conjugates

Abstract

The invention provides a conjugate comprising a peptide that binds to the Calcitonin Gene-Related Peptide Receptor that is linked to a therapeutic or a detectable radionuclide. The conjugates are useful for imaging the Calcitonin Gene-Related Peptide Receptor and for treating diseases wherein the activity of the Calcitonin Gene-Related Peptide Receptor is implicated.

Description

[0001] CONJUGATES

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims priority to United States Provisional Application Number 63 / 553,499 that was filed on February 14, 2024. The entire content of the application referenced above is hereby incorporated by reference herein.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0005] This invention was made with government support under BC 180720 and BC 180720 awarded by the United States Department of Defense. The government has certain rights in the invention.

[0006] BACKGROUND

[0007] The Calcitonin Gene-Related Peptide Receptor (CGRPR) is an important therapeutic target for a variety of disease states. The CGRPR is a G-protein coupled receptor (GPCR) and member of the calcitonin receptor family (Russo, A. F. & Hay, D. L., Physiol Rev 103, 1565- 1644 (2023); and Russell, F. A., et al., Physiol Rev 94, 1099-1142 (2014)). It is comprised of the calcitonin-like receptor (CLR) and receptor activity -modifying protein 1 (RAMP1) subunit (Figure 1). The primary ligand of the CGRPR is calcitonin gene-related peptide (CGRP). Together they form a physiological axis that is critical to cardiovascular; gastrointestinal; pulmonary; immune, and reproductive system homeostasis. This receptor-ligand pair is involved or has emerging involvement with a variety of pathologies including migraine, peripheral pain conditions, cancer, inflammatory bowel conditions such as ulcerative colitis, arthritis, inflammation, infection and neuroinflammatory diseases such as Alzheimer’s disease (Russell, F. A., et al., Physiol Rev 94, 1099-1142 (2014); Ailani, J., et al., Neurology 99, 841-853 (2022); Balcziak, L. K. & Russo, A. F., Front Neurol 13, 874193 (2022); Blumenfeld, A., et al., Neurol Ther 10, 469-497 (2021); Close, L. N., et al., Cephalalgia 39, 428-434 (2019); de Prado, B. M. & Russo, A. F., Drug Discov Today Ther Strateg 3, 593-597 (2006); Russo, A. F., Br J Clin Pharmacol 80, 403-414 (2015); Russo, A. F Annu Rev Pharmacol Toxicol 55, 533-552 (2015); Wattiez, A. S., et al., Expert Opin Ther Targets 24, 91-100 (2020); Wattiez, A. S., et al., Handb Exp Pharmacol 255, 85-107 (2019); Assas, M. B., J Transl Med 19, 23 (2021); Atanasova, K. R. & Reznikov, L. R., Respir Res 19, 149 (2018); Choksi, T., et al., Br J Pharmacol 136, 784-792 (2002); Clifton, M. S., et al., Am J Physiol Gastrointest Liver Physiol 293, G36-44 (2007); Hagner, S., et al., Peptides 23, 109-116 (2002); Hagner, S., et al., Digestion 66, 197-203 (2002); Hagner, S., et al., Cell Tissue Res 310, 41-50 (2002); Hendrikse, E. R., et al., Cephalalgia 39, 403-419 (2019); Kitabatake, Y., et al., Biol Pharm Bull 27, 896-898 (2004); Labastida-Ramirez, A., et al., J Headache Pain 24, 125 (2023); Li, F. J., et al., Dig Dis Sci 58, 686-693 (2013); Pujo, J., et al., Gut Microbes 15, 2188874 (2023); Rubio-Beltran, E. & van den Brink, A. M., Handb Exp Pharmacol 255, 131-140 (2019); Singh, Y., et al., CNS Neurosci Ther 23, 457-461 (2017); Walsh, D. A., et al., Br J Clin Pharmacol 80, 965-978 (2015); Wei, P., et al., Comput Struct Biotechnol J 18, 843-851 (2020); Wende, B., et al., Int J Mol Sci 24 (2023); Wu, W ., et al., Clin Immunol 245, 109154 (2022); Xiong, J., et al., Front Neurosci 17, 1184766 (2023); Yang, D., et al., Cell 185, 4190-4205 e4125 (2022); and Yuan, K., et al., Int Immunopharmacol 102, 108426 (2022)). Despite their promise in the diagnosis and therapy of several pathologies, few radiopharmaceuticals have been evaluated for this receptor system.

[0008] When cancers such as breast (BCa) or prostate (PCa) have metastasized to bone, the 5- year survival rates for patients are dismal. When skeletal -related events (SREs) occur, the prognosis of these patients becomes even worse. Cancer-induced bone pain is the most common and intractable SRE in bone metastatic cancer, and it impairs quality of life. Recently, neural involvement and its influence on cancer progression, bone metastasis development and CIBP has been appreciated in preclinical and clinical settings and research suggests that signaling between the calcitonin gene-related peptide (CGRP) and its receptor is a potential therapeutic target for BCa and PCa bone metastases. If successful, this innovative paradigm would 1) create a treatment strategy that does not rely on bone-remodeling pathways for efficacy; 2) be the first to study the effects of systemic radionuclide therapy on bone metastasis and CIBP and 3) provide a relationship describing the effects of each therapy class at the cellular, tissue and behavioral levels.

[0009] Currently there is a need for therapeutic and detectible conjugates that bind to the CGRPR . Such conjugates would be useful for treating diseases associated with the CGRPR and for imaging the CGRPR in a variety of systems to further elucidate its activity.

[0010] SUMMARY

[0011] In one aspect the present invention provides conjugates that bind to the calcitonin gene- related peptide (CGRP) receptor. The conjugates are useful for treating diseases and conditions that are related to the calcitonin gene-related peptide (CGRP), which include cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors), colitis, Crohn’s disease, pain, migraine, brain injury, and inflammatory bowel disease. The conjugates are also useful as imaging agents (e.g., PET and SPEC imaging agents). For example, they can be used to image pain states, migraine, brain injury, and inflammatory bowel disease.

[0012] In one embodiment, a conjugate comprising: a peptide that binds to the Calcitonin Gene- Related Peptide Receptor that is linked to a therapeutic or a detectable radionuclide is provided.

[0013] In one embodiment, a pharmaceutical composition comprising a conjugate as described herein and a pharmaceutically acceptable excipient is provided.

[0014] In one embodiment, a method for imaging the Calcitonin Gene-Related Peptide Receptor comprising contacting the Calcitonin Gene-Related Peptide Receptor with a conjugate as described herein that comprises a detectable radionuclide under conditions that allow the conjugate to bind to the Calcitonin Gene-Related Peptide Receptor and detecting the detectable radionuclide is provided.

[0015] In one embodiment, a method for imaging a Calcitonin Gene-Related Peptide Receptor in a nerve cell comprising contacting a nerve cell that comprises the Calcitonin Gene-Related Peptide Receptor with a conjugate as described herein that comprises a detectable radionuclide under conditions that allow the conjugate to bind to the Calcitonin Gene-Related Peptide Receptor and detecting the detectable radionuclide is provided.

[0016] In one embodiment, a method for treating migraine, a peripheral pain condition (e.g., fibromyalgia), cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors), an inflammatory bowel condition (e.g., ulcerative colitis or Chron’s disease), arthritis, inflammation, infection or a neuroinflammatory disease (e.g., Alzheimer’s disease) in an animal, comprising administering a conjugate as described herein to the animal is provided.

[0017] In one embodiment, a method for treating cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors) in an animal, comprising administering a conjugate as described herein to the animal is provided.

[0018] In one embodiment, a method for treating bone metastasis in an animal, comprising administering a conjugate as described herein to the animal is provided.

