Compounds and compositions thereof for the treatment of cancer - Patents.com

Abstract

The present invention relates to compounds that contain a metal chelator and two fragments capable of binding to PSMA, their compositions and their use in methods of treatment.

Description

[Technical field]

[0001] The present invention relates to compounds that contain a metal chelator and two fragments capable of binding to PSMA, their compositions and their use in methods of treatment. [Background technology]

[0002] Prostate cancer is the leading cause of cancer-related death in men, and is currently treated using one or more techniques selected from surgery, radiation therapy, chemotherapy and hormone therapy.There are various potential means for treatment, but not all options are suitable for a given patient, and not all treatments administered are successful.

[0003] The drawbacks of treatment options such as radiotherapy and chemotherapy include the possibility that patients may experience undesirable side effects, which is often due to the limited specificity that certain compounds can have for target cancer sites.This means that in addition to the low efficiency of treatment, patients may have to undergo treatment regimens that involve additional discomfort.Furthermore, damage to healthy tissue may occur, again because the treatment administered acts at sites other than the target cancer site.

[0004] It is known that prostate cancer is often characterized by the overexpression of prostate specific membrane antigen (PSMA), but the ability of administered compounds to target cancer sites that overexpress target antigen (in the presence of any naturally expressed antigen) in vivo is often limited.In addition, even if radiotherapy or chemotherapy agents show the ability to specifically target PSMA, they must also have appropriate retention and metabolism.

[0005] In regard to treating prostate cancer by identifying and targeting the site that overexpresses PSMA, one approach to improve the binding of a given compound to cancer site is to increase the PSMA targeting moiety of the compound.This may include increasing the number of PSMA targeting moieties in the compound, but this increases the size of the compound, and therefore also changes, potentially unfavorably, properties such as solubility, retention and metabolism (all of which may be related to molecular weight).For example, the compound must be soluble under physiological conditions, must be transported in the circulatory system, must have sufficient binding at the target site, and must have favorable metabolism and toxicity profile (for example, minimal accumulation in the liver to limit hepatotoxicity, minimal accumulation in the kidney to limit nephrotoxicity).

[0006] Additionally, particularly in the case of radiotherapeutic agents (ie, radiopharmaceuticals), the compound must also be capable of coordinating, retaining, and delivering the appropriate radionuclide to the cancer site.

[0007] There is a need for compounds that can exhibit improved binding affinity to cancer sites expressing PSMA and have the ability to exhibit radiotherapeutic and radioimaging properties at the intended site. There is also a need for compounds that are not only sufficiently stable during use to not be degraded, but also metabolized and excreted after a period of time. Summary of the Invention

[0008] The compounds of the present invention comprise a metal chelator and two lysine-urea-glutamic acid (Lys-urea-Glu) moieties, each linked to the metal chelator by a separate linker. The Lys-urea-Glu moiety binds to prostate-specific membrane antigen (PSMA), which is overexpressed on the surface of some cancers, such as prostate cancer. The linker that links the Lys-urea-Glu moiety to the metal chelator contains two alkylene chains linked by two phenylalanine residues, with various intervening amide bonds linking these groups together. The alkylene linker and phenylalanine residues that connect the Lys-urea-Glu moiety to the metal chelator function to isolate the Lys-urea-Glu moiety from the metal chelator. This ensures that the activities of the Lys-urea-Glu moiety and the metal chelator do not interfere with each other. However, it is important that the separation of the metal chelator from the Lys-urea-Glu moiety is not so great that the metal chelator is unable to deliver the metal contained within it to the site targeted by the Lys-urea-Glu moiety.The inventors have discovered that compounds of formula (I) disclosed herein that contain two moieties capable of binding to PSMA provide for more efficient methods of radioimaging and treatment in which a compound of formula (I) complexed with a radionuclide is administered to a subject.

