WO2005049095A2 - Contrast agent imaging angiotensin ii receptors - Google Patents
Contrast agent imaging angiotensin ii receptors Download PDFInfo
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- WO2005049095A2 WO2005049095A2 PCT/NO2004/000358 NO2004000358W WO2005049095A2 WO 2005049095 A2 WO2005049095 A2 WO 2005049095A2 NO 2004000358 W NO2004000358 W NO 2004000358W WO 2005049095 A2 WO2005049095 A2 WO 2005049095A2
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- contrast agent
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- losartan
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- cpn216
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- 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
Definitions
- the present invention relates to targeted contrast agents suitable for use in diagnostic imaging techniques in which a disease state may be imaged. More specifically the invention relates to contrast agents for the imaging of diseases associated with the up-regulation of the Angiotensin II type receptor AT-
- the invention describes ligands designed to have increased potency and optimised excretion and biodistribution profiles compared to existing pharmaceutical preparations.
- CHF congestive heart failure
- atherosclerosis fibrosis in organs like heart, lungs and liver.
- Angiotensin II (Ang II) - the octapeptide (Asp-Arg-Val-Tyr-lle-His-Pro-Phe) - is a pleiotropic vasoactive peptide that binds to two distinct receptors: the Ang II type 1 (AT- ⁇ ) and type 2 (AT 2 ) receptors.
- Ang II type 1 AT- ⁇
- AT 2 type 2 receptors.
- RAAS aldostrone system
- AT-i receptor activation triggers a variety of intracellular systems, including tyrosine kinase- induced protein phosphorylation, production of arachidonic acid metabolites, alteration of reactive oxidant species activities, and fluxes in intracellular Ca 2+ concentrations.
- AT 2 receptor activation leads to stimulation of bradykinin, nitric oxide production, and prostaglandin metabolism, which are, in large part, opposite to the effects of the AT-i receptor.
- Angiotensin receptors signalling, vascular pathophysiology, and interactions with ceramide).
- Ang II is the active component of the renin-angiotensin-aldosterone system (RAAS). It plays an important physiological role in the regulation of blood pressure, plasma volume, sympathetic nervous activity, and thirst responses. Ang II also has a pathophysiological role in cardiac hypertrophy, myocardial infarction, hypertension, chronic obstructive pulmonary disease, liver fibrosis and atherosclerosis. It is produced systemically via the classical RAAS and locally via tissue RAAS.
- RAAS renin-angiotensin-aldosterone system
- circulating renal-derived renin cleaves hepatic-derived angiotensinogen to form the decapeptide angiotensin I (Ang I), which is converted by angiotensin-converting enzyme (ACE) in the lungs to the active Ang II.
- Ang I can also be processed into the heptapeptide Ang-(1-7) by tissue endopeptidases.
- the RAAS system is illustrated schematically in Figure 1 hereto which is based on Figure 1 in the article by Foote et al. in Ann. Pharmacother. 27: 1495-1503 (1993).
- RAAS In addition to the RAAS playing an important role in the normal cardiovascular homeostasis, over activity of the RAAS has been implicated in the development of various cardiovascular diseases, such as hypertension, congestive heart failure, coronary ischemia and renal insufficiency. After myocardial infarction (Ml), RAAS becomes activated. Specifically the ATi receptor seems to play a prominent role in post-MI remodelling, since AT-i receptor expression is increased after Ml and in left ventricular dysfunction. Therefore drugs that interfere with RAAS, such as ACE inhibitors and AT-i receptor antagonists, have been shown to be of great therapeutic benefit in the treatment of such cardiovascular disorders.
- ACE inhibitors and AT-i receptor antagonists drugs that interfere with RAAS, have been shown to be of great therapeutic benefit in the treatment of such cardiovascular disorders.
- Tissue repair involves inflammatory cells, including members of the monocyte/macrophage lineage, integral to initiating the repair process; and myofibroblasts, phenotypically transformed interstitial fibroblasts, responsible for collagen turnover and fibrous tissue formation.
- Ang II angiotensin II
- this peptide regulates expression of TGF-beta 1 via angiotensin (AT ⁇ receptor-ligand binding. It is this cytokine that contributes to phenotypic conversion of fibroblasts to myofibroblasts (myoFb) and regulates myofibroblast turnover of collagen.