[0019] In one embodiment, a conjugate as described herein for use in medical therapy is provided. In one embodiment, a conjugate as described herein for use in medical imaging is provided.

[0020] In one embodiment, a conjugate as described herein for the prophylactic or therapeutic treatment of migraine, a peripheral pain condition (e.g., fibromyalgia), cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors), an inflammatory bowel condition (e.g., ulcerative colitis or Chron’s disease), arthritis, inflammation, infection or a neuroinflammatory disease (e.g., Alzheimer’s disease) is provided.

[0021] In one embodiment, a conjugate as described herein for the prophylactic or therapeutic treatment of cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors) is provided.

[0022] In one embodiment, a conjugate as described herein for the prophylactic or therapeutic treatment of bone metastasis is provided.

[0023] In one embodiment, the use of a conjugate as described herein to prepare a medicament for treating migraine, a peripheral pain condition (e.g., fibromyalgia), cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors), an inflammatory bowel condition (e.g., ulcerative colitis or Chron’s disease), arthritis, inflammation, infection or a neuroinflammatory disease (e.g., Alzheimer’s disease) in an animal is provided.

[0024] In one embodiment, the use of a conjugate as described herein to prepare a medicament for treating cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors) in an animal is provided.

[0025] In one embodiment, the use of a conjugate as described herein to prepare a medicament for treating bone metastasis in an animal is provided.

[0026] In one embodiment, a conjugate comprising: a peptide that binds to the Calcitonin Gene- Related Peptide Receptor that is linked to a chelating group for a therapeutic or a detectable radionuclide is provided.

[0027] Processes and intermediates disclosed herein that are useful for preparing the conjugates are also provided.

[0028] BRIEF DESCRIPTION OF DRAWINGS

[0029] Fig- 1 : is a depiction of the CGRPR. The biologically active receptor requires the coassociation of RAMP- 1 and CLR. Fig. 2: shows the structures of three representative anti-CGRPR peptide chelator conjugates (1-3). Conjugates were prepared by CPC Scientific, Inc. using standard solidphase peptide synthesis and standard isothiocyanate coupling chemistry.

[0030] Fig. 3: depicts the ESI-LC-MS chromatogram of DOTA-Bn-NCS-C6-FV-Hyp- TDVGPFAF. The observed mass of the conjugate is in excellent agreement with the theoretically calculated mass of the conjugate. The low background in the spectrum demonstrates that the conjugate was prepared in high purity.

[0031] Fig. 4: The synthetic scheme for radiolabeling DOTA-Bn-NCS-C6-FV-Hyp- TDVGPFAF conjugate with89Zr. Using89ZrCL and HEPES resulted in an excellent radiochemical yield of 98.5%.

[0032] Figs. 5A and 5B: show quality control of89Zr-DOTA-Bn-NCS-C6-FV-Hyp- TDVGPFAF conjugate by Radio-TLC. Formation of89Zr-DOTA-Bn-NCS-C6-FV-Hyp- TDVGPFAF conjugate was confirmed by radio-TLC using a mobile phase consisting of 50 mM EDTA (pH 5) on Varian ITLC-SA strips. In the ITLC-SA system, (A) free89Zr formed a complex with EDTA and eluted with the solvent front (Rf = 1), (B) while the89Zr-DOTA-Bn- NCS-C6-FV-Hyp-TDVGPFAF conjugate remained at the origin (Rf = 0).

[0033] Fig. 6: shows quality control of89Zr-DOTA-Bn-NCS-C6-FV-Hyp-TDVGPFAF conjugate by radio-HPLC. The identity of the radioactive complex89Zr-DOTA-Bn-NCS-C6- FV-Hyp-TDVGPFAF conjugate was further confirmed by comparing its radio-HPLC elution profile to the UV-HPLC spectrum of nonradioactive DOTA-Bn-NCS-C6-FV-Hyp-TDVGPFAF conjugate. UV-HPLC chromatogram (243 nm) of nonradioactive DOTA-Bn-NCS-C6-FV-Hyp- TDVGPFAF conjugate (top) compared with radio-HPLC chromatogram of89Zr-DOTA-Bn- NCS-C6-FV-Hyp-TDVGPFAF conjugate (bottom).

[0034] Fig. 7: illustrates the biodistribution results of89Zr-DOTA-Bn-NCS-C6-FV-Hyp- TDVGPFAF at 4 hours post-injection. Data was collected in female nude mice bearing HTB- 10 human neuroblastoma tumors in the flank. The agent undergoes both renal and hepatobiliary excretion with renal excretion being a preferred route. Except for the large intestine, the radiopharmaceutical demonstrates minimal retention in benign tissues.

[0035] Fig- 8 : shows the retention of a radiopharmaceutical in HTB-10 tumors. Given the small number of CGRPR on HTB-10 cells (~ 1000 receptors / cell) the uptake of the radiopharmaceutical was modest (Lang, M., et al., J Med Chem 49, 616-624 (2006)). However, co-inj ection of blockade did reduce the tissue-associated radioactivity by approximately 50%. This suggests that the in vivo interaction between the CGRPR on HTB- 10 cells and the radiopharmaceutical results from a specific receptor-mediated interaction.

[0036] Fig- 9 : Retention of the radiopharmaceutical in the large intestine, liver, and kidney. Liver retention is minimal compared to the retention in the kidney. This suggest that renal excretion is a preferred route of bio-clearance. There is no significant difference in the retention of the radiopharmaceutical in these two tissues when peptide blockade is administered to animals receiving the radiopharmaceutical. This suggests that the retention in vivo is a non-specific interaction and reflects radiopharmaceutical excretion over time. In contrast, the radiopharmaceutical uptake in the large intestine was significant compared to all other tissues examined. In addition, radiopharmaceutical uptake could be reduced upon the co-inj ection of peptide blockade. This suggests that radiopharmaceutical uptake in the large intestine reflects receptor-mediated uptake in addition to the excretion of the radiopharmaceutical through the hepatobiliary route. This specific retention is not surprising considering the large number of CGRPR+ neurons located within the large intestine (Russo, A. F. & Hay, D. L., Physiol Rev 103, 1565-1644 (2023)).

[0037] Fig. 10: illustrates representative radiopharmaceuticals and corresponding data from Example 3.

[0038] Fig. 11: shows biodistribution data from Example 4.

[0039] Fig. 12: shows tumor-to-muscle data from Example 5.

[0040] Fig. 13: shows survival data from Example 6.

[0041] Figs. 14A-14D: show radiochemical purity of [l uIn]In-DOTA using radio-TLC. (A) [n iIn]In-l, (B) [mIn]In-2, (C) [mIn]In-3, (D) [i nIn]InC13; In this ITLC-SA system, uncomplexed [n iIn]In eluted with the solvent front (Rf ~ 1), while [n iIn]In-DOTA-peptide remained at the origin (Rf ~ 0)

[0042] Figs. 15A-15D: show In vitro serum stability of [niIn]In-DOTA maintained at 37°C after 7 days using radio-TLC. (A) [inIn]In-l, (B) [niIn]In-2, (C) [niIn]In-3, (D) [inIn]InC13; In this ITLC-SA system, un-complexed [niIn]In eluted with the solvent front (Rf ~ 1), while [inIn]In-DOTA-peptide remained at the origin (Rf ~ 0)

[0043] Figs. 16A-16D: show radiochemical purity of [177Lu]Lu-DOTA using radio-TLC. (A) [177LU]LU-1, (B) [177LU]LU-2, (C) [177LU]LU-3, (D) [177Lu]LuCh; In this ITLC-SA system, un- complexed [177Lu]Lu eluted with the solvent front (Rf ~ 1), while [177Lu]Lu-DOTA-peptide remained at the origin (Rf ~ 0)

