-8S, Meyer GJ, Macke H, Schuhmacher J, Knapp WH, Hofmann M. 68Gallium-labelled DOTA-derivatised peptide ligands. Eur J Nucl Med MoI Imaging. 2004;31 :1097-104 and Rufini V, Calcagni ML, Baum RP. Imaging of neuroendocrine tumors. Semin Nucl Med. 2006;36:228-47. Of particular interest is the recent development Of68Ga labeled peptides targeting endocrine tumor receptors (von Falck C, Boerner AR, Galanski M, Knapp WH. Neuroendocrine tumour of the mediastinum: fusion of (18)F-FDG and (68)Gallium- DOTATOC PET/CT datasets demonstrates different degrees of differentiation. Eur J Nucl Med MoI Imaging. 2007, Velikyan I, Sundberg AL, Lindhe O, Hoglund AU, Eriksson O, Werner E, Carlsson J, Bergstrom M, Langstrom B, Tolmachev V. Preparation and evaluation of (68)Gallium-DOTA-hEGF for visualization of EGFR expression in malignant tumors. J Nucl Med. 2005;46:1881-8., Zhang H, Schuhmacher J, Waser B, Wild D, Eisenhut M, Reubi JC, Maecke HR. DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours. Eur J Nucl Med MoI Imaging. 2007, Dimitrakopoulou-Strauss A, Georgoulias V, Eisenhut M, Herth F, Koukouraki S, Macke HR, Haberkorn U, Strauss LG. Quantitative assessment of SSTR2 expression in patients with non-small cell lung cancer using(68)Gallium-DOTATOC PET and comparison with (18)F- FDG PET. Eur J Nucl Med MoI Imaging. 2006;33:823-30, Koukouraki S, Strauss LG, Georgoulias V, Eisenhut M, Haberkorn U, Dimitrakopoulou-Strauss A. Comparison of the pharmacokinetics of (68)Gallium-DOTATOC and [ (18)F]FDG in patients with metastatic neuroendocrine tumours scheduled for (9O)Y-DOTATOC therapy. Eur J Nucl Med MoI Imaging. 2006;33:l 115-22 and Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC, Maecke H. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med MoI Imaging. 2007. Through the use of DOTA or DTPA as the chelating group, various peptides had been successfully labeled with 68Ga for PET imaging, including analogs of somatostatin, epidermic growth factor receptor (EGFR), substance P, bombesin, gastrin and CCK as described in Antunes P, Ginj M, Walter MA, Chen J, Reubi JC, Maecke HR. Influence of different spacers on the biological profile of a DOTA-somatostatin analogue. Bioconjug Chem. 2007; 18:84-92, van Hagen PM, Breeman WA, Reubi JC, Postema PT, van den Anker-Lugtenburg PJ, Kwekkeboom DJ, Laissue J, Waser B, Lamberts SW, Visser TJ, Krenning EP. Visualization of the thymus by substance P receptor scintigraphy in man. Eur J Nucl Med. 1996;23:1508-13 and Behr TM, Behe MP. Cholecystokinin-B/Gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies. Semin Nucl Med. 2002;32:97-109.
These metal complexes when labeled with other radionuclides can also be useful as radiotherapeutic agents, thus providing a "see and treat" approach in tumor diagnosis and treatment (Ginj M, Chen J, Walter MA, Eltschinger V, Reubi JC, Maecke HR. Preclinical evaluation of new and highly potent analogues of octreotide for predictive imaging and targeted radiotherapy. Clin Cancer Res. 2005; 11 :1136-45, van Essen M, Krenning EP, Kooij PP, Bakker WH, Feelders RA, de Herder WW, Wolbers JG, Kwekkeboom DJ. Effects of therapy with [177Lu-DOTAO, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med. 2006;47: 1599-606 and Frilling A, Weber F, Saner F, Bockisch A, Hofmann M, Mueller-Brand J, Broelsch CE. Treatment with (9O)Y- and (177)Lu- DOTATOC in patients with metastatic neuroendocrine tumors. Surgery. 2006; 140:968-76; discussion 76-7.
Previously, Gallium complexes OfN2S2 (bisaminoethanethiolate,) (Kung HF, Liu B-L, Mankoff D, Kung M-P, Billings JJ, Francesconi LC, Alavi A. A new myocardial imaging agent: synthesis, characterization, and biodistribution of gallium-68-B AT-TECH. J Nucl Med. 1990;31 :1635-40, Francesconi LC, Liu B-L, Billings JJ, Carroll PJ, Graczyk G, Kung HF. Synthesis, characterization and solid state structure of a neutral gallium(III) amino thiolate complex: a potential radiopharmaceutical for PET imaging. J Chem Soc Chem Comm. 1991;2:94-95 and Zheng YY, Saluja S, Yap GP, Blumenstein M, Rheingold AL, Francesconi LC. Gallium and Indium Complexes of Bis(amino thiol) (N(2)S(2)) Ligands. Inorg Chem. 1996;35:6656-66) as well as NS3 (Cutler CS, Giron MC, Reichert DE, Snyder AZ, Herrero P, Anderson CJ, Quarless DA, Koch SA, Welch MJ. Evaluation of gallium-68 tris(2- mercaptobenzyl)amine: a complex with brain and myocardial uptake. Nucl Med Biol. 1999;26:305-16) have been reported. Thus, it has previously been found that stable radioisotopic complexes can be prepared from gallium radioisotopes and the ligand tetraethylcyclohexyl- bisaminoethanethiol.