- Angiotensin-converting enzyme (ACE) inhibition or ATi receptor antagonism each prevent many of these molecular and cellular responses that eventuate in fibrosis and therefore have been found to be protective interventions. (See: Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol. 1997 Sep; 17(5):467-91 and references therein).
- Ang II may regulate tissue fibrosis via the activation of mesenchymal cells.
- Ang II stimulates the proliferation of cardiac fibroblasts in vitro via activation of AT-i.
- ATi receptors has also been demonstrated on cardiac fibroblasts in vitro.
- Most of the profibrotic effects of Ang II appear to be mediated via this receptor; however, increased AT 2 expression on cardiac fibroblasts has been detected in hypertrophied human heart, and the balance between the expression of these two subtypes may be critical in determining the response to Ang II.
- the Ang II receptors can be distinguished according to inhibition by specific antagonists. ⁇ receptors are selectively antagonized by biphenylimidazoles, such as Losartan, whereas tetrahydroimidazopyridines specifically inhibit AT 2 receptors.
- the AT 2 receptor may also be selectively activated byCGP-42112A. This is a hexapeptide analog of Ang II, which may also inhibit the AT 2 receptor, depending on concentration).
- Two other angiotensin receptors have been described: AT 3 and AT 4 subtypes.
- the ATi receptor has two functionally distinct subtypes, AT 1A and AT 1B , with >95% amino acid sequence homology.
- the second major angiotensin receptor isoform is the AT 2 receptor. It has low amino acid sequence homology (-34%) with AT 1A or AT 1B receptors. Although the exact signaling pathways and the functional roles of AT 2 receptors are unclear, these receptors may antagonize, under physiological conditions, AT mediated actions inhibiting cell growth and by inducing apoptosis and vasodilation. The exact role of AT 2 receptors in cardiovascular disease remains to be defined.
- T a t yp i ca i Other receptors for Ang II besides AT-i and AT 2 are known and are generally referred to as T a t yp i ca i (see Kang et al., Am. Heart J. 127: 1388-1401 (1994)).
- the suppression of Ang ll's effects has been used therapeutically, for example in the management of hypertension and heart failure.
- renin inhibitors which block the conversion of angiotensinogen to angiotensin I (the precursor to Ang II); by the use of angiotensin converting enzyme (ACE) inhibitors that block the conversion of angiotensin I to Ang II (and also block bioconversion of bradykinin and prostaglandins); by the use of anti- Ang II -antibodies; and by the use of Ang II -receptor antagonists.
- ACE angiotensin converting enzyme
- Beta blockers are most commonly used in treatment of arrhythmias. Anti-arrhythmic drugs have had limited overall success and calcium channel blockers can sometimes induce arrhythmias. No single agent shows superiority, with the possible exception of amiodarone. Short-term anti-arrhythmic benefit has been found to be offset by, depending on the specific drug, neutral or negative effects on mortality (Sanguinetti MC and Bennett, PB: Anti- arrhythmic drug target choices and screening. Circulation 2003, 93(6): 491-9257-263). Clearly better anti-arrhythmic drugs are needed.
- Ang II receptor sites in vivo using targeted contrast agents in which the targeting binding ligand has affinity for Ang ll-receptor sites.
- the Ang II receptors are generally accessible to such contrast agents when they are administered into the blood stream. Accordingly, using such targeted contrast agents it is possible to detect diseases and disorders such as heart failure, atherosclerosis and restricted blood flow, as well as other vascular diseases and disorders, and also to monitor the progression of treatment for such diseases and disorders.
- WO 98/18496 discloses contrast agents comprising Ang ll-receptor antagonists labelled for in vivo imaging.
- US patent no. 5,138,069 discloses substituted imidazoles for use as Ang II receptor blockers. Further, US patent no. 5,264,581 (Cariani) discloses radioiodinated imidazole Ang II antagonists. Summary of the invention
- the affinity of the ligand for the selected binding site may be negatively affected.
- compositions of matter of the present invention are useful diagnostic contrast agents for in vivo imaging of the mammalian body.
- the patients undergoing the imaging procedure may also be on 'sartan' drug therapy.
- 'Sartans' e.g. Losartan are Ang II receptor antagonists used in treatment of hypertension.
- a contrast agent targeting Ang II receptors will experience a competition with the treatment drug for binding to the same receptor site. It is therefore considered desirable to develop contrast agents possessing higher affinity for the ] receptor than the prescribed drug to avoid deleterious competition effects of the cold drug i.e. the prescribed non-detectable 'sartan' drug.