[0009] The inventors have discovered that, in contrast to compounds containing one Lys-urea-Glu moiety, the compounds disclosed herein exhibit improved binding and retention at sites expressing PSMA, i.e., an increased percentage of the administered compound is bound and retained at the desired site. This improves the efficiency of treating and imaging cancers associated with PSMA overexpression. Because the compounds disclosed herein exhibit improved binding to target sites, lower or higher doses of the compounds can be administered to a subject as needed. For example, the compounds disclosed herein can chelate the appropriate radionuclides, which means that a lower dose of radiation can be administered to a subject to provide imaging, or a higher dose of radiation can be administered to a subject for required standard treatment. When a lower dose of radiation is administered, this reduces the likelihood and / or severity of any undesirable side effects caused by the administration of the radionuclides, i.e., off-target radiation damage.

[0010] Since the compound of the present invention contains a radionuclide for radioimaging and radiotherapy, the compound must be retained for a sufficient time for imaging or treatment, but the compound must also be metabolized and excreted from the subject after a certain time.The inventors have discovered that although the compound of the present invention contains two PSMA binding moieties and therefore has a larger molecular weight, the compound shows improved binding and retention to provide better images during radioimaging and retention at cancer sites expressing PSMA, and also shows the necessary stability and physical properties for metabolism within the desired time frame.

[0011] In a first aspect, the present invention provides a compound of formula (I): [ka] wherein each linker may be the same or different; M is a residue of a metal chelator selected from the group consisting of: or a pharma- ceutically acceptable salt, complex, isomer, solvate or prodrug thereof. [Table 1] TIFF2024542539000003.tif95170

[0012] In some embodiments, the linkers in the compound of formula (I) are identical. In other embodiments, the linkers in the compound of formula (I) are different. In some embodiments, each linker contains one or more of the following groups or fragments thereof: [Table 2]

[0013] In some embodiments, the compound of Formula (I) has one of the following structures: [ka] TIFF2024542539000006.tif242170

[0014] In certain embodiments, the metal chelator in the compound of Formula (I) forms a complex with an ion of a metal selected from the group consisting of Cu, Lu, Ac, Tc, Gd, Ga, In, Co, Re, Fe, Mg, Ag, Rh, Pt, Cr, Ni, V, Ir, Zn, Cd, Mn, Ru, Pd, Hg, Ti, Lu, Sc, Zr, Y, Ac, As, Ra, and Pb.

[0015] In some embodiments, the metal ion complexed in the metal chelator is a radionuclide.

[0016] In some embodiments, the compound of formula (I) is 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 90Y, 111 In, 177 Lu, 188 Re, 211 As, 212 Pb and 225 Ac.

[0017] In a second aspect, the present invention provides a composition comprising a compound of formula (I) as defined in the first aspect and one or more pharma- ceutically acceptable excipients.

[0018] The inventors believe that the present compounds can be used as radiopharmaceuticals or radioimaging agents if the radionuclide-coordinated compounds can be sufficiently bound to a desired site and deliver the radionuclide to that site for imaging or treatment.

[0019] In a third aspect, the present invention provides a method for radioimaging of cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) of the first aspect or a composition of the second aspect coordinated with a radionuclide.

[0020] In certain embodiments, methods for radioimaging include imaging by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0021] In a fourth aspect, the present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) of the first aspect or a composition of the second aspect coordinated with a radionuclide.

[0022] In certain embodiments, the cancer is characterized by overexpression of prostate specific membrane antigen (PSMA). In further embodiments, the cancer is prostate cancer.

[0023] In a fifth aspect, the present invention provides the use of a radionuclide-coordinated compound of formula (I) of the first aspect in the manufacture of a medicament for radioimaging of cancer.

[0024] In certain embodiments, radioimaging comprises imaging by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0025] In a sixth aspect, the present invention provides the use of a radionuclide-coordinated compound of formula (I) of the first aspect in the manufacture of a medicament for treating cancer.

[0026] In some embodiments, the cancer is characterized by overexpression of prostate-specific membrane antigen (PSMA).