[0044] Figs. 17A-17D: show / / ? vitro serum stability of [177Lu]Lu-DOTA maintained at 37°C after 7 days using radio-TLC. (A) [177Lu]Lu-l, (B) [177Lu]Lu-2, (C) [177Lu]Lu-3, (D) [177Lu]LuCh; In this ITLC-SA system, un-complexed [177Lu]Lu eluted with the solvent front (Rf ~ 1), while [177Lu]Lu-DOTA-peptide remained at the origin (Rf ~ 0)

[0045] Figs. 18A-18D: show radiochemical purity of225Ac-DOTA225Ac-DOTA using radio- TLC. (A)225AC-1, (B)225AC-2, (C)225AC-3, (D)225AC(NO3)3; In this ITLC-SA system, uncomplexed225Ac eluted with the solvent front (Rf ~ 1), while225Ac-DOTA-peptide remained at the origin (Rf ~ 0)

[0046] Figs. 19A-19D: show In vitro serum stability of225Ac-DOTA by Radio-TLC. In vitro serum stability of225Ac-DOTA maintained at 37°C after 7 days using radio-TLC. (A)225Ac-1, (B)225Ac-2, (C)225Ac-3, (D)225Ac(NO3)s; In this ITLC-SA system, un-complexed225Ac eluted with the solvent front (Rf ~ 1), while225Ac-DOTA-peptide remained at the origin (Rf ~ 0)

[0047] DETAILED DESCRIPTION

[0048] The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

[0049] The term "about", means ± 10% of the stated value.

[0050] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., Ci-8 means one to eight carbons). Examples include (Ci-Cs)alkyl, (C2-Cs)alkyl, Ci-Ce)alkyl, (C2-Ce)alkyl and (C3-Ce)alkyl. Examples of alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers.

[0051] The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).

[0052] The term "amino acid," comprises the residues of the natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyl, Hyp, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai) in D or L form, as well as unnatural amino acids (e.g. phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic acid, statine, l,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citruline, a-methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). The term also comprises natural and unnatural amino acids bearing a conventional amino protecting group (e.g. acetyl or benzyloxycarbonyl), as well as natural and unnatural amino acids protected at the carboxy terminus (e.g. as a (Ci-Ce)alkyl, phenyl or benzyl ester or as an amide; or as an a-methylbenzyl amide). Other suitable amino and carboxy protecting groups are known to those skilled in the art (See for example, T.W. Greene, Protecting Groups In Organic Synthesis,' Wiley: New York, 1981, and references cited therein). An amino acid can be linked to the remainder of a conjugate as described herein through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as, for example, through the sulfur of cysteine.

[0053] The term "peptide" describes a sequence of 2 to 25 amino acids (e.g. as defined hereinabove) or peptidyl residues. The sequence may be linear or cyclic. For example, a cyclic peptide can be prepared or may result from the formation of disulfide bridges between two cysteine residues in a sequence. A peptide can be linked to the remainder of a conjugate as described herein through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as, for example, through the sulfur of a cysteine. A specific peptide comprises 3-25, 5-21, 8-12, or 11 amino acids. Peptide derivatives can be prepared as disclosed in U.S. Patent Numbers 4,612,302; 4,853,371; and 4,684,620, or as described in the Examples hereinbelow. Peptide sequences specifically recited herein are written with the amino terminus on the left and the carboxy terminus on the right.

[0054] As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy- protecting groups include phenyl sulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4thedition, Wiley-Interscience, New York, 2006.

[0055] As used herein a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

[0056] The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and / or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and / or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention,

[0057] The phrase "therapeutically effective amount" or “effective amount” includes but is not limited to an amount of a conjugate of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0058] The term “animal” includes mammals, fish, amphibians, reptiles, birds and invertebrates. The term “mammal” includes humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the animal is a mammal. In one embodiment, the animal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient.

[0059] The conjugates disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.

[0060] It is understood by one skilled in the art that this invention also includes any conjugate that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a - CH3 group may be substituted with -CD3.

[0061] The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with a conjugate as described herein to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.

[0062] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. A conjugate as described herein can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of a conjugate as described herein, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active conjugate, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0063] It will be appreciated by those skilled in the art that a conjugate as described herein having a chiral center may exist in and be isolated in optically active and racemic forms. Some conjugates as described herein may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a conjugate as described herein, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

[0064] When a bond in a conjugate as described herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a conjugate as described herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the conjugate may be at least 51% the absolute stereoisomer depicted. In another embodiment, the conjugate may be at least

[0065] 60% the absolute stereoisomer depicted. In another embodiment, the conjugate may be at least

[0066] 80% the absolute stereoisomer depicted. In another embodiment, the conjugate may be at least

[0067] 90% the absolute stereoisomer depicted. In another embodiment, the conjugate may be at least

[0068] 95 the absolute stereoisomer depicted. In another embodiment, the conjugate may be at least 99% the absolute stereoisomer depicted.

[0069] Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded. Specifically, (Ci-Ce)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, secbutyl, pentyl, 3-pentyl, or hexyl; and (Ci-Ce)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

[0070] Chelating Groups and Radionuclides

[0071] A number of radionuclides and chelating groups are known, along with synthetic methods and synthetic intermediates that can be used to incorporate the chelating groups into conjugates. See Holik, H.A., et al., Molecules, 2022, 27(10), 3062. Additionally, radionuclides that are particularly useful for therapeutic applications as well as radionuclides that are particularly useful for imaging (e.g., PET and SPEC imaging) are known. Chelating groups that pair well with specific chelators are also known. See Holik, H.A., et al., Molecules, 2022, 27(10), 3062.

[0072] Chelating Groups

[0073] A variety of chelating groups and methods for their preparation are known, for example, see International Patent Application Publication Number WO2017 / 161356 (for example, pages 8-17 therein).

[0074] In one embodiment, the chelating group is selected from the group consisting of DOTA, PCTA, DOTMA, TCMC, DOTATATE, DOTATOC, DOTANOC, DTP A, 1B4M- DTPA, CHX=A”-DTPA, NOTA, NODAGA, NODASA, NETA, TETA, CB-TE2A, H2dedpa, H2octapa, H2CHXdedpa, H2CXHoctapa, HYNIC, EDD / HYNIC-TOC, Sar bicyclic chelatorsT3,4BCPP, N(NOEt)2isomers, HBED-CC, PCTA-NCS, MANOTA, THP, DFO, DFO*, and DFOcyclo*. In one embodiment, the chelating group is DOTA or DOTMA. In one embodiment, the chelating group is DOTA.

[0075] A variety of chelating groups and methods for their preparation are known, for example, see International Patent Application Publication Number WO2017 / 161356 (for example, pages 8-17 therein). Radionuclides

[0076] In one embodiment, the radionuclide is suitable for PET imaging. In one embodiment, the radionuclide is selected from the group consisting of isotopes:nC,18F,13N,150,44SC,52Mn,60Cu,61Cu,62Cu,64Cu,68Ga,76Br,82Rb,86Y,89Zr,94Tc,134Ce, 149 / 152^ i34j^a,anj i24j jn oneembodiment, the radionuclide is selected from the group consisting of isotopes:18F,64Cu,68Ga, and89Zr. In one embodiment, the radionuclide is64Cu. In one embodiment, the radionuclide is89Zr.

[0077] In one embodiment, the radionuclide is suitable for SPECT imaging. In one embodiment, the radionuclide is selected from the group consisting of isotopes:67Ga,n iIn,155Tb123I,125I,1311,203Pb, and "Tc. In one embodiment, the radionuclide is selected from the group consisting of isotopes:99Tc,U1ln, and123I.