The clinical applications of radioisotopic complexes also depend on the biodistribution properties of the specific radiopharmaceutical agents. Thus, for example, high definition imaging of heart tissue requires not only efficient myocardial uptake of the radiopharmaceutical agent but, as well, retention of the radioactivity in the targeted issue. The ideal radioisotopic complex will exhibit a biodistribution pattern which will provide higher concentrations of the radioisotopic complex in the targeted tissue relative to the blood levels and relative to its concentration in adjacent non-targeted tissues. Thus, the significant properties of radioisotopic complex designed for imaging the heart are high myocardial tissue uptake, good heart/blood ratios, and prolonged retention of the radiopharmaceutical concentrations in the myocardial tissues relative to that in the blood and of other tissues/organs in the thoracic cavity.
One unique feature of the Gallium bisaminoethanethiolate complexes is that they have a plus one charge. When dissolved in water, the stabilizing counterion dissociated to form a Gallium bisaminothiolate (GaBAT) a plus one charge ion. It is believed that the highly lipophilic plus one charged complexes become trapped in the myocardial tissue similar to those 99mTc myocardial imaging agents (99mTc-MIBI and Tetrafosamine). One aspect of the present invention is related to novel radioisotopic complexes having suitable organ uptake and retention. One aspect is directed to Gallium radioisotropic complexes of tricyclohexyl analogs of bisaminoethanethiolate having improved myocardial uptake and retention. A need continues to exist in the art for radioactive metal complexes useful for imaging. A need continues to exist in the art for imaging agents for myocardial perfusion studies using PET.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula I and radioisotopic complexes of Formula II, wherein bisaminothiolate tricyclohexyl ligands and Gallium-68 bisaminothiolate tricyclohexyl complexes are generated.
Such complexes are highly lipophilic, possessing two additional methylene moieties with a plus one charge, whereby the radioactive complex is trapped in the myocardial tissue at an with increased incident, hence enhancing it's myocardial perfusion and retention and subsequent efficacy as an imaging agent.
This invention therefore relates to compounds of Formula I:
Figure imgf000006_0001
or pharmaceutically acceptable salts such as chloride or bromide salts, wherein each of A1, A2 and A3 are the same or different, and are optionally substituted cycloalkyl, R1 through R6 are independently hydrogen or alkyl, whilst R7 and R8 are independently hydrogen or alkyl; and RP is hydrogen or a sulfhydryl protecting group.
Further, this invention relates to complexes of Formula II:
Figure imgf000007_0001
II
or a pharmaceutically acceptable salts thereof; wherein, A1, A2 and A3 are the same or different, and are optionally substituted cycloalkyl. R1 through R6 are independently hydrogen or alkyl and R7 and R8 are independently hydrogen or alkyl and M is a metal, where in some embodiments is M is a radioisotope. A" is a monovalent counterion, wherein some embodiments the counterion is a halide. The complexes are radioisotopic complexes and imaging agents, with increased lipophilicity and a +1 cationic charge.
In vivo tests indicate that complexes of Formula II are lipid-soluble, and that the compounds exhibit high uptake in the heart as well as in the liver, providing further evidence that the radioisotopic complexes of the present invention should therefore be useful as tracers for myocardial perfusion imaging. In addition since said complexes may be prepared using Gallium- 68 isotopes, the complexes of the invention also offer the advantage of being available to institutions not having the use of an on-site cyclotron.
Another aspect of the present invention is directed to method for the formation of metal chelates by mixing a compound of Formula I with a metal or metal salt under conditions that provide formation of a metal chelate. Another aspect of the present invention is directed to metal chelates formed by the preceeding process.
Another aspect of the present invention is directed to kits for formation of radiodiagnostic imaging agents, comprising a compound of Formula I provided in a vial. One or more excipients for forming a chlelate can also be provided. Another aspect of the present invention is directed to methods of radioimaging comprising administering a chelate of Formula II to a subject and thereafter imaging. A preferred aspect is directed to myocardial perfusion imaging, employing a radiogallium complex of Formula II, and imaging using PET.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a preferred retro-synthetic route of compounds of Formula I from synthons of
Formulas IF and III'. FIG. 2 provides a scheme for a preferred synthetic route for synthesizing compounds of
Formulas HA, HB, HC, HD and III. FIG. 3 provides a scheme for a preferred synthetic route for synthesizing compounds of
Formulas IA, IB, IC and ID. FIG. 4 A depicts a TLC profile of a preferred embodiment of the present invention, complex
67Ga-R FIG. 4B provides the structure of a preferred embodiment of the present invention, complex
67 Ga-B.
FIG. 4C provides the structure of preferred embodiment of the present invention, complex 67/ G- a-
A1 FIG. 4D provides a comparison of the heart uptake of two embodiments of the present invention,
67 Ga-A and 67Ga-B.
FIG. 5 Autoradiography of a preferred embodiment of the present invention, 67/ Ga-B, in healthy Sprague Dawley rat heart (upper row) and in a Sprague Dawley rat which underwent a procedure to have the anterior branch of the left main coronary artery permanently ligated (lower row).