- the in vivo detectable moiety can be any moiety capable of detection either directly or indirectly in an in vivo diagnostic imaging procedure e.g. by MRI, optical imaging, scintigraphy, SPECT, PET , X-ray, ultrasound, electrical impedance or magnetometric procedures.
- compositions of matter of the present invention are useful for the in vivo diagnostic imaging of a range of disease states (congestive heart failure (CHF), artherosclerosis, fibrosis in organs like heart, lungs and liver) where the up regulation of Ang II receptor sites is known to be involved.
- CHF congestive heart failure
- artherosclerosis artherosclerosis
- fibrosis fibrosis in organs like heart, lungs and liver
- V is an organic group having binding affinity for an angiotensin II receptor site
- L is an amino acid-comprising biomodifier or linker moiety
- R is a moiety detectable in an in vivo imaging procedure of a human or animal body.
- the ligand V may be any organic compound having affinity for Ang II receptors. Compounds having a marked affinity for particular types of Ang II receptors, such as AT-i or AT 2 , are generally preferred. Imidazole Ang II antagonist ligands are preferred and most preferred are ligands such as Losartan, Valsartan, Candesartan and Eprosartan.
- the moiety R must be able to carry the imageable moiety or moieties denoted M. By carrying is meant any form of association between the moiety R and M such as a chemical bond, e.g. covalent bond or electrovalent or ionic bonds or by absorption or any other type of association.
- R can be any imageable moiety.
- R and/or Y T M represents a chelating agent.
- R and/or Y T M will depend of the imaging modality utilised in the diagnosis.
- R and/or ⁇ YiM must be capable of detection either directly or indirectly in an in vivo diagnostic imaging procedure, and comprise e.g. moieties which emit or may be caused to emit detectable radiation (eg. by radioactive decay, fluorescence excitation, spin resonance excitation, etc.), moieties which affect local electromagnetic fields (eg. paramagnetic, superparamagnetic, ferrimagnetic or ferromagnetic species), moieties which absorb or scatter radiation energy (eg.
- one moiety R is covalently bound directly to L forming an N-alkyl glycine unit.
- Chelating agents of formula (II) and (e) hereinafter are also particularly preferred.
- imageable moieties are known from e.g. WO 98/18496, the content of which is incorporated by reference. Imaging modalities and imageable moieties R and M are described in more detail hereinafter:
- the compound of formula (I) comprises a moiety Y ⁇ carrying one or more imageable moieties M useful in the Radio and SPECT imaging modality.
- M is a gamma emitter with low or no alpha- and beta-emission and with a half-life of more than one hour.
- Preferred groups M are the radionuclides 67 Ga, 111 ln, 123 l, 125 l, 131 l, 81m ⁇ K- r, aa Mo,
- M can further be represented by the following isotopes or isotope pairs for use both in imaging and therapy without having to change the radiolabeling methodology or chelator: 47 Sc 21 ; 141 Ce 58 ; 188 Re 75 ; 177 Lu 71 ; 199 Au 79 ; 47 Sc 21 ; 131 l 53 ; 67 Cu 29 ; 131 l 53 and 123 l 53 ; 188 Re 75 and
- Y ⁇ denotes a chelating agent suitable for forming a stable chelate with M.
- chelating agents are well known from the state of art and typical examples of such chelating agents are described in Table I of WO 01/77145.
- each R 1 , R 2 , R 3 and R 4 is independently H or C ⁇ - ⁇ 0 alkyl, C 3-10 alkylaryl, C 2- ⁇ oalkoxyalkyl, C- O hydroxyalkyl, C 1-10 alkylamine, C 1-10 fluoroalkyl, or 2 or more R groups, together with the atoms to which they are attached form a carbocyclic, heterocyclic, saturated or unsaturated ring. More particularly preferred are chelating agents of formula (II) where R 1 , R 2 and R 3 are hydrogen or methyl groups and R 4 is an alkylamine group, most specifically a compound of formula (e), herein denoted cPN216.
- cPN216 a compound of formula (e)
- Y-i is when the chelate is cPN216 and when the imaging moiety M is 99m Tc.
- chelating agent can be represented by formulas a, b, c and d.