[0078] In one embodiment, the radionuclide is suitable for targeted radionuclide therapy (alpha, beta-emitters or auger). In one embodiment, the radionuclide is selected from the group consisting of isotopes:67Cu,177Lu,89Sr,90Y,117Sn,131I,153Sm,166Ho,186Re,188Re,161Tb,211At,212Pb,212Bi,213Bi,223Ra,224Ra,225Ac, and227Th. In one embodiment, the radionuclide is selected from the group consisting of isotopes:67Cu,90Y,177Lu,211At,212Pb,225Ac,U 1ln, and227Th.

[0079] In one embodiment, the radionuclide isU1ln,177Lu, or225Ac.

[0080] Linking Groups

[0081] The nature of the linking group is not critical, provided the final conjugate has the requisite properties for its intended use (e.g., as an imaging agent or as a therapeutic agent.

[0082] The linker can vary in length and atom composition and for example can be branched or non-branched or cyclic or a combination thereof. The linker may also modulate the properties of the targeted conjugate such as but not limited to solubility, stability and aggregation.

[0083] Linking groups and methods for introducing linking groups into conjugates are described in International Patent Application Publication Number WO2017 / 161356.

[0084] In one embodiment the linker comprises about 3-5000 atoms. In one embodiment the linker comprises about 3-4000 atoms. In one embodiment the linker comprises about 3-2000 atoms. In one embodiment the linker comprises about 3-1000 atoms. In one embodiment the linker comprises about 3-750 atoms. In one embodiment the linker comprises about 3-500 atoms. In one embodiment the linker comprises about 3-250 atoms. In one embodiment the linker comprises about 3-100 atoms. In one embodiment the linker comprises about 3-50 atoms. In one embodiment the linker comprises about 3-25 atoms.

[0085] In one embodiment the linker comprises about 10-5000 atoms. In one embodiment the linker comprises about 10-4000 atoms. In one embodiment the linker comprises about 10-2000 atoms. In one embodiment the linker comprises about 10-1000 atoms. In one embodiment the linker comprises about 10-750 atoms. In one embodiment the linker comprises about 10-500 atoms. In one embodiment the linker comprises about 10-250 atoms. In one embodiment the linker comprises about 10-100 atoms. In one embodiment the linker comprises about 10-50 atoms. In one embodiment the linker comprises about 10-25 atoms.

[0086] In one embodiment the linker comprises atoms selected from H, C, N, S and O.

[0087] In one embodiment the linker comprises atoms selected from H, C, N, S, P and O.

[0088] In one embodiment the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 1000 (or 1-750, 1-500, 1-250, 1-100, 1- 50, 1-25, 1-10, 1-5, 5-1000, 5-750, 5-500, 5-250, 5-100, 5-50, 5-25, 5-10 or 2-5 carbon atoms) wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, 3-7 membered heterocycle, 5-6-membered heteroaryl or carbocycle and wherein each chain, 3-7 membered heterocycle, 5-6-membered heteroaryl or carbocycle is optionally and independently substituted with one or more (e.g. 1, 2, 3, 4, 5 or more) substituents selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, (Ci-Ce)alkanoyl, (Ci-Ce)alkanoyloxy, (Ci- Ce)alkoxycarbonyl, (Ci-Ce)alkylthio, azido, cyano, nitro, halo, -N(Ra)2, hydroxy, oxo (=0), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein each Rais independently H or (Ci-Ce)alkyl. In one embodiment the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 1000 (or 1-750, 1-500, 1-250, 1-100, 1- 50, 1-25, 1-10, 1-5, 5-1000, 5-750, 5-500, 5-250, 5-100, 5-50, 5-25, 5-10 or 2-5 carbon atoms) wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, , wherein each Rais independently H or (Ci-Ce)alkyl.

[0089] In one embodiment, the linker comprises one or more amino acids or peptides. In one embodiment, the linker comprises at least one amino acid. In one embodiment, the linker comprises at least two amino acids. In one embodiment, the linker comprises at least three amino acids.

[0090] In one embodiment, the linker comprises 10-100 atoms selected from H, C, N, S and O. In one embodiment, the linker comprises 10-100 atoms selected from H, C, N, S and O, including one or more amino acids.

[0091] In one embodiment, the linker comprises 10-50 atoms selected from H, C, N, S and O.

[0092] In one embodiment, the linker comprises 10-50 atoms selected from H, C, N, S and O, including one or more amino acids.

[0093] In one embodiment, the linker is covalently bonded to the chelating group through a nitrogen atom of the linker. In one embodiment, the linker is covalently bonded to the chelating group through the methylene of a 4-benzyl group.

[0094] In one embodiment, the linker is covalently bonded to the N-terminus of the peptide that binds to the Calcitonin Gene-Related Peptide Receptor through a carbonyl group of the linker forming an amide bond.

[0095] In one embodiment, the linker comprises 10-50 atoms selected from H, C, N, S and O; the linker is covalently bonded to the chelating group through a nitrogen atom of the linker; and the linker is covalently bonded to the N-terminus of the peptide that binds to the Calcitonin Gene-Related Peptide Receptor through a carbonyl group of the linker forming an amide bond.

[0096] In one embodiment, the linker comprises 10-50 atoms selected from H, C, N, S and O; the linker is covalently bonded to the chelating group through a methylene of a 4-benzyl group of the linker; and covalently bonded to the N-terminus of the peptide that binds to the Calcitonin Gene-Related Peptide Receptor through a carbonyl group of the linker forming an amide bond.

[0097] In one embodiment, the linker comprises: wherein n is 0, 1, 2, 3, 4, 5, or 6. In one embodiment, the linker is: wherein n is 0, 1, 2, 3, 4, 5, or 6.

[0098] In one embodiment the linker is:

[0099] In one embodiment, the linker comprises a ring that can be formed using click chemistry.

[0100] In one embodiment, the linker comprises 10-50 atoms selected from H, C, N, S and O and includes a ring that can be formed using click chemistry.

[0101] In one embodiment, the peptide that binds to the Calcitonin Gene-Related Peptide Receptor is an antagonist of the Calcitonin Gene-Related Peptide Receptor.

[0102] In one embodiment, the peptide that binds to the Calcitonin Gene-Related Peptide Receptor is an agonist of the Calcitonin Gene-Related Peptide Receptor.

[0103] Processes for preparing conjugates of the invention are also provided as further embodiments of the invention.

[0104] The conjugates can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. In one embodiment, the conjugates are administered intravenously or intraperitoneally.

[0105] In some embodiments, the radionuclide is present in a final concentration in the chelate solution that provides a volumetric radioactivity of at least about 100 MBq / mL, for example at least about 250 MBq / mL In some embodiments, the radionuclide is present in a final concentration in the chelate solution that provides a volumetric radioactivity from about 100 to about 1000 MBq / mL, for example from about 100 to about 750 MBq / mL, from about 100 to about 500 MBq / mL, from about 100 to about 250 MBq / mL, from about 250 to about 1000 MBq / mL, from about 250 to about 750 MBq / mL, from about 250 to about 500 MBq / mL, from about 500 to about 1000 MBq / mL, from about 500 to about 750 MBq / mL, or from about 750 to about 1000 MBq / mL. In preferred embodiments, the radionuclide is present in a final concentration in the chelate solution that provides a volumetric radioactivity from about 250 to about 500 MBq / mL

[0106] A stabilizer against radiolytic degradation can be included in the solutions to reduce the cleavage of the chemical bonds of the molecules which form the radiopharmaceutical product due to the high energy emissions released during the constant decay of the included radionuclide. The stabilizer can be selected from gentisic acid (2,5-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof ( e.g., sodium ascorbate, methionine, N-acetyl cysteine, histidine, melatonin, ethanol, and Se-methionine. In one embodiment, the stabilizer is selected from gentisic acid and salts thereof and ascorbic acid and salts thereof. In some embodiments, the stabilizer is present in a final concentration in the chelate solution of at least about 0.2 mg / mL, at least about 0.5 mg / mL, at least about 1.0 mg / mL, or at least about 2.7 mg / mL.