[0027] In other embodiments, the cancer is prostate cancer.

[0028] The invention will now be described, by way of example only, with reference to the following non-limiting drawings. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 is a graph showing radio-HPLC chromatograms of A) HBED-bisPSMA precursor and B) [68Ga]Ga-HBED-bisPSMA sample. [Diagram 2] The mean ± SEM of the percent injected dose per gram of tissue weight (%ID / g) of 68Ga-HBED-CC-bis(PSMA), 64Cu-DOTA-bis(PSMA) and 64Cu-NOTA-bis(PSMA) at the two tissue biodistribution time points is shown for each tissue. [Diagram 3] The mean ± SEM of the percent injected dose per gram of tissue weight (%ID / g) of 68Ga-HBED-CC-bis(PSMA), 64Cu-DOTA-bis(PSMA) and 64Cu-NOTA-bis(PSMA) at the two tissue biodistribution time points indicated for each tissue is shown by the split y-axis. [Figure 4] The percent injected dose per gram of tissue weight (%ID / g) of 68Ga-HBED-CC-bis(PSMA), 64Cu-DOTA-bis(PSMA) and 64Cu-NOTA-bis(PSMA) at the two tissue biodistribution time points is shown for each tissue, with data for each mouse shown as the mean ± SEM (n=5 or 4). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Throughout the following specification and claims, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of other integers or steps or group of integers or steps.

[0031] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. With respect to the present invention, the following terms are defined below.

[0033] As used herein, the term "residue" refers to a portion of a compound obtained by removal of one or more atoms. The removed atom or atoms may be hydrogen atoms. One of skill in the art will appreciate that, for example, if the compound contains a carboxylic acid (-COOH) functional group, the residue found in the compound of formula (I) is the carboxylate of an amino acid (i.e., -COOH). - ) which is attached to the remainder of the compound.

[0034] The term "pharmaceutically acceptable salts" as used herein means salts that retain the desired biological activity of the above compounds, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared from inorganic or organic acids. Examples of these inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Pharmaceutically acceptable salts also include salts in which the main compound functions as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Additionally, those skilled in the art will recognize that acid addition salts can be prepared by reacting the compound with a suitable inorganic or organic acid by any of several known methods. Alternatively, alkali metal and alkaline earth metal salts can be prepared by reacting the compound with a suitable base by a variety of known methods.The following are further examples of acid salts which can be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, hydrogensulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate. Further information regarding pharma- ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. For substances that are solids, those skilled in the art will understand that the compounds, substances and salts of the invention may exist in different crystalline forms or polymorphs, and that all of these forms are intended to be within the scope of the invention and specific formulas.

[0035] The term "complex" as used herein means a moiety that contains a ligand and a metal coordinated to an appropriate moiety of the ligand. For example, the compounds of formula (I) disclosed herein function as a ligand for one or more metal ions, which are coordinated to the ligand via a metal chelator.

[0036] As used herein, the term "isomer" means and includes all regioisomers and stereoisomers of the compounds of the present invention. Examples of stereoisomers include diastereomers and enantiomers, where appropriate.

[0037] The compounds of formula (I) disclosed herein include a metal chelator (M). Examples of metal chelators (M) for use in the compounds of the present invention include: [Table 3] TIFF2024542539000008.tif95170

[0038] It will be understood that the residue of the metal chelator is selected to bind tightly to the intended radionuclide for imaging or therapy and in light of the intended use of the compound. There are studies that have shown that conjugates containing the same targeting compound but different macrocyclic chelators have different biodistribution profiles (von Witting, E. et al. European Journal of Pharmaceutics and Biopharmaceutics, 2019, 140, 109-120; Bogdan, M. et al. International Journal of Oncology, 2016, 2124-2134). Even when the radionuclide has the same valence, there may be differences in biodistribution. Heppeler, A et al. conjugated with DOTA and 67 Ga or 90 Somatostatin analogues that form complexes with Y were investigated (Heppeler, A, et al. Chemistry, 1999, 5, 1974-1981). 67 The analogues that form complexes with Ga are 90 Compared with the Y complex, it had five times higher affinity for the somatostatin receptor type 2 and two times higher tumor uptake. These significant differences were due to the 67 Ga and 90 This is due to differences in the coordination geometries of Y, resulting in differences in the conformations of the conjugated peptides.