- Q Qe are independently Q groups, where Q is H, alkyl, aryl or an amine protecting .group,
- R is H, C 1-4 alkyl, C 2- alkoxyalkyl, C 1-4 hydroxyalkyl, or
- Non-metal radionuclides such as 123 l, 125 1 and 131 l may be covalently linked to the moiety L by a substitution or addition reaction well known from the state of art.
- the compound of formula (I) comprises a moiety R useful in the PET imaging modality.
- R then denotes a radioemitter with positron-emitting properties.
- Preferred groups R are the radionuclides 11 C, 18 F, 68 Ga, 13 N, 15 O and 82 Rb. 18 F is specifically preferred.
- the metallic radioemitters 82 Rb and 68 Ga chelated with a chelating agent Yi are also preferred.
- Thiol coupling chemistry, 18 F-synthons and labelled peptides prepared using the thiol coupling chemistry are described in WO 03/080544, the content of which is incorporated herein by reference.
- M denotes a metallic radionuclide
- Y- denotes a chelating agent suitable for forming a stable chelate with M.
- chelating agents are well known from the state of art and typical examples of such chelating agents are described in Table I of WO 01/77145 and to the previous part on Radio and SPECT imaging.
- Yi is the DOTA chelating agent and M is 68 Ga which can be readily introduced in to the chelate using microwave chemistry.
- Non-metal radionuclides such as 18 F may be covalently linked to the moiety L by a substitution or addition reaction well known from the state of art and also described eg. in WO03/080544 which is hereby incorporated by reference.
- R of the compound of formula (I) comprises a moiety YiCarrying one or more imageable moieties M useful in the MR imaging modality.
- M here denotes a paramagnetic metal such those mentioned in US patent 4647447, Gd 3+ , Dy 3+1 Fe 3+ and Mn 2+ are particularly preferred and
- Y-i denotes a chelating agent, in particular a chelating agent such as acyclic or cyclic polyaminocarboxylates (e.g. DTPA, DTPA-BMA, DOTA and DO3A) as described e.g. in US patent 4647447 and WO 86/02841.
- M may also denote metal oxides such as superparamagnetic, ferrimagnetic or ferromagnetic species which are absorbed by R, e.g. such that R functions as a coating to the metal oxide.
- metal oxides for use as MR contrast agents are described e.g. in US patent 6 230 777 which is hereby incorporated by reference.
- R of the compound of formula (I) comprises a moiety Y- carrying one or more imageable moieties M useful in the X-ray imaging modality.
- M here denotes a heavy metal such as W, Au and Bi preferably in the form of oxides which may be absorbed to R.
- R can also be represented by iodinated aryl derivatives particularly well known as X-ray contrast agents, e.g. lopamironTM and OmnipaqueTM. These agents can e.g. be linked via a amide or amine function to V of formula (I).
- the compound of formula (I) comprises R in the form of gas filled microvesicles.
- Such ultrasound imaging agents can be utilised in the imaging of receptors e.g. when they are functionalised for binding to a peptide as described in the state of art e.g. in WO98/18500.
- the moiety R of formula (I) may be any moiety capable of detection either directly or indirectly in an optical imaging procedure.
- the detectable moiety can be a light scatterer (e.g. a coloured or uncoloured particle), a light absorber or a light emitter. More preferably R is represented by a dye such as a chromophore or a fluorescent compound.
- the moiety R can be any dye that interacts with light in the electromagnetic spectrum with wavelengths from the ultraviolet light to the near- infrared. In a preferred version R has fluorescent properties.
- Preferred organic dye moieties include groups having an extensive delocalized electron system, eg. cyanines, merocyanines, indocyanines, phthalocyanines, naphthalocyanines, triphenylmethines, porphyrins, pyrilium dyes, thiapyrilium dyes, squarylium dyes, croconium dyes, azulenium dyes> indoanilines, benzophenoxazinium dyes, benzothiaphenothiazinium dyes, anthraquinones, napthoquinones, indathrenes, phthaloylacridones, trisphenoquinones, azo dyes, intramolecular and intermolecular charge-transfer dyes and dye complexes, tropones, tetrazines, bis(dithiolene) complexes, bis(benzene-dithiolate) complexes, iodoaniline dyes, bis(S,O-d
- Fluorescent proteins such as green fluorescent protein (GFP) and modifications of GFP that have different absorption/emission properties are also useful.