[0107] In some embodiments, the radionuclide is present in a final concentration in the chelate solution that provides a volumetric radioactivity of at least about 100 MBq / mL, for example at least about 250 MBq / mL. In some embodiments, the radionuclide is present in a final concentration in the chelate solution that provides a volumetric radioactivity from about 100 to about 1000 MBq / mL, for example from about 100 to about 750 MBq / mL, "

[0108] “Secular equilibrium" is defined as the point in which the quantity of a radioactive isotope remains constant because its product rate equals its decay rate. In the radiopharmaceutical solutions described herein, secular equilibrium is considered to be reached when the quantity of daughter isotopes for an alpha emitting radionuclide are considered to remain nearly constant. In some embodiments, the chelate solution is maintained at about 25 degrees Celsius for at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, or at least 24 hours until secular equilibrium is reached.

[0109] In some embodiments, the process further comprises filtering the chelate solution to remove any residual solid components prior to administration to a subject.

[0110] In some embodiments, the radiopharmaceutical compositions prepared by the processes described herein is delivered to a subject at a therapeutically effective amount comprised between about 2000 and about 10000 MBq, for example from about 2000 to about 9000 MBq, from about 2000 to about 8000 MBq, from about 2000 to about 7000 MBq, from about 2000 to about 6000 MBq, from about 2000 to about 5000 MBq, from about 2000 to about 4000 MBq, from about 2000 to about 3000 MBq, from about 3000 to about 10000 MBq, from about 3000 to about 9000 MBq, from about 3000 to about 8000 MBq, from about 3000 to about 7000 MBq, from about 3000 to about 6000 MBq, from about 3000 to about 5000 MBq, from about 3000 to about 4000 MBq, from about 4000 to about 10000 MBq, from about 4000 to about 9000 MBq, from about 4000 to about 8000 MBq, from about 4000 to about 7000 MBq, from about 4000 to about 6000 MBq, from about 4000 to about 5000 MBq, from about 5000 to about 10000 MBq, from about 5000 to about 9000 MBq, from about 5000 to about 8000 MBq, from about 5000 to about 7000 MBq, from about 5000 to about 6000 MBq, from about 6000 to about 10000 MBq, from about 6000 to about 9000 MBq, from about 6000 to about 8000 MBq, from about 6000 to about 7000 MBq, from about 7000 to about 10000 MBq, from about 7000 to about 9000 MBq, from about 7000 to about 8000 MBq, from about 8000 to about 10000 MBq, from about 8000 to about 9000 MBq, or from about 9000 to about 10000 MBq.

[0111] The radiopharmaceuticals may be administered with or without amino acid therapy and with or without electrolytes. The amino acid preparation administered without electrolytes, containing 4.93 g 1-1 lysine and 17.6gJ-l arginine and with a tonicity of 880 mosmJ-1, Thus, the present conjugates may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active conjugates may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active conjugates. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active conjugates in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0112] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active conjugate, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active conjugate may be incorporated into sustained-release preparations and devices.

[0113] The active conjugate may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active conjugate can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0114] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active conjugate in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0115] For topical administration, the present conjugates may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

[0116] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present conjugates can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

[0117] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0118] Examples of useful dermatological compositions which can be used to deliver the conjugates to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).

[0119] Useful dosages of the conjugates can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949. The amount of the conjugate required for use in treatment will vary with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

[0120] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

[0121] The invention will now be illustrated by the following non-limiting Examples.

[0122] EXAMPLES

[0123] Example 1. Preparation of Representative Conjugates

[0124] Peptide sequences for the conjugates of the invention can be prepared using standard peptide synthesis methods. Peptides can be linked to a metal chelating group either directly or through a linking group using available starting materials, reagents, and techniques. The resulting conjugates that comprise a peptide that binds to the Calcitonin Gene-Related Peptide Receptor and a metal chelating group can be radiolabeled using known methods or as described in the following paragraph.

[0125] Radiochemistry

[0126] The complexation of ^4Cu to DOTA-Bn-NCS-C6-FV-Hyp-TDVGPFAF was achieved by reacting TDVGPFAF, 118 pL of 0.1 M NHqOAc (pH, 8.0), and 37 MBq of64CuC12 in 0.1N hydrochloric acid for 1.5 h at 95°C. The reaction was further purified using a previously published method (Wadas, T. J., et al., JNuclMed 49, 1819-1827 (2008)). Purity after purification was greater than 95% based on and radio-HPLC analysis.

[0127] The complexation was achieved by reacting 1 pg (6.3 x 10-4pmol) of DOTA-Bn-NCS-C6-FV-Hyp- TDVGPFAF, 118 pL of 0.5 M HEPEs (pH, 7.2), and 37 MBq of89ZrClq in 0.1N hydrochloric acid for 1.0 h at 95°C. The reaction was further purified using a previously published method (Bhatt, N. B., et al., Dalton Trans 47, 13214-13221 (2018); Bhatt, N. B., Pandya, D. N. & Wadas, T. J. Recent Advances in Zirconium-89 Chelator Development. Molecules 23 (2018); Pandya, D. N., et al., Chem Sci 8, 2309-2314 (2017); Pandya, D. N., et al., J NuclMed 60, 696-701 (2019); Pandya, D. N., et al., Chem Sci 8, 2309-2314 (2017); Pandya, D. N., et al., Inorg Chem 59, 17473-17487 (2020); and Pandya, D. N., et al., Theranostics 6, 698-709 (2016)). Purity after purification was greater than 95% based on and radio-HPLC analysis. Example 2. Biodistribution

[0128] A biodistribution study was conducted as previously described (Pandya, D. N., et al., Chem Sci 8, 2309-2314 (2017); Pandya, 59, 17473-17487 (2020); and Pandya, D. N., et al., Theranostics 6, 698-709 (2016)). Briefly, healthy female nude mice (8 weeks old) bearing HTB-10 tumors were injected with89Zr-DOTA- Bn-NCS-C6-FV-Hyp-TDVGPFAF (0.74 MBq, 25 ng in 150 pL / mouse) via the tail vein. Animals were sacrificed at selected time points after injection, and organs of interest were removed, weighed, and counted on a y-counter (Revity). Blocking studies were also performed using healthy female nude mice (8 weeks old) bearing HTB-10 tumors to examine in vivo uptake specificity.89Zr-DOTA-Bn-NCS-C6-FV-Hyp-TDVGPFAF (0.74 MBq, 40 ng in 150 pL / mouse) was co-injected with 175 pg of DOTA-Bn-NCS-C6-FV- Hyp-TDVGPFAF via the tail vein. The percentage injected dose per gram and percentage injected dose per organ were calculated by comparing them with a weighed, counted standard.

[0129] Example 3. Preparation and Testing Representative Radiopharmaceuticals

[0130] Figure 10 shows data for nine representative radiopharmaceuticals. Each peptide chelator conjugate shown in Figure 2 was radiolabeled with In-111, Lu- 177 and Ac-225. Each radiopharmaceutical was prepared in excellent radiochemical purity and specific activity. The LogD data demonstrates that all the radiopharmaceuticals displayed hydrophilic character. Finally, the serum stability data demonstrates that all the radiopharmaceuticals are stable in human serum and resist degradation by serum proteins over a seven-day period.