[0039] In one embodiment, the present invention provides a compound of formula (I): [ka] wherein each linker may be the same or different; M is: [Table 4] is a residue of a metal chelating agent selected from the group consisting of or a pharma- ceutically acceptable salt, complex, isomer, solvate or prodrug thereof.

[0040] In another embodiment, the present invention provides a compound of formula (I): [ka] wherein each linker may be the same or different; M is: [Table 5] is a residue of a metal chelating agent selected from the group consisting of or a pharma- ceutically acceptable salt, complex, isomer, solvate or prodrug thereof.

[0041] It will be appreciated that the above embodiments of formula (I) contain chelators, of which macrocyclic and acyclic chelators containing 3 or 4 coordinating nitrogen atoms are representative. One skilled in the art would reasonably expect that embodiments of the invention containing other macrocyclic or acyclic chelators would exhibit similar pharmacological properties to these embodiments.

[0042] Examples of compounds of the present invention that contain metal chelators include the following: [ka] TIFF2024542539000014.tif189170 TIFF2024542539000015.tif217170

[0043] The structures shown above represent specific positional isomers of the compounds of formula (I). The present invention also contemplates different positional isomers of the compounds of the present invention, where the linker may be attached to the metal chelator through different atoms of the chelator. Without wishing to be bound by theory, the inventors believe that specific positional isomers of a particular compound may provide advantages such as improved stability of the complex formed by complexing the compound with a metal ion, optimal isolation of the end group attached to the linker, and favorable overall shape and size of the compound. The structures shown above represent racemates (i.e., forms in which the stereochemical configuration is not determined) of a particular compound or specific stereoisomers of a particular compound. The present invention also contemplates different stereoisomers (including enantiomers and diastereomers) of the compounds described herein. Without wishing to be bound by theory, the inventors believe that specific enantiomers of the compounds disclosed herein may provide significant advantages over their corresponding racemates, such as improved binding affinity and overall efficacy.

[0044] Examples of ions which may form complexes with the compounds of the invention include ions of metals selected from the group consisting of Cu, Lu, Ac, Tc, Gd, Ga, In, Co, Re, Fe, Mg, Ag, Rh, Pt, Cr, Ni, V, Ir, Zn, Cd, Mn, Ru, Pd, Hg, Ti, Lu, Sc, Zr, Lu, Sc, Zr, Y, Ac, As, Ra and Pb.

[0045] In some embodiments, the complexed metal ion in the metal chelator is a radionuclide.

[0046] In some embodiments, the compound of formula (I) is 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 90Y, 111 In, 177 Lu, 188 Re, 211 As, 212 Pb and 225 Ac.

[0047] The metal chelators described herein may be complexed with one or more metal ions, where a particular metal chelator may form a preferred complex with one or more metal ions. For example, a compound of the invention that includes DOTA as a metal chelator may be complexed with a Lu ion. In certain embodiments, a compound of the invention includes a DOTA chelator and a Lu ion. In other embodiments, a compound of the invention includes a DOTA chelator and a Lu ion. 177 In other embodiments, the compounds of the invention comprise a DOTA chelator and an Ac ion. In some embodiments, the compounds of the invention comprise a DOTA chelator and 225 In some embodiments, the compounds of the invention include a DOTA chelator and an In ion. In other embodiments, the compounds of the invention include a DOTA chelator and an In ion. 111 In other embodiments, the compounds of the invention comprise a DOTA chelator and a Y ion. In some embodiments, the compounds of the invention comprise a DOTA chelator and a Y ion. 90 In other embodiments, the compounds of the invention comprise a DOTA chelator and a Re ion. In some embodiments, the compounds of the invention comprise a DOTA chelator and a Re ion. 188 In other embodiments, the compounds of the invention comprise a DOTA chelator and a Ga ion. In some embodiments, the compounds of the invention comprise a DOTA chelator and a Ga ion. 68 In other embodiments, the compounds of the invention comprise a DOTA chelator and a Cu ion. In some embodiments, the compounds of the invention comprise a DOTA chelator and a 67 In other embodiments, the compounds of the invention include a DOTA chelator and an As ion. In some embodiments, the compounds of the invention include a DOTA chelator and an As ion.211 Contains As ions.