FIG.6 . X-ray Crystal (Ortep diagram) of the a preferred embodiment of the present invention, complex 67Ga-B
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The present invention is directed to novel compounds useful for forming radioisotopic complexes, radioisotopic complexes, their use as imaging agents for positron emission tomography (PET) and, in certain embodiments, to novel gallium complexes with enhanced myocardial uptake and retention, due to the lipid-solubility and cationic nature of such novel complexes.
Compounds of Formula I and radioisotopic complexes of Formula II, or their pharmaceutically acceptable salts, hydrates, solvates, and prodrugs; are prepared from radioisotopes such as, for example, 68Gallium or 67Gallium, wherein the complexes formed are stable 1 charged cations. The radioisotopic complexes of the present invention display enhanced lipophilicity and enhanced uptake in the heart and greater retention in said tissue, therefore such Gallium complexes will be useful as myocardial profusion imaging agents. Such examples of radioisotopes are mentioned only by way of illustration and without implied limitation, 68Gallium and 67Gallium radioisotopes are preferred.
The present invention is directed to compounds of Formula I, or pharmaceutically acceptable salts thereof; wherein A1, A2 and A3 are the same or different cycloalkyl, wherein at least one of A1, A2 or A3 is substituted, R1 through R6 are independently hydrogen or alkyl and R7 and R8 are independently hydrogen or alkyl; and RP is hydrogen or sulfhydryl protecting group.
In some embodiments of compounds of Formula I, A1, A2 and A3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which is optionally substituted.
In some embodiments A1, A2 and A3 are independently selected from the group consisting of cyclopentyl, cyclohexyl or cycloheptyl, which are optionally substituted. In some embodiments the compound A1, A2 and A3 are optionally mono, di or tri substituted with substituents that are independently amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_6)alkyl, amino(Ci_6)alkyl, hydroxy(Ci_6)alkyl, halo(Ci_6)alkyl, cyano(Ci_6)alkyl, thio(Ci_6)alkyl, carboxy(Ci_6)alkyl, aryl(Ci_6)alkyl, (Ci_6)alkoxy(Ci_6)alkyl, (C2_6)alkenyl, amino(C3-io)alkenyl, hydroxy(C3-io)alkenyl, halo(C2-6)alkenyl, cyano(C2-6)alkenyl, thio(C3-io)alkenyl, carboxy(C3-io)alkenyl, aryl(C2-6)alkenyl, (C2-6)alkynyl, (Ci_6)heteroalkyl, (C2- 6)heteroalkenyl, (C2-6)heteroalkynyl, (Ci_6)alkoxy, (C3-io)alkenyloxy, (Ci-6)alkylenedioxy, amino(C2-6)alkoxy, hydroxy(C2-6)alkoxy, halo(Ci_6)alkoxy, cyano(Ci_6)alkoxy, thio(Ci_6)alkoxy, carboxy(C2-6)alkoxy, aryl(Ci_6)alkoxy, (Ci_6)alkoxy(C2-6)alkoxy, halo(Ci_6)alkoxy(C2-6)alkoxy, mono(Ci_6)alkylamino, di(Ci_6)alkylamino, (Ci_6)alkylcarbonylamino, (C2- 6)alkenylcarbonylamino, (C6-i4)arylcarbonylamino, (Ci_6)alkoxycarbonylamino, (C6_io)aryloxycarbonylamino, (Ci_6)alkylcarbonyl, (C2_6)alkenylcarbonyl, (C6_io)arylcarbonyl, (Ci_6)alkoxycarbonyl, (C6-i4)aryloxycarbonyl, (Ci_6)alkylsulfonylamino, (C2- 6)alkenylsulfonylamino, (C6-i4)arylsulfonylamino or X-((CRaRb)2θ)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or C 1-4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
In some embodiments A1, A2 and A3 are cyclohexyl optionally substituted by hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy. In some embodiments A1 is unsubstituted. In some embodiments A2 is unsubstituted. In some embodiments A is mono substituted at the 2 position or mono substituted at the 3 position. In some embodiments A is mono substituted at the 4 position and substituted with a substituent that is methoxy, 3-fluoropropoxy, 3-hydroxypropoxy and X- ((CRaRb)2θ)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or C i_4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
In some embodiments of the compound of Formula I, R1 through R8 are independently hydrogen or (d_6)alkyl. In some embodiments R1 through R8 are independently hydrogen, methyl, ethyl, propyl, a butyl, pentyl and hexyl, wherein the group may be straight chained or branched and in further embodiments R1 through R8 are each hydrogen. In some embodiments of the compound of Formula I, Rpis hydrogen, methoxymethyl, methoxyexthoxyethyl, p- methoxybenzyl and benzyl. In some embodiments, each Rp is hydrogen.