[0131] The radiopharmaceuticals shown in Figure 10 are representative conjugates of the invention and can be identified as follows:

[0132] [n iIn]In-l : Peptide Chelator Conjugate 1 labeled with In-111. [n iIn]In-2: Peptide Chelator Conjugate 2 labeled with In-111. [n iIn]In-3 : Peptide Chelator Conjugate 3 labeled with In-111. [177LU]LU-1 : Peptide Chelator Conjugate 1 labeled with Lu-177. [177LU]LU-2: Peptide Chelator Conjugate 2 labeled with Lu-177 [177LU]LU-3 : Peptide Chelator Conjugate 3 labeled with Lu-177 [225Ac]Ac-l : Peptide Chelator Conjugate 1 labeled with Ac-225 [225Ac]Ac-2: Peptide Chelator Conjugate 2 labeled with Ac-225 [225Ac] Ac-3: Peptide Chelator Conjugate 3 labeled with Ac-225

[0133] All radiopharmaceuticals were prepared using protocols similar to those described by (Pandya, D. N., et al., Theranostics 6, 698-709 (2016); and Lang, M., et al., J Med Chem 49, 616-624 (2006). Briefly, The complexation of225Ac,n iIn or177Lu with each peptide was achieved by reacting the peptide (5-10 pg (5-10 pL,1.0 mg / mL in water)) with225Ac(NO3)3l uInC13 or177LuCh (3.4 MBq) that was diluted in 100 pL of water containing 10 pL of 20% L-ascorbic acid. The pH of the resulting solution was adjusted to 5.5-6 using 1 M Tris buffer (10-12 pL), and then incubated at 60°C for 1 hour. Reaction progress and radiochemical purity of were measured without further purification using, radio-TLC, gamma counting of radio-HPLC fractions, or radio-HPLC.

[0134] In vitro serum stability was carried out by adding 50 pL of the radiopharmaceutical (2 MBq) to 900 pL of human serum. The solutions (n = 3) were incubated at 37 °C for 7days and were analyzed daily using radio-TLC, ITLC with gamma counting or size exclusion chromatography using a Superdex 200 10 / 300 GL™ column (GE Healthcare Life Sciences, Piscataway, NJ) and phosphate buffered saline (PBS) as eluent with a flow rate of 0.5 mL / min.

[0135] Example 4 Biodistribution

[0136] Figure 11 shows the biodistribution of [n iIn]In-l in selected tissues. This data was collected at 1 hour, 4 hours, and 24 hours. This data demonstrates that the radiopharmaceutical rapidly excretes from the blood pool and has low to modest retention in Liver, Kidney and bone tissues. This pharmacokinetic data is consistent with the excretion profiles of other peptide-based radiopharmaceuticals.

[0137] Studies were completed as described by Pandya, D. et al., Theranostics 6, 698- 709 (2016). Tumor bearing animals (n = 6 / cohort / time point) were injected with [n iIn]In- 1 and then sacrificed at 1 hour, 4 hours, and 24 hours post-injection. Tumors and organs of interest were removed, weighed, and counted on a gamma counter. Percent injected dose / gram (%ID / g) was determined based on comparison to a known counting activity standard. Example 5 Tumor to Muscle Ratio

[0138] Figure 12 shows the tumor-to-muscle ratio of tumor-bearing mice injected with [i nIn]In-l at 4 hours post-injection. The tumor / muscle ratio was excellent, suggesting improved selectivity for CGRPR+tissues over CGRPR' tissues. The ratio is significantly diminished upon co-inj ection of blockade with peptide chelator conjugate 1. This reduction in the tumor-to-muscle ratio suggests a receptor mediated interaction between the radiopharmaceutical and the CGRP receptor in vivo, and that the radiopharmaceutical is interacting with the receptor as desired.

[0139] The radiopharmaceutical was evaluated in nude mice bearing HTB-10 (SK-N-MC) neuroblastoma tumors, which endogenously express the CGRPR (n = 6 / cohort) (Hay, D. L. & Poyner, Cardiovasc Drug Rev 23, 31-42 (2005); and Hay, D. L., et al., Peptides 25, 2019-2026 (2004)). The HTB-10 cell line is a neuroblastoma cell line that endogenously expresses the CGRPR. It is considered a canonical cell line that is used in CGRPR research. Studies were completed as described by Pandya, D. et al., Theranostics 6, 698-709 (2016).

[0140] Example 6 Survival Study

[0141] Figure 13 shows results from a survival study of [177Lu]Lu-l in nude mice bearing HTB-10 tumors. Tumors were allowed to grow and then the mice were randomly divided into three cohorts. There were two control cohorts consisting of a saline treatment group (Group A; n = 10; black, solid line) and non-radioactive peptide treatment group (Group B; n = 10; red, dotted line) and a [177Lu]Lu-l treatment group (Group C; n = 8; blue, hyphenated line). Each cohort received two treatment doses over a 14-day period. Each dose was separated by 7 days.

[0142] The [177LU]LU-1 treatment group received two doses and each dose consisted of 500 microcuries of the radiopharmaceutical. The non-radioactive peptide group (Group B) received a mass of peptide that was consistent with the mass of peptide injected in Group C. Animals were removed from the study once clinical end points were met. Those endpoints were tumors that exceeded 2000 mm3or that were ulcerated. Animals receiving the radiopharmaceutical (Group C) had a significant survival benefit when compared to those animals not receiving the radiopharmaceutical (Groups A and B). Also, no survival benefit was observed in Group B This suggests that the delivery of the Lu-177 (and its therapeutic radiation) to the tumor is the cause of the survival benefit and not the peptide ligand interacting with the CGRPR receptor. Or put another way, the peptide alone does not exert a therapeutic effect on the tumors. Moreover, ataxia, nonambulation, paralysis or behaviors that would indicate cardiotoxicity, neurotoxicity, or other effects suggesting the radiotherapy was negatively affecting normal CGRPR+tissues were not observed.

[0143] Studies were completed as described by Pandya, D. et al., Theranostics 6, 698-709 (2016). Briefly, animals were inoculated with HTB-10 tumor cells in the flank and then randomly divided into cohorts. Tumor growth was monitored by manual tumor volume measurements using calipers. When tumors reached an appropriate size, the cohorts received intravenous injections of either saline, the non-radioactive peptide chelator conjugate 1 or [177Lu]Lu-l (Verhoeven, M., et al., Mol Imaging Biol 26, 114-123 (2024); Berglund, H., et al., Eur J Nucl Med Mol Imaging 51, 768-778 (2024); and Mohajershojai, T., et al., Cancers (Basel) 15 (2023)). Animals were monitored daily for signs of distressed behavior. Cohorts were followed until clinical endpoints ( tumor volume > 2000 mm3 or ulcerated tumor) were reached. As animals reached clinical endpoints they were euthanized. Tissues were harvested and stained with anti-Ki-67 or anti-caspase-3 to assess cell proliferation and apoptosis, respectively. Tissues can also be stained with anti-CGRPR, anti-LC3B, or anti-P-galactosidase mAbs (Abeam, Inc.) to assess CGRPR expression, autophagy, and senescence, respectively.

[0144] Example 7 Histological Analysis

[0145] Ki-67 Ki-67 is a way to measure how fast cancer cells in a tumor are dividing. Ki-67 is a protein that is found only in cells that are dividing. A high Ki-67 proliferation index means many cells are dividing quickly and that the cancer is likely to grow and spread.

[0146] Ki-67 staining of HTB-10 tumors sections harvested from mice used in therapy studies and histological analysis revealed that mice treated with radiotherapy exhibited lower staining intensities within their tumors when compared to mice treated with saline or peptide chelator conjugate 1. This suggests that the radiotherapy exerted a therapeutic effect and reduced cell proliferation within the tumors.