[0048] In other embodiments, the compounds of the invention include HBED-CC as a metal chelator capable of forming a complex with a Ga ion. In certain embodiments, the compounds of the invention include an HBED-CC chelator and a Ga ion. In certain embodiments, the compounds of the invention include an HBED-CC chelator and 68 In another embodiment, the compound of the present invention comprises HBED as a metal chelator capable of forming a complex with a Ga ion. In an embodiment, the compound of the present invention comprises an HBED chelator and a Ga ion. In an embodiment, the compound of the present invention comprises an HBED chelator and 68 Contains Ga ions.

[0049] In other embodiments, the compounds of the invention comprise a NOTA chelator and an Ac ion. In some embodiments, the compounds of the invention comprise a NOTA chelator and 225 In some embodiments, the compounds of the invention contain a NOTA chelator and an In ion. In other embodiments, the compounds of the invention contain a NOTA chelator and an In ion. 111 In other embodiments, the compounds of the invention comprise a NOTA chelator and a Y ion. In some embodiments, the compounds of the invention comprise a NOTA chelator and a Y ion. 90 In other embodiments, the compounds of the invention comprise a NOTA chelator and a Re ion. In some embodiments, the compounds of the invention comprise a NOTA chelator and a Re ion. 188 In other embodiments, the compounds of the invention comprise a NOTA chelator and a Ga ion. In some embodiments, the compounds of the invention comprise a NOTA chelator and a Ga ion. 68 In other embodiments, the compounds of the invention comprise a NOTA chelator and a Cu ion. In some embodiments, the compounds of the invention comprise a NOTA chelator and a 67 Contains Cu ions.

[0050] In other embodiments, the compounds of the invention comprise a DOTAGA chelator and an Ac ion. In some embodiments, the compounds of the invention comprise a DOTAGA chelator and 225 In some embodiments, the compounds of the invention contain a DOTAGA chelator and an In ion. In other embodiments, the compounds of the invention contain a DOTAGA chelator and an In ion. 111 In other embodiments, the compounds of the invention comprise a DOTAGA chelator and a Y ion. In some embodiments, the compounds of the invention comprise a DOTAGA chelator and a Y ion. 90 In other embodiments, the compounds of the invention comprise a DOTAGA chelator and a Re ion. In some embodiments, the compounds of the invention comprise a DOTAGA chelator and a Re ion. 188 In other embodiments, the compounds of the invention comprise a DOTAGA chelator and a Ga ion. In some embodiments, the compounds of the invention comprise a DOTAGA chelator and a Ga ion. 68 In other embodiments, the compounds of the invention comprise a DOTAGA chelator and a Cu ion. In some embodiments, the compounds of the invention comprise a DOTAGA chelator and a 67 Contains Cu ions.