The present invention is also directed to the production of metal chelates whereby in some embodiments, a metal chelate is produced by mixing a compound of Formula I with a metal salt. In some embodiments the metal salt is a salt of a metal that is Technetium-99m, Rhenium-188, Cobalt-57, cold Gallium, Gallium-68, Gallium-67, Indium-111, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201. In some embodiments the metal is gallium. In some embodiments the metal chelate is stabilized by counterion that is halide, sulfate, nitrate, carboxylate or phosphate. In some embodiments said counterion is halide.
The present invention is also directed to complexes of Formula II or pharmaceutically acceptable salts thereof; wherein A1, A2 and A3 are the same or different cycloalkyl, wherein at least one of A1, A2 or A3 is substituted, R1 through R6 are independently hydrogen or alkyl and R7 and R8 are independently hydrogen or alkyl, and M is a metal In some embodiments of the complexes of present invention A1 A2 and A3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which are optionally substituted. In some embodiments A1, A2 and A3 are independently cyclopentyl, cyclohexyl or cycloheptyl, which are optionally substituted. In some embodiments A1, A2 and A3 are optionally mono, di or tri substituted with substituents that are amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_6)alkyl, amino(Ci_6)alkyl, hydroxy(Ci_6)alkyl, halo(Ci_6)alkyl, cyano(Ci_6)alkyl, thio(Ci_6)alkyl, carboxy(Ci_6)alkyl, aryl(Ci_6)alkyl, (Ci_6)alkoxy(Ci_6)alkyl, (C2.6)alkenyl, amino(C3-io)alkenyl, hydroxy(C3-io)alkenyl, halo(C2-6)alkenyl, cyano(C2-6)alkenyl, thio(C3-io)alkenyl, carboxy(C3-io)alkenyl, aryl(C2-6)alkenyl, (C2-6)alkynyl, (Ci_6)heteroalkyl, (C2- 6)heteroalkenyl, (C2-6)heteroalkynyl, (d_6)alkoxy, (C3_i0)alkenyloxy, (Cl-β)alkylenedioxy, amino(C2-6)alkoxy, hydroxy(C2-6)alkoxy, halo(Ci_6)alkoxy, cyano(Ci_6)alkoxy, thio(Ci_6)alkoxy, carboxy(C2-6)alkoxy, aryl(Ci_6)alkoxy, (Ci_6)alkoxy(C2-6)alkoxy, halo(Ci_6)alkoxy(C2-6)alkoxy, mono(Ci_6)alkylamino, di(Ci_6)alkylamino, (Ci_6)alkylcarbonylamino, (C2- 6)alkeny lcarbony lamino , (C6-14)ary lcarbony lamino , (Ci _δ)alkoxy carbony lamino , (C6_io)aryloxycarbonylamino, (Ci_6)alkylcarbonyl, (C2_6)alkenylcarbonyl, (C6_io)arylcarbonyl, (Ci_6)alkoxycarbonyl, (C6-i4)aryloxycarbonyl, (Ci_6)alkylsulfonylamino, (C2- 6)alkenylsulfony lamino, (C6-i4)arylsulfonylamino or X-((CRaRb)2θ)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or C 1-4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
In some embodiments A1, A2 and A3 are cyclohexyl optionally substituted by hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy. In some embodiments A1 is unsubstituted, in some embodiments A2 is unsubstituted. In some embodiments A3 is mono substituted at the 2 position, in some embodiments A3 is mono substituted at the 3 position. In some embodiments A3 is mono substituted at the 4 position and in some embodiments A3 is substituted with a substituent selected from the group comprising a methoxy, a 3-fluoropropoxy, 3-hydroxypropoxy and X- ((CRaRb)2θ)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or C i_4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
In some embodiments of the complexes of the present invention R1 through R8 are independently hydrogen or (Ci_6)alkyl. In some embodiments R1 through R8 are independently hydrogen, methyl, ethyl, propyl, a butyl, pentyl or hexyl, wherein the group may be straight chained or branched. In some embodiments R1 through R8 are each hydrogen. In complexes of Formula II of the present invention, M, is a metal that is Technetium-99m, Rhenium-188, Cobalt-57, Gallium-68, Gallium-67, cold Gallium, Indium-I l l, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201. In some embodiments M is Gallium-68, in some embodiments M is Gallium-67 and in some embodiments M is cold Gallium whilst A is substituted with a radioactive 18-Fluoropropoxy to produce a radioactive complex.
In some embodiments complexes of Formula II are stabilized by a counterion A", that is halide, sulfate, nitrate, carboxylate or phosphate.I In some embodiments the counterion is halide.
The present invention is also directed to radioactive imaging kits comprising a first vial of a compound of Formula I, and second vial of a salt of a radioactive metal, wherein the contents of the first vial and the contents of the second vial are mixed to form a radioisotopic complex suitable for use as an imagining agent. In some embodiments, the methods of imaging comprise administering the radioisotopic complex to a subject and thereafter imaging said subject. In some embodiments, the method of imaging will comprise myocardial perfusion imaging, comprising administering the radioisotopic complex of Formula II to a subject; thereafter imaging the heart of said subject. In some embodiments said subject will in be human and in some embodiments said subject will be mammalian. Complexes of Formula II of the present invention have a formal cationic charge of +1.