[0147] Tissues were harvested at the time of euthanasia and embedded in optimum cutting temperature (OCT) compound (Miles, Inc., Elkhart, IN). Frozen sections (4-6 pm) were cut, fixed in ice-cold acetone, and stained using procedures similar to those described by Pandya, D. N., et al., Theranostics 6, 698-709 (2016); and Graefe C, et al., Mol Biol Rep. Aug;46(4):4631-4643 (2019).

[0148] Example 8 Additional Histological Analysis

[0149] Caspase-3 is a biomarker for apoptotic cell death. Caspase-3 staining of HTB-10 tumor sections and histological analysis revealed that mice treated with radiotherapy exhibited higher staining intensities within tumors when compared to mice treated with saline or peptide chelator conjugate 1. This suggests that the radiotherapy exerted a therapeutic effect that increased the amount of cell death (apoptosis) within the tumor.

[0150] This data is consistent with the Ki-67 data from Example 7. In the section depicting a tumor from an animal that received saline treatment, the tumor architecture appears normal. There are numerous groups of tumor cells surrounded by a microenvironment of support cells and connective tissue. Staining for caspase-3 is minimal. In the section depicting a tumor from an animal that received radiotherapy, the tumor architecture is disrupted and staining for caspase-3 is intense.

[0151] Histology analysis: Tissues were harvested at the time of euthanasia and embedded in optimum cutting temperature (OCT) compound (Miles, Inc., Elkhart, IN). Frozen sections (4-6 pm) were cut, fixed in ice-cold acetone, and stained using procedures similar to those described by Pandya, D. N., et al., Theranostics 6, 698-709 (2016); and Kaushal V, et al., Methods Mol Biol . 1133: 141-54 (2014).

[0152] Example 9. Radiochemical Purity and Serum Stability

[0153] The radiochemical purity and serum stability were confirmed using procedures similar to those described by Pandya, D. N., et al., Theranostics 6, 698-709 (2016). Data is shown in Figures Briefly, radiochemical purity of each radiopharmaceutical was measured without further purification using radio-TLC, which was conducted on a Bioscan AR 2000 radio- TLC scanner equipped with a 10% methane: argon gas supply and a PC interface running Winscan v.3 analysis software (Eckert & Ziegler, Berlin, DE). Varian ITLC-SG strips were employed using a 0.9% NaCl / 10 mM NaOH and 30:70 10% NEUOAc / methanol solution as eluents.

[0154] In vitro serum stability was carried out by adding 50 pL of each radiopharmaceutical to 900 pL of human serum. The solutions (n = 3) were incubated at 37 °C for 7 days and were analyzed daily using radio-TLC.

[0155] Example 10. Representative Dosage Forms

[0156] In some embodiments, pharmaceutical compositions disclosed herein can comprise between about 0.1 % and about 45%, and especially, about 1 and about 15%, by weight of the total of one or more of the compounds based on the weight of the total composition including carrier or diluents. Illustratively, dosage levels of the administered active ingredients can be: intravenous, about 0.01 to about 20 mg / kg; intraperitoneal, about 0.01 to about 100 mg / kg; subcuta-neous, about 0.01 to about 100 mg / kg; intramuscular, about 0.01 to about 100 mg / kg; orally about 0.01 to about 200 mg / kg, or about 1 to about 100 mg / kg; intranasal instillation, about 0.01 to about 20 mg / kg; and aerosol, about 0.01 to about 20 mg / kg of animal (body) weight.

[0157] The following illustrate representative pharmaceutical dosage forms, containing a conjugate of the invention ('Compound X'), for therapeutic or prophylactic use in humans.

[0158] (i) Tablet 1 mg / tablet

[0159] Compound X= 100.0

[0160] Lactose 77.5

[0161] Povidone 15.0

[0162] Croscarmellose sodium 12.0

[0163] Microcrystalline cellulose 92.5

[0164] Magnesium stearate 3,0

[0165] 300.0 (ii) Tablet 2 mg / tablet

[0166] Compound X= 20.0

[0167] Microcrystalline cellulose 410.0

[0168] Starch 50.0

[0169] Sodium starch glycolate 15.0

[0170] Magnesium stearate 5,0

[0171] 500.0

[0172] (iii) Capsule mg / capsule

[0173] Compound X= 10.0

[0174] Colloidal silicon dioxide 1.5

[0175] Lactose 465.5

[0176] Pregelatinized starch 120.0

[0177] Magnesium stearate 3,0

[0178] 600.0

[0179] (iv) Injection 1 (1 mg / ml) mg / ml

[0180] Compound X= (free acid form) 1.0

[0181] Dibasic sodium phosphate 12.0

[0182] Monobasic sodium phosphate 0.7

[0183] Sodium chloride 4.5

[0184] 1.0 N Sodium hydroxide solution

[0185] (pH adjustment to 7.0-7.5) q.s.

[0186] Water for injection q.s. ad 1 mL

[0187] (v) Injection 2 (10 mg / ml) mg / ml

[0188] Compound X= (free acid form) 10.0

[0189] Monobasic sodium phosphate 0.3

[0190] Dibasic sodium phosphate 1.1

[0191] Polyethylene glycol 400 200.0

[0192] 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s.

[0193] Water for injection q.s. ad 1 mL

[0194] (vi) Aerosol mg / can

[0195] Compound X= 20.0

[0196] Oleic acid 10.0

[0197] Trichloromonofluoromethane 5,000.0

[0198] Dichlorodifluoromethane 10,000.0

[0199] Di chlorotetrafluoroethane 5,000.0

[0200] The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

[0201] All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

CLAIMSWhat is claimed is:

1. A conjugate comprising: a peptide that binds to the Calcitonin Gene-Related Peptide Receptor that is linked to a therapeutic or a detectable radionuclide; wherein the peptide that binds to the Calcitonin Gene-Related Peptide Receptor comprises the sequence TDVGPFAF (SEQ ID NO: 1).

2. The conjugate of claim 1, wherein the peptide that binds to the Calcitonin Gene-Related Peptide Receptor comprises or consists of a sequence selected from the group consisting of FV- Aib-TDVGPFAF (SEQ ID NO: 2), FV-Tic-TDVGPFAF (SEQ ID NO: 3), and FV-Hyp- TDVGPFAF (SEQ ID NO: 4).

3. The conjugate of any one of claims 1-2, which comprises a linking group that links the peptide that binds to the Calcitonin Gene-Related Peptide Receptor to a chelating group for the therapeutic or a detectable radionuclide.

4. The conjugate of claim 3, wherein the linking group comprises about 3 to about 50 atoms.

5. The conjugate of claim 3, wherein the linking group comprises one or more amino acids or peptides.

6. The conjugate of claim 3, wherein the linking group comprises about 10 to about 50 atoms selected from H, C, N, S and O.

7. The conjugate of claim 3, wherein the linking group comprises:

8. The conjugate of claim 3, wherein the linking group comprises:wherein n is 0, 1, 2, 3, 4, 5, or 6.

9. The conjugate of claim 3, wherein the linking group is:wherein n is 0, 1, 2, 3, 4, 5, or 6.

10. The conjugate of claim 3, wherein the linking group is:

11. The conjugate of claim 3, wherein the linking group comprises a ring that can be formed using click chemistry.

12. The conjugate of claim 3, wherein the linking group comprises 10-50 atoms selected from H, C, N, S and O and includes a ring that can be formed using click chemistry.

13. The conjugate of any one of claims 3-12, wherein the chelating group is selected from the group consisting of: DOTA, PCTA, DOTMA, TCMC, DOTATATE, DOTATOC, DOTANOC, DTP A, 1B4M-DTPA, CHX=A”-DTPA, NOTA, NOD AGA, NODASA, NETA, TETA, CB-TE2A, H2dedpa, H2octapa, H2CHXdedpa, H2CXHoctapa, HYNIC, EDD / HYNIC- TOC, Sar bicyclic chelatorsT3,4BCPP, N(NOEt)2isomers, HBED-CC, PCTA-NCS, MANOTA, THP, DFO, DFO*, and DFOcyclo*.