[0051] In other embodiments, the compounds of the invention comprise a DOTAGA chelator and an Ac ion. In some embodiments, the compounds of the invention comprise a DOTAGA chelator and 225 In some embodiments, the compounds of the invention contain a NOTAGA chelator and an In ion. In other embodiments, the compounds of the invention contain a NOTAGA chelator and an In ion. 111 In other embodiments, the compounds of the invention comprise a NOTAGA chelator and a Y ion. In some embodiments, the compounds of the invention comprise a NOTAGA chelator and a Y ion. 90 In other embodiments, the compounds of the invention comprise a NOTAGA chelator and a Re ion. In some embodiments, the compounds of the invention comprise a NOTAGA chelator and a Re ion. 188In other embodiments, the compounds of the invention comprise a NOTAGA chelator and a Ga ion. In some embodiments, the compounds of the invention comprise a NOTAGA chelator and a Ga ion. 68 In some embodiments, the compounds of the present invention comprise a NOTAGA chelator and a Ga ion. In other embodiments, the compounds of the present invention comprise a NOTAGA chelator and a Cu ion. 67 Contains Cu ions.

[0052] The term "solvate" as used herein refers to a complex of a compound formed by a solute and a solvent, which may show various stoichiometries.These solvents in the solvate should not interfere with the biological activity of the solute.Examples of suitable solvents include water, ethanol or acetic acid.Methods of solvating a compound are generally known in the art.

[0053] The term "prodrug" as used herein means and includes derivatives that are converted to the compounds of the present invention in vivo.These derivatives will be easily conceived by those skilled in the art, and include, for example, compounds that contain free hydroxyl groups that are converted to ester derivatives, or compounds that contain ring nitrogen atoms that are converted to N-oxides.Examples of ester derivatives include alkyl esters, phosphate esters, and esters formed from amino acids.

[0054] The terms "treat", "treatment", "prevent", "prevention" and grammatical equivalents used herein refer to any use of treating the described neuroendocrine tumor, preventing, delaying or postponing the establishment of disease, or preventing, hindering, delaying or reversing the progression of disease. Thus, terms such as "treat" and "prevent" should be considered in their broadest context. For example, treatment does not necessarily mean that a patient is treated until complete recovery. When a disease exhibits or is characterized by multiple symptoms, treatment or prevention does not necessarily treat, prevent, hinder, delay or reverse all of the symptoms, but may prevent, hinder, delay or reverse one or more of the symptoms.

[0055] The term "cancer" as used herein broadly encompasses neoplastic diseases characterized by abnormal cell growth with the potential to invade or spread to other parts of the body. Cancer can be benign, i.e., not spread to other parts of the body. Cancer can be malignant, i.e., cancer cells can spread through the circulatory or lymphatic system. As used herein, the term includes all malignant or cancerous disease states. Cancer can exist as a tumor.

[0056] The term "cancer" as used herein broadly encompasses neoplastic diseases characterized by abnormal cell proliferation with the potential to invade or spread to other parts of the body. Cancer can be benign, i.e., not spread to other parts of the body. Cancer can be malignant, i.e., cancer cells can spread through the circulatory or lymphatic system. As used herein, the term includes all malignant, i.e., cancerous, disease states. Cancer can exist as a tumor. Thus, the term "tumor" is generally used to define any malignant cancerous or precancerous cell proliferation, and may include leukemia, but particularly relates to solid tumors or solid cancers, such as melanoma, colon cancer, lung cancer, ovarian cancer, skin cancer, breast cancer, pancreatic cancer, pharyngeal cancer, brain cancer, prostate cancer, liver cancer, CNS cancer, and renal cancer (as well as other cancers).

[0057] In some embodiments, the cancer is associated with overexpression of prostate-specific membrane antigen (PSMA). In certain embodiments, the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and / or neck cancer, or renal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma (HCC), brain cancer, and hematological malignancies, such as lymphoma or leukemia. In certain embodiments, the cancer is prostate cancer. In other embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.

[0058] The present invention contemplates the use of a compound of formula (I) complexed with a suitable radionuclide for the treatment of cancer in a subject. In some embodiments, the compound of formula (I) complexed with a radionuclide may be used to treat cancers associated with overexpression of PSMA. In other embodiments, the compound of the present invention complexed with a radionuclide is used to treat a cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and / or neck cancer, or renal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma (HCC), brain cancer, and hematological malignancies such as lymphoma or leukemia. In certain embodiments, the compound of the present invention complexed with a radionuclide is used to treat prostate cancer.