- GFP green fluorescent protein
- Complexes of certain rare earth metals e.g., europium, samarium, terbium or dysprosium are used in certain contexts, as are fluorescent nanocrystals (quantum dots).
- the invention may be exemplified by Losartan derivatives and is based on attachment of biomodifier/linker and reporter moieties to the imidazol 5-position.
- the principle also applies to other compounds having structural similarities, e.g. Valsartan, Candesartan and Eprosartan, possessing suitable anchoring sites in the part of the molecule corresponding to the Losartan imidazole ring.
- the biomodifier/linker moiety L may be to distance a relatively bulky reporter, such as a metal complex, from the active site of the binding ligand' V.
- the biomodifier/linker moiety can be selected to increase the binding affinity of the composition for the receptor.
- the biomodifier/linker moiety comprises 1-40 amino acids, and preferred 1-20 amino acids, and more preferred 1-10 amino acids and most preferred 1-5 amino acids.
- the biomodifier/linker moiety may comprise one or more dicarboxylic acid units (e.g. diglycoloyl units, glycolyl units, succinyl, glutaryl units), ethyleneglycol units, diamines, PEG or PEG like units or combinations of the above.
- linker group can also be used to modify the biodistribution of the resulting metal complex of the conjugate e.g. the introduction of amino acids with different properties can decrease the liver up-take.
- High affinity refers to compounds having a Ki ⁇ 5nM and preferably ⁇ 0.1 nM and most preferred Ki's in the pM or sub pM range calculated from competitive binding assays for AT ! and where the Ki value was determined by competition with the known high affinity vector 125 l-Sar ⁇ lle 8 -angiotensin II.
- the Ki for Ang II in this assay system is around 5 nM.
- Ang ll-receptor antagonists derived from the so called 'sartan' class of drugs such as Valsartan, Candesartan and Eprosartan and preferably Losartan, labelled with an imaging moiety are useful diagnostic imaging agents for in vivo imaging of a human or animal body.
- One preferred embodiment of the invention is the 99m Tc labelled contrast agents 99m Tc (Losartan-Leu-diglycolyl-cPn216), 99 Tc (Losartan-Leu-Gly-diglycolyl-cPn216), 99m Tc (Losartan-Leu- ⁇ -Ala-diglycolyl-cPn216) and 99m Tc (Losartan-Leu-Lys(Propionyl-PEG(12)-Ac)- Diglycoloyl-cPn216).
- the contrast agent of formula (I) are preferably administered as a pharmaceutical formulation comprising the compound of formula (I) in a form suitable for administration to a mammal, such as a human.
- the administration is suitable carried out by injection or infusion of the formulation such as an aqueous solution.
- the formulation may contain one or more pharmaceutical acceptable additives and/or excipients e.g. buffers; solubilisers such as cyclodextrins; or surfactants such as Pluronic, Tween or phospholipids.
- stabilisers or antioxidants such as ascorbic acid, gentisic acid or para-aminobenzoic acid and also bulking agents for lyophilisation such as sodium chloride or mannitol may be added.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount (e.g. an amount effective for enhancing image contrast in an in vivo imaging procedure) of a composition of general formula I or a salt thereof, together with one or more pharmaceutically acceptable adjuvants, excipients or diluents.
- the invention provides the use of a composition of formula I for the manufacture of a contrast medium for use in a method of diagnosis involving administration of said contrast medium to a human or animal body and generation of an image of at least part of said body.
- the invention provides a method of generating enhanced images of a human or animal body previously administered with a contrast agent composition comprising a composition of matter as defined by formula I, which method comprises generating an image of at least part of said body.
- the invention further provides a. method for the monitoring of the effect of treatment of heart failure and other diseases associated with up-regulation of the AT ! receptor.
- the invention provides a kit for the preparation of a radiopharmaceutical composition of formula (I) comprising a ligand-chelate conjugate and a reducing agent.
- a radiopharmaceutical composition of formula (I) comprising a ligand-chelate conjugate and a reducing agent.
- the reducing agent is a stannous salt.
- the kit may further comprise one or more stabilisers, antioxidants, bulking agents for lyophilisation and solubilisers.
- Scheme 1 shows the solid phase synthesis of Losartan linker chelating agent conjugate.
- the circle donates a solid support particle.