14. The conjugate of any one of claims 3-12, wherein the chelating group is DOTA orDOTMA.

15. The conjugate of any one of claims 3-12, the chelating group is:

16. The conjugate of claim 3, which comprises the structure:

17. The conjugate of claim 3, which comprises the structure:

18. The conjugate of claim 3, which comprises the structure:

19. The conjugate of any one of claims 1-18, which comprises a detectable radionuclide.

20. The conjugate of claim 19, wherein the detectable radionuclide is selected from the following isotopes:UC,18F,13N,150,44Sc,52Mn,60Cu,61Cu,62Cu,64Cu,68Ga,76Br,82Rb,86Y,89Zr,94TC,134Ce, 149 / 152Tb134^and124j21. The conjugate of claim 19, wherein the detectable radionuclide is selected from18F,64Cu,68Ga, and89Zr.

22. The conjugate of claim 19, wherein the detectable radionuclide is64Cu.

23. The conjugate of claim 19, wherein the detectable radionuclide is89Zr.

24. The conjugate of claim 19, wherein the detectable radionuclide is selected from the following isotopes:67Ga,i nIn,155Tb123I,1251,1311,203Pb, and "Tc.

25. The conjugate of claim 19, wherein the detectable radionuclide is selected from the following isotopes: "Tc,luIn, and123I.

26. The conjugate of any one of claims 1-18, which comprises a therapeutic radionuclide.

27. The conjugate of claim 26, wherein the therapeutic radionuclide is selected from the following isotopes:67Cu,177Lu,89Sr,90Y,117Sn,131I,153Sm,166Ho,186Re,188Re,161Tb,211At,212Pb,212Bi,213Bi,223Ra,224Ra,225Ac, and227Th.

28. The conjugate of claim 26, wherein the therapeutic radionuclide is selected from the following isotopes:67Cu,90Y,177Lu,211At,212Pb,225Ac,U 1ln, and227Th.

29. The conjugate of any one of claims 1-18, which comprisesU1ln,177Lu, or225Ac.

30. A pharmaceutical composition comprising a conjugate as described in any one of claims 1-29 and a pharmaceutically acceptable excipient.

31. A method for imaging the Calcitonin Gene-Related Peptide Receptor comprising contacting the Calcitonin Gene-Related Peptide Receptor with a conjugate as described in any one of claims 19-25 and detecting the detectable radionuclide.

32. A method for imaging a Calcitonin Gene-Related Peptide Receptor in a nerve cell comprising contacting a nerve cell that comprises the Calcitonin Gene-Related Peptide Receptor with a conjugate as described in any one of claims 19-25 that comprises a detectable radionuclide under conditions that allow the conjugate to bind to the Calcitonin Gene-Related Peptide Receptor and detecting the detectable radionuclide.

33. A method for treating migraine, a peripheral pain condition, cancer, an inflammatory bowel condition, arthritis, inflammation, infection or a neuroinflammatory disease in an animal, comprising administering a conjugate as described in any one of claims 26-29 to the animal.

34. A method for treating cancer in an animal, comprising administering a conjugate as described in any one of claims 26-29 to the animal.

35. A method for treating bone metastasis in an animal, comprising administering a conjugate as described in any one of claims 26-29 to the animal.

36. The method of claim 35, wherein the bone metastasis is associated with breast cancer or prostate cancer.

37. A conjugate as described in any one of claims 26-29 for use in medical therapy.

38. A conjugate as described in any one of claims 19-25 for use in medical imaging.

39. A conjugate as described in any one of claims 26-29 for the prophylactic or therapeutic treatment of migraine, a peripheral pain condition, cancer, an inflammatory bowel condition, arthritis, inflammation, infection or a neuroinflammatory disease.

40. A conjugate as described in any one of claims 26-29 for the prophylactic or therapeutic treatment of cancer.

41. A conjugate as described in any one of claims 26-29 for the prophylactic or therapeutic treatment of bone metastasis.

42. The conjugate of claim 41, wherein the bone metastasis is associated with breast cancer or prostate cancer.

43. The use of a conjugate as described in any one of claims 26-29 to prepare a medicament for treating migraine, a peripheral pain condition, cancer, an inflammatory bowel condition, arthritis, inflammation, infection or a neuroinflammatory disease in an animal.

44. The use of a conjugate as described in any one of claims 26-29 to prepare a medicament for treating cancer in an animal.

45. The use of a conjugate as described in any one of claims 26-29 to prepare a medicament for treating bone metastasis in an animal.

46. The use of claim 45, wherein the bone metastasis is associated with breast cancer or prostate cancer.

47. A conjugate comprising: a peptide that binds to the Calcitonin Gene-Related Peptide Receptor that is linked to a chelating group for a therapeutic or a detectable radionuclide; wherein the peptide that binds to the Calcitonin Gene-Related Peptide Receptor comprises the sequence TDVGPFAF (SEQ ID NO: 1).

48. The conjugate of claim 47, wherein the peptide that binds to the Calcitonin Gene-Related Peptide Receptor comprises or consists of a sequence selected from the group consisting of FV- Aib-TDVGPFAF (SEQ ID NO: 2), FV-Tic-TDVGPFAF (SEQ ID NO: 3), and FV-Hyp- TDVGPFAF (SEQ ID NO: 4).

49. The conjugate of any one of claims 47-48, wherein the peptide that binds to the Calcitonin Gene-Related Peptide Receptor is linked to the chelating group for a therapeutic or a detectable radionuclide through a linking group.

50. The conjugate of claim 49, wherein the linking group comprises about 3 to about 50 atoms.

51. The conjugate of claim 49, wherein the linking group comprises one or more amino acids or peptides.

52. The conjugate of claim 49, wherein the linking group comprises about 10 to about 50 atoms selected from H, C, N, S and O.

53. The conjugate of claim 49, wherein the linking group comprises:

54. The conjugate of claim 49, wherein the linking group comprises:wherein n is 0, 1, 2, 3, 4, 5, or 6.

55. The conjugate of claim 49, wherein the linking group is:wherein n is 0, 1, 2, 3, 4, 5, or 6.

56. The conjugate of claim 49, wherein the linking group is:

57. The conjugate of claim 49, wherein the linking group comprises a ring that can be formed using click chemistry.

58. The conjugate of claim 49, wherein the linking group comprises 10-50 atoms selected from H, C, N, S and O and includes a ring that can be formed using click chemistry.

59. The conjugate of any one of claims 47-58, wherein the chelating group is selected from the group consisting of: DOTA, PCTA, DOTMA, TCMC, DOTATATE, DOTATOC, DOTANOC, DTP A, 1B4M-DTPA, CHX=A”-DTPA, NOTA, NOD AGA, NODASA, NETA, TETA, CB-TE2A, H2dedpa, H2octapa, H2CHXdedpa, H2CXHoctapa, HYNIC, EDD / HYNIC- TOC, Sar bicyclic chelatorsT3,4BCPP, N(NOEt)2isomers, HBED-CC, PCTA-NCS, MANOTA, THP, DFO, DFO*, and DFOcyclo*.

60. The conjugate of any one of claims 47-58, wherein the chelating group is DOTA or DOTMA.

61. The conjugate of any one of claims 47-58, wherein the chelating group is:

62. The conjugate of claim 61, which has the structure:

63. The conjugate of claim 61, which has the structure:

64. The conjugate of claim 61, which has the structure:

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