Methods of Preparation and Examples
The generation of the bisaminothiolate (N2S2) ligands of the present invention can be described via a retrosynthetic route. Figure 1 depicts how the final N2S2 ligand, Structure 1, can be achieved from Structures, II and III. The formation of a diimine linkage between diamine II and dialdehyde III and the subsequent reduction of imine and disulfide bonds affords the target (Structure I).
The preparation of synthons H(A-D) and III are depicted in Figure 2. The Strecker amino-cyanation reaction of cyclohexanone afforded the aminonitrile 2. The subsequent hydrogenation of the HCl salt of 2 over PtO2 yielded the diamine HA as its dihydrochloride salt. Synthesis of HB was achieved starting from 1 ,4-cyclohexanedione monoethyleneketal 3. The reduction of the free keto group in 3 followed by the methylation of the resulting alcohol affords methoxy derivative 5. Deprotection of the keto group and consequent Strecker reaction affords 7 as a mixture of cis and trans isomers. The hydrogenation of the nitrile group of the HCl salt of 7 over Adam's catalyst affords HB as its dihydrochloride salt. For the preparation of H(C-D), the free hydroxy group in 4 was allylated and the resulting allyloxy compound was subjected to hydroboration/oxidation to obtain hydroxypropyloxy derivative 10. Subsequent deblocking, Strecker and reduction methods affords HD as a mixture of diastereomers. SN2 displacement of mesyl group in 11, obtained by the mesylation of free OH in 10, by fluoride ion (TBAF) affords the fluoropropyl derivative 12. Further deblocking, Strecker, followed by a reduction sequence affords HC (as a mixture of diastereomers). The preparation of III is achieved by treating cyclohexanecarboxaldehyde with sulfurmonochloride.
The preparation of compounds I(A-D) from H(A-D) and III is depicted in Figure 3. Treatment of dialdehyde III with the free base of HA in refluxing methanol afforded the diimine 17. Red- Al reduction of 17 in refluxing toluene results in cleavage of disulfide bond along with the reduction of diimine moiety to afford 18 which is then purified as its dihydrochloride salt. A similar sequence of reactions of H(B-D) with III afforded I(B-D) (Figure 3) as mixture of diastereomers. The radioisotope is reacted with the N2S2 ligands. No-carrier-added [67Ga] citrate (1 mCi/mL) is added to the N2S2 ligand (1 mg) in 0.5 rnL of water. The mixture is vortexed and heating at 750C for 0.5 hr. The percent labeling yield is measured by thin-layer chromatography (Silica gel plate, developing solvent: acetone: acetic acid 3:1, v/v) see FIG 4A. The radiochemical purity (RCP) of [67 GaJBiaminothiolate-tricyclohexyl complex (FIG 4B) is determined to be > 90%. This material was used directly for animal studies. The effect of acidity and reaction time on the formation of this complex can also be determined by the same TLC technique.
Analysis of complexes are performed by 1H NMR, using a Bruker DPX 200 spectrometer and tetramethylsilane as an internal standard. High resolution mass spectrometries were also measured. Microwave reactions were performed on a Biotage Initiator™ microwave reactor. Tetrahydrofuran (THF) was distilled immediately before use from sodium benzophenone ketyl. All other chemicals were purchased from Aldrich Chemical Co. and used without further purification. HPLC systems were used to determine the purities of target compounds. Two HPLC measurements were performed using an Agilent 1100 Series with an isocratic pump and a UV detector. Measurements were performed on a Phenomenex Gemini analytical C-18 column (250 x 4.6 mm, 5 micron) with acetonitrile/ammonium formate buffer (10 mM) 80/20, v/v flow rate 1.0 mL/min at 254 nm (System A), and on a Hamilton PRP- 1 analytical column (250 x 4.1 , 10 micron) with acetonitrile/dimethyl glutarate buffer (5 mM pH 7) 90/10, v/v flow rate 1.0 mL/min at 254 nm (System B). Male CDl rats weighing 200-225 g were used in all the studies.
Biodistribution studies were performed using utilizing Sprague Dawley rats. (Tables 1 and 2). Under isoflurane anesthesia, 0.2 ml of saline solution (containing 10-100 mCi of radioactive tracer) was injected into the femoral vein. The rats were sacrificed at the time indicated by cardiac excision while under anesthesia. Organs of interest were removed and weighed, and the radioactivity was counted. The percent dose per organ was calculated by comparing the tissue counts to counts of 1% of the initial dose (aliquots of the injected material diluted 100 times) measured at the same time. The [67Ga]biaminothiolate-tricyclohexyl (Ga-B) complex was also compared to other myocardial perfusion imaging complexes including the [67Ga]biaminothiolato-tetraethyl-cyclohexyl (Ga-A) complex of the prior invention (FIG 4C). It can be seen from FIG 5 that in vivo bio-distribution of this novel 67Gallium-complex which are tested in normal rats exhibited excellent heart uptake and retention with a heart uptake compared to 1.68 % dose/organ (Ga-A) after 2 minutes and a retention of 0.9, compared to 0.26 % dose/organ for Gallium-A after 60 minutes.