- the affinity of the compounds was determined as the dissociation constant (K d ) and measured by displacement of a radiolabelled ligand of known affinity.
- the affinity of the compound for the ATi receptor has been determined in a competition assay using membranes from CHO cells expressing the receptor. Binding of 125 I-Sar ⁇ -lle 8 - Angiotensin II, a ligand known to bind very efficiently to ATi. receptors, was competed with various concentrations of the test substance.
- the K ⁇ is the concentration of the competing ligand in the competition assay which would occupy 50% of the receptors if no radoligand was present. K, is calculated using the Cheng-Prussoff equation:
- (L) is the concentration of the radiolabelled ligand used and the Kd is the dissociation constant of the radiolabelled ligand for the receptor.
- IC 50 is the concentration of competing ligand which displaces 50% of the specific binding of the radioligand.
- the IC 50 value for a compound may vary between experiments depending on the radioligand concentration, whereas the K is an absolute value.
- a preparation is made by dissolving 0,1 mg freeze-dried cPn216 derived compound in 0,2 ml (distilled and oxygen-free) water. This solution is transferred into a 10 ml nitrogen filled vial. 0,5 ml carbonate buffer, 0,5 ml Na 99m TcO 4 solution and 0,1 ml Sn-MDP solution are added. The preparation is left at room temperature for 20 minutes.
- Carbonate buffer has a pH of 9,2 and contains 8,4 mg NaHCO 3 and 10,6 mg Na 2 CO 3 per ml water. It is purged with nitrogen gas for at least 15 minutes before use.
- Sn-MDP solution This solution contains 0,131 mg SnCI 2 *2H 2 O and 0,925 mg MDP
- Losartan MSD, 0.236 g, 0.558 mmol
- triethylamine Fluka, 0.233 ml, 1.67 mmol
- DMF DMF
- Fmoc-Leu-OH (Novabiochem, 0.030 g, 0.084 mmol) and Fmoc-amino PEG diglycolic acid (Polypure, 0.045 mg, 0.084 mmol) were successively coupled to an aliquot of the resin bound amino-losartan from c) (0.042 mmol) in DMF using standard coupling reagents (HATU and DIEA) and standard Fmoc-cleavage protocol (20% piperidine in DMF). Completion of couplings were checked by standard Kaiser test.
- the second diglycoloyl unit was introduced using diglycolic anhydride (Aldrich, 0.010 g, 0.084 mmol) and DIEA (0.014 ml, 0.084 mmol).
- diglycolic anhydride Aldrich, 0.010 g, 0.084 mmol
- DIEA 0.014 ml, 0.084 mmol
- To the resin containing a terminal carboxyl function
- the chelate cPn216 0.029 g, 0.084 mmol
- PyAOP Applied Biosystems, 0.022 g, 0.042 mmol
- DIEA 0.014 ml, 0.084 mmol
- Examples 19-46 Losartan-Leu derivatives comprising a reporter moiety Compounds of the general formula (V) are listed in Table 2 and were synthesised on solid support as described in Example 1. Biotin and fluorescein-NHS ester were purchased from Fluka and Pierce, respectively. In the cases where Tc chelate cPn216 is attached via a glutaryl linker three different synthetic methods were used. In most cases an active ester of formula (VI) was used. As an alternative the corresponding free acid was coupled using reagents like PyAOP or HATU, but in that case the coupling had to repeated several times.
- the glutaryl-cPn216 moiety was attached in a two step reaction, as described for the corresponding diglycoloyl derivative in Example 1 , by first reacting the resin with glutaric anhydride and in a subsequent step activate the resin bound carboxylic acid and couple cPn216 as the free amine of formula (VII).
- VIII fully Boc-protected building block (VIII) (GB 0416062.8) was used.
- the products were purified by reverse phase chromatography (Phenomenex Luna C18(2) columns) using suitable gradients of acetonitrile/water containing 0.1% TFA or formic acid and were analysed by LC-MS using electrospray ionisation.