[0059] The present invention also discloses the use of a compound of formula (I) complexed with a suitable radionuclide for radioimaging a subject. In an embodiment, a compound of formula (I) complexed with a suitable radionuclide is used for radioimaging cancers associated with overexpression of PSMA. In another embodiment, the compound of the present invention is used for radioimaging cancers selected from the group consisting of breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and / or neck cancer, or renal cancer, gastric cancer, liver cancer, pancreatic cancer, brain cancer, and hematological malignancies such as lymphoma or leukemia. In another embodiment, a compound of formula (I) complexed with a radionuclide is used for radioimaging prostate cancer.

[0060] The term "subject" as used herein means a mammal, including humans, primates, livestock animals (e.g., sheep, pigs, cows, horses, donkeys), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), performance and show animals (e.g., horses, livestock, dogs, cats), pet animals (e.g., dogs, cats) and captive wild animals. Preferably, the mammal is a human or a laboratory test animal. More preferably, the mammal is a human.

[0061] The term "therapeutically effective amount" or "effective amount" refers to an amount sufficient to achieve beneficial or desired clinical results. An effective amount can be administered in one or more doses. In radioimaging, an effective amount refers to an amount sufficient to show the localization of the compound administered to a subject by detecting decay products from a radioisotope complexed with the compound of formula (I). In treatment, an effective amount refers to an amount sufficient to palliate, improve, stabilize, reverse, slow down and / or postpone the progression of cancer.

[0062] The compounds are generally used in the form of pharmaceutical compositions formulated according to the desired mode of administration, and are prepared in a manner well known in the art.

[0063] In the above embodiment, the composition of the present invention contains ethanol as a component. The ethanol used in the composition may be absolute ethanol. Alternatively, the ethanol used in the composition may not have been subjected to a drying process and may be hydrated. The ethanol is preferably pharmaceutical grade ethanol. The ethanol present in the composition may help prevent the radiolysis of the radiolabeled complex of formula (I).

[0064] In the above embodiment, the composition of the present invention also contains sodium chloride as an ingredient. The sodium chloride in the formulation of the present invention may be provided as a saline solution. A saline solution is defined as an aqueous solution of sodium chloride. For example, normal saline is defined as an aqueous solution of sodium chloride with a concentration of 0.9% (w / v). In one embodiment of the present invention, the sodium chloride in the formulation is provided by a saline solution.

[0065] In the above embodiment, the composition of the present invention contains gentisic acid, or its pharma- ceutically acceptable salt and / or hydrate as an ingredient. Gentisic acid is also known as 2,5-dihydroxybenzoic acid, 5-hydroxysalicylic acid or hydroquinone carboxylic acid. Salts of gentisic acid can include sodium salt and sodium salt hydrate. Reference to gentisic acid can include reference to its salt, if relevant. The inventors have determined that gentisic acid or its salt in the composition can help prevent or minimize the radiolysis of the radiolabeled complex of formula (I).

[0066] In another embodiment, the present invention provides a pharmaceutical pack or kit containing one or more containers filled with one or more components of the pharmaceutical composition of the present invention. In the pack or kit, at least one container having a unit dosage form of the drug can be found. Conveniently, in the kit, the single dosage form can be provided as a sterile vial, so that the clinician can use the vial as is, which has the desired amount and concentration of compound and radionuclide, which may be mixed before use. The container can be accompanied by various written materials, such as instructions for use or notices reflecting approval by a government agency for manufacture, use or sale for human administration in a format prescribed by the government agency regulating the manufacture, use or sale of pharmaceuticals, imaging agents or biological agents.

[0067] The compound of the present invention can be used or administered in combination with one or more additional drugs that are anti-cancer drugs and / or one or more procedures (e.g., surgery, radiation therapy) for the treatment of the above-mentioned disorders / diseases.These components can be administered in the same formulation or in separate formulations.When administered in separate formulations, the compound of the present invention can be administered sequentially or simultaneously with the other drugs.