Therefore the biological behavior of the [67 GaJBiaminothiolate- tricyclohexyl (Ga-B) complex suggests that this agent, as well as related complexes within the scope of Formula II should provide an enhanced myocardial perfusion imaging in comparison to the less lipophilic complexes.
Complexes of the present invention also indicate that the highly lipophilic plus one charged complexes are trapped in the myocardial tissue in a similar fashion to 99mTc myocardial imaging agents as presented in Tables 3, and 4 for the bio-distribution in Sprague Dawley rats after an IV injection of [Tc-99m] sestaMIBI via the femoral vein.
Table 1 : Biodistribution Of67Ga-B in a dual isotope study with 99mTc-sestamibi in rats Uptake of 67Ga-2 Time after injection (min)
2 30 60 120
Blood 0 .58 ± 0 .10 0.14 ± 0 .01 0 .07 ± 0 .01 0.06 ± 0 .00
Heart 3 .00 ± 0 .41 1.69 ± 0 .14 1 .25 ± 0 .16 0.80 ±0. 09
Muscle 0 .15 ± 0 .02 0.14 ± 0 .00 0 .13 ± 0 .03 0.10 ± 0 .02
Lung 2 .22 ± 0 .67 0.60 ± 0 .26 0 .36 ± 0 .05 0.30 ± 0 .14
Kidney 5 .48 ± 0 .93 3.60 ± 0 .56 1 .74 ± 0 .21 0.96 ± 0 .14
Spleen 2 .23 ± 0 .66 0.58 ± 0 .13 0 .44 ± 0 .07 0.45 ± 0 .02
Liver 5 .00 ± 0 .67 2.44 ± 0 .24 1 .50 ± 0 .20 1.08 ± 0 .06
Skin 0 .24 ± 0 .05 0.15 ± 0 .03 0 .09 ± 0 .02 0.07 ± 0 .01
Brain 0 .04 ± 0 .01 0.02 ± 0 .00 0 .01 ± 0 .00 0.01 ± 0 .00
(% dose/gram, average of 3 rats ± SD)
Table 2: Heart/Tissue Ratio Of67Ga-B in a dual isotope study with 99mTc-sestamibi in rats
Heart/Blood 5.20 ± 1 .14 12.1 ± 1 .32 17.9 ± 3 .43 13.3 ± 1 .49
Heart/Liver 0.60 ± 0 .11 0.70 ± 0. 09 0.83 ± 0 .15 0.74 ± 0 .08
Heart/Muscle 20.0 ± 3 .81 12.1 ± 1. 00 9.61 ± 2 .53 8.00 ± 1 .83
Table 3: Biodistribution of 99mTc-sestamibi in a dual isotope study with 67Ga-B in rats Uptake of 99mTc-sestamibi: Time after injection (min)
2 30 60 120
Blood 0.17 ± 0 .01 0.03 ± 0 .00 0.02 ± 0 .00 0.02 ± 0 .00
Heart 2.65 ± 0 .16 2.19 ± 0 .16 2.43 ± 0 .17 2.72 ± 0 .15
Muscle 0.13 ± 0 .03 0.13 ± 0 .04 0.12 ± 0 .03 0.17 ± 0 .05
Lung 1.43 ± 0 .28 0.53 ± 0 .05 0.42 ± 0 .08 0.31 ± 0 .02
Kidney 7.60 ± 0 .56 4.30 ± 0 .32 2.24 ± 0 .08 1.80 ± 0 .34
Spleen 2.66 ± 1 .03 1.30 ± 0 .35 1.03 ± 0 .08 0.74 ± 0 .23
Liver 2.60 ± 0 .28 1.41 ± 0 .26 0.60 ± 0 .14 0.30 ± 0 .14
Skin 0.28 ± 0 .06 0.17 ± 0 .05 0.18 ± 0 .02 0.18 ± 0 .03
Brain 0.04 ± 0 .00 0.03 ± 0 .00 0.02 ± 0 .00 0.02 ± 0 .00
(% dose/gram, average of 3 rats ± SD)
Table 4: Heart/Tissue Ratio of 99mTc-sestamibi in a dual isotope study

Claims

Heart/Blood 15.6 ± 1.31 73.0 ± 5.33 122. O ± 8.53 136. O ± 7.50Heart/Liver 1.01 ± 0 .12 1.60 ± 0 .31 4.05 ± 0 .99 9.06 ± 4 .25Heart/Muscle 20.4 ± 4 .86 16.9 ± 5 .34 20.2 ± 5 .24 17.0 ± 5 .08What is Claimed:
1. A compound of Formula I :
Figure imgf000015_0001
I or a pharmaceutically acceptable salt thereof; wherein:
A1, A2 and A3 are the same or different cycloalkyl, wherein at least one of A1, A2 or
A3 is substituted;
R1, R2, R3, R4, R5, and R6 are independently hydrogen or alkyl;
R7 and R8 are independently hydrogen or alkyl; and
RP is hydrogen or sulfhydryl protecting group.