Abstract
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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EP04808852A EP1699494A2 (en) | 2003-11-24 | 2004-11-23 | Contrast agent imaging angiotensin ii receptors |
JP2006541065A JP2007512321A (en) | 2003-11-24 | 2004-11-23 | Contrast agent |
US10/559,880 US7431914B2 (en) | 2003-11-24 | 2004-11-23 | Contrast agent |
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NO20035228A NO20035228D0 (en) | 2003-11-24 | 2003-11-24 | Imaging agents |
NO20035228 | 2003-11-24 | ||
GBGB0416062.8A GB0416062D0 (en) | 2004-07-19 | 2004-07-19 | Improved N4 chelator conjugates |
GB0416062.8 | 2004-07-19 |
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WO2005049095A2 true WO2005049095A2 (en) | 2005-06-02 |
WO2005049095A3 WO2005049095A3 (en) | 2006-01-12 |
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EP (1) | EP1699494A2 (en) |
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Cited By (5)
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EP1768708A2 (en) * | 2004-07-19 | 2007-04-04 | GE Healthcare Limited | N4 chelator conjugates |
JP2009518372A (en) * | 2005-12-08 | 2009-05-07 | ジーイー・ヘルスケア・リミテッド | New contrast agent for fibrosis |
US8114863B2 (en) | 2005-10-07 | 2012-02-14 | Guerbet | Compounds comprising short aminoalcohol chains and metal complexes for medical imaging |
US8926945B2 (en) | 2005-10-07 | 2015-01-06 | Guerbet | Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium |
US8986650B2 (en) | 2005-10-07 | 2015-03-24 | Guerbet | Complex folate-NOTA-Ga68 |
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BRPI0518328A2 (en) * | 2004-11-22 | 2008-11-11 | Ge Healthcare As | contrast agent, pharmaceutical composition, use of a contrast agent, method for generating enhanced images of an animal or human body, and kit for the preparation of a radiopharmaceutical composition |
US9364568B2 (en) | 2010-07-15 | 2016-06-14 | Warsaw Orthopedic, Inc. | Methods to diagnose degenerative disc disease |
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WO2003006070A2 (en) | 2001-07-10 | 2003-01-23 | Amersham Plc | Improved chelator conjugates |
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US5489425A (en) * | 1987-06-24 | 1996-02-06 | The Dow Chemical Company | Functionalized polyamine chelants |
WO1992005784A1 (en) * | 1990-10-02 | 1992-04-16 | Warner-Lambert Company | 4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine derivatives and analogues as angiotensin ii receptor antagonists |
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JP4510444B2 (en) | 2001-07-10 | 2010-07-21 | ジーイー・ヘルスケア・アクスイェ・セルスカプ | Peptide-based compounds |
GB0130305D0 (en) * | 2001-12-19 | 2002-02-06 | Amersham Plc | Compounds for imaging alzheimers disease |
US7211240B2 (en) * | 2002-03-01 | 2007-05-01 | Bracco International B.V. | Multivalent constructs for therapeutic and diagnostic applications |
NO20030115D0 (en) * | 2003-01-09 | 2003-01-09 | Amersham Health As | Imaging agents |
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2004
- 2004-11-23 JP JP2006541065A patent/JP2007512321A/en active Pending
- 2004-11-23 EP EP04808852A patent/EP1699494A2/en not_active Withdrawn
- 2004-11-23 WO PCT/NO2004/000358 patent/WO2005049095A2/en active Application Filing
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1768708A2 (en) * | 2004-07-19 | 2007-04-04 | GE Healthcare Limited | N4 chelator conjugates |
EP1768708B1 (en) * | 2004-07-19 | 2017-05-17 | GE Healthcare Limited | N4 chelator conjugates |
US8114863B2 (en) | 2005-10-07 | 2012-02-14 | Guerbet | Compounds comprising short aminoalcohol chains and metal complexes for medical imaging |
EP2457914A1 (en) | 2005-10-07 | 2012-05-30 | Guerbet | Compounds comprising short aminoalcohol chains and metal complexes for medical imaging |
US8926945B2 (en) | 2005-10-07 | 2015-01-06 | Guerbet | Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium |
US8986650B2 (en) | 2005-10-07 | 2015-03-24 | Guerbet | Complex folate-NOTA-Ga68 |
JP2009518372A (en) * | 2005-12-08 | 2009-05-07 | ジーイー・ヘルスケア・リミテッド | New contrast agent for fibrosis |
Also Published As
Publication number | Publication date |
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JP2007512321A (en) | 2007-05-17 |
US20060193768A1 (en) | 2006-08-31 |
EP1699494A2 (en) | 2006-09-13 |
US7431914B2 (en) | 2008-10-07 |
WO2005049095A3 (en) | 2006-01-12 |
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