2. The compound of claim 1 , wherein A1, A2 and A3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which is optionally substituted.
3. The compound of claim 1, wherein A1, A2 and A3 are independently cyclopentyl, cyclohexyl or cycloheptyl, any of which is optionally substituted.
4. The compound of claim 1 , wherein A1, A2 and A3 are optionally mono, di or tri substituted with a substitutent that is amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_6)alkyl, amino(Ci_6)alkyl, hydroxy(Ci_6)alkyl, halo(Ci_6)alkyl, cyano(Ci_6)alkyl, thio(Ci_6)alkyl, carboxy(Ci_6)alkyl, aryl(Ci_6)alkyl, (Ci_6)alkoxy(Ci_ 6)alkyl, (C2-6)alkenyl, amino(C3_io)alkenyl, hydroxy(C3_i0)alkenyl, halo(C2-6)alkenyl, cyano(C2-6)alkenyl, thio(C3_io)alkenyl, carboxy(C3_io)alkenyl, aryl(C2_6)alkenyl, (C2. 6)alkynyl, (Ci_6)heteroalkyl, (C2_6)heteroalkenyl, (C2_6)heteroalkynyl, (Ci_6)alkoxy, (C3-io)alkenyloxy, (Cl-6)alkylenedioxy, amino(C2-6)alkoxy, hydroxy(C2-6)alkoxy, halo(Ci_6)alkoxy, cyano(Ci_6)alkoxy, thio(Ci_6)alkoxy, carboxy(C2-6)alkoxy, aryl(Ci_ 6)alkoxy, (Ci_6)alkoxy(C2-6)alkoxy, halo(Ci_6)alkoxy(C2-6)alkoxy, mono(Ci_6)alkylamino, di(Ci_6)alkylamino, (Ci_6)alkylcarbonylamino, (C2_6)alkenylcarbonylamino, (C6-i4)arylcarbonylamino,
(Ci_6)alkoxycarbonylamino, (C6-io)aryloxycarbonylamino, (Ci_6)alkylcarbonyl, (C2-6)alkenylcarbonyl, (Ce-io)arylcarbonyl, (Ci_6)alkoxycarbonyl, (C6-i4)aryloxycarbonyl, (Ci_6)alkylsulfonylamino, (C2-6)alkenylsulfonylamino, (C6-i4)arylsulfonylamino or X- ((CRaRb)2θ)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or (C 1.4) alkyl and n is an integer from 1 to 6.
5. The compound of claim 1, wherein A1, A2 and A3 are each cyclohexyl, optionally substituted with hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy.
6. The compound of claim 1 , wherein R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen or (Ci_6)alkyl.
7. The compound of claim 6, wherein R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen, methyl, ethyl, or straight chain or branched chain propyl, butyl, pentyl or hexyl.
8. The compound of claim 6, wherein R1, R2, R3, R4, R5, R6, R7 and R8 are each hydrogen.
9. The compound of claim 1, wherein each Rp is independently hydrogen, methoxymethyl, methoxyexthoxyethyl, p-methoxybenzyl or benzyl.
10. The compound of claim 1, wherein each Rpis hydrogen.
11. The compound of claim 5, wherein A1 is unsubstituted.
12. The compound of claim 5, wherein A2 is unsubstituted.
13. The compound of claim 5, wherein A , 3 is mono substituted at the 2 position.
14. The compound of claim 5, wherein A is mono substituted at the 3 position.
15. The compound of claim 5, wherein A3 is mono substituted at the 4 position.
16. The compound of claim 15, wherein A3 is substituted with a substituent that is methoxy, 3-fluoropropoxy, 3-hydroxypropoxy, or X-((CRaRb)2θ)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or
(C i_4)alkyl and n is an integer from 1 to 6.
17. A metal chelate produced by mixing a compound of claim 1 with a metal salt under conditions suitable to form a metal chelate.
18. The chelate of claim 17, wherein said metal salt is a salt of Technetium-99m,Rhenium- 188, Cobalt-57, cold Gallium, Gallium-68, Gallium-67, Indium-I l l, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201.
19. The chelate of claim 17, wherein said chelate is stabilized by a counterion that is halide, sulfate, nitrate, carboxylate or phosphate.
20. The chelate of claim 17, wherein said chelate is stabilized by a counterion that is halide.
21. The chelate of claim 17, wherein said metal salt is gallium citrate.
22. A complex of Formula II
Figure imgf000017_0001
II or a pharmaceutically acceptable salt thereof; wherein:
A1, A2 and A3 are the same or different cycloalkyl, wherein at least one of A1, A2 or A3 is substituted;
R1 R2, R3, R4, R5, and R6 are independently hydrogen or alkyl;
R7 and R8 are independently hydrogen or alkyl;
M is a metal; and
A" is a monovalent counterion.
23. The complex of claim 22, wherein A1 , A2 and A3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which is optionally substituted.
24. The complex of claim 22, wherein A1, A2 and A3 are independently cyclopentyl, cyclohexyl or cycloheptyl, any of which is optionally substituted.
25. The complex of claim 22, wherein A1, A2 and A3 are optionally mono-, di- or tri- substituted with a substituent that is amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_6)alkyl, amino(Ci_6)alkyl, hydroxy(Ci_6)alkyl, halo(Ci_6)alkyl, cyano(Ci_6)alkyl, thio(Ci_6)alkyl, carboxy(Ci_6)alkyl, aryl(Ci_6)alkyl, (Ci_6)alkoxy(Ci_ 6)alkyl, (C2-6)alkenyl, amino(C3_io)alkenyl, hydroxy(C3_io)alkenyl, halo(C2_6)alkenyl, cyano(C2-6)alkenyl, thio(C3-io)alkenyl, carboxy(C3-io)alkenyl, aryl(C2-6)alkenyl, (C2- 6)alkynyl, (Ci_6)heteroalkyl, (C2-6)heteroalkenyl, (C2-6)heteroalkynyl, (Ci_6)alkoxy, (C3-io)alkenyloxy, (Cl-β)alkylenedioxy, amino(C2-6)alkoxy, hydroxy(C2-6)alkoxy, halo(Ci_6)alkoxy, cyano(Ci_6)alkoxy, thio(Ci_6)alkoxy, carboxy(C2-6)alkoxy, aryl(Ci_ 6)alkoxy, (Ci_6)alkoxy(C2-6)alkoxy, halo(Ci_6)alkoxy(C2-6)alkoxy, mono(Ci_6)alkylamino, di(Ci_6)alkylamino, (Ci_6)alkylcarbonylamino, (C2-6)alkenylcarbonylamino, (C6-i4)arylcarbonylamino, (Ci_6)alkoxycarbonylamino, (C6-io)aryloxycarbonylamino, (Ci_6)alkylcarbonyl, (C2_6)alkenylcarbonyl, (C6_io)arylcarbonyl, (Ci_6)alkoxycarbonyl, (C6-i4)aryloxycarbonyl, (Ci_6)alkylsulfonylamino, (C2-6)alkenylsulfonylamino, (C6-i4)arylsulfonylamino or X-((CRaRb)2θ)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or (C i_4)alkyl and n is an integer from 1 to 6.
26. The complex of claim 22, wherein A1, A2 and A3 are each cyclohexyl optionally substituted with hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy.
27. The complex of claim 22, wherein R1, R2, R3, R4, R5, R6, R7, and R8 are independently hydrogen or (Ci_6)alkyl.
28. The complex of claim 27, wherein R1, R2, R3, R4, R5, R6, R7, and R8 are independently hydrogen, methyl, ethyl, or straight chain or branched propyl, butyl, pentyl or hexyl.
29. The complex of claim 28, wherein R1, R2, R3, R4, R5, R6, R7, and R8 are each hydrogen.
30. The complex of claim 26, wherein A1 is unsubstituted.
31. The complex of claim 26, wherein A2 is unsubstituted.
32. The complex of claim 26, wherein A3 is mono substituted at the 2 position.
33. The complex of claim 26, wherein A is mono substituted at the 3 position.
34. The complex of claim 26, wherein A3 is mono substituted at the 4 position.
35. The complex of claim 34, wherein A3 is substituted with a substituent that is methoxy, 3- fluoropropoxy, 3-hydroxypropoxy or X-((CRaRb)2O)n, wherein X is halo or hydroxy and Ra and Rb are each independently hydrogen or
(C i_4)alkyl and n is an integer from 1 to 6.
36. The complex of claim 22, wherein M, is Technetium-99m, Rhenium- 188, Cobalt-57, Gallium-68, Gallium-67, cold Gallium, Indium-I l l, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201.
37. The complex of claim 22, wherein the complex is stabilized by a counterion that is halide, sulfate, nitrate, carboxylate or phosphate.
38. The complex of claim 37, wherein the complex is stabilized by a counterion that is halide.
39. The complex of claim 22, wherein M is Gallium-68.
40. A complex of claim 22, wherein M is Gallium-67.
41. A complex of claim 22, wherein M is cold Gallium and A3 is substituted with 18Fluoropropoxy .
42. A kit for forming a radioactive imaging agent comprising;
1) a compound of claim 1, and
2) a salt of a radioactive metal; wherein the compound and the salt are mixed under conditions that form a radioisotopic complex suitable for use as an imaging agent.
43. A method of imaging, comprising administering the radioisotopic complex of claim 41, to a subject; and thereafter imaging said subject.
44. A method of myocardial perfusion imaging, comprising administering a radioisotopic complex of claim 22 to a subject; and thereafter imaging the heart of said subject.
45. A radioisotopic complex of claim 22, wherein the radioisotopic complex has a formal cationic charge of +1.
46. A radioisotopic complex, wherein A1, A2 and A3 are each unsubstituted cyclohexyl, R1, R2, R3, R4, R5, R6, R7, and R8 are each hydrogen, M is Gallium-67 or Gallium-68 and A" is a monovalent counterion.
47. A compound wherein A1, A2 and A3 are each unsubstituted cyclohexyl, R1 , R2, R3, R4, R5, R6, R7, and R8 are independently hydrogen or alkyl and RP is hydrogen or sulfhydryl protecting group,
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