[0068] The compound of the present invention can be administered in combination with one or more additional drugs, including anticancer drugs, and can also be used in combination therapy.In this case, the compounds are usually administered in combination with each other.Therefore, to achieve the desired effect, one or more compounds of the present invention can be administered simultaneously (as a combined preparation) or sequentially.This is particularly desirable when the therapeutic profile of each of the two compounds is different, and the combined effect of the two drugs can improve the therapeutic outcome.

[0069] The pharmaceutical composition of the present invention for parenteral injection contains sterilized aqueous or non-aqueous solution, dispersion, suspension or emulsion, and sterile powder that is reconstituted immediately before use into sterile injectable solution or dispersion.Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oil (e.g., olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants.

[0070] These compositions may contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin.

[0071] If desired, and for more effective distribution, the compounds can be incorporated into slow-release or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres.

[0072] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium immediately before use.

[0073] In another aspect, the present invention also provides a process for the preparation of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof.

[0074] Compounds of formula (I) may be prepared by a series of peptide coupling steps using suitable amine and carboxylic acid derivatives. The coupling partners may require the introduction of one or more protecting groups, which are then removed after the coupling reaction. A list of suitable protecting groups for organic synthesis and procedures for their introduction and removal can be found in TW Greene's Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1991. When peptide coupling steps are used to prepare the compounds of the invention or their precursors, the reaction may be carried out under solution or solid phase conditions, as appropriate, in the presence of one or more bases or other reagents. The coupling partners used in a given reaction step may be modified with one or more suitable groups, such as leaving groups, that facilitate the coupling reaction. The preparation of compounds of formula (I) may include the selection and introduction of one or more protecting groups, etc., that facilitate the coupling of the components with the required site selectivity.

[0075] For example, the steps required to prepare compounds of formula (I) may involve the introduction of one or more nitrogen or oxygen protecting groups at one or more amine or carboxylic acid functionalities.

[0076] The term "oxygen protecting group" as used herein means a group that can prevent the oxygen moiety from reacting during further derivatization of the protected compound and can be easily removed when desired. In one embodiment, the protecting group is removable under physiological conditions by natural metabolic processes. Examples of oxygen protecting groups include acyl groups (e.g., acetyl), ethers (e.g., methoxymethyl ether (MOM), α-methoxyethoxymethyl ether (MEM), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyran (THP)), and silyl ethers (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS) and triisopropylsilyl (TIPS) groups).

[0077] The term "nitrogen protecting group" as used herein means a group that can prevent the nitrogen moiety from reacting during further derivatization of the protected compound and can be easily removed when desired. In one embodiment, the protecting group is removable under physiological conditions by natural metabolic processes, and essentially the protected compound functions as a prodrug of the active non-protected species.Examples of suitable nitrogen protecting groups which can be used include formyl, trityl, phthalimido, acetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl; urethane type blocking groups, e.g. benzyloxycarbonyl (CBz), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl. , 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl (tBoc), 2-(4-xenyl)-isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-tolylsulfono)-ethoxycarbonyl, 2-(methylsulfono)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilyl)ethoxycarbonyl, methylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzoisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, etc.; benzoylmethylsulfono group, 2-nitrophenylsulfenyl, diphenylphosphine oxide, etc.The actual nitrogen protecting group used is not critical so long as the derivatized nitrogen group is stable to the conditions of subsequent reactions and can be selectively removed as needed without substantially damaging the remainder of the molecule, including any other nitrogen protecting groups. Further examples of these groups can be found in Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis, Second edition; Wiley-Interscience: 1991; Chapter 7; McOmie, JFW (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, PJ, Protecting Groups, Second Edition, Thieme Medical Pub., 2000.

[0078] Compounds of formula (I) disclosed herein, or pharma- ceutically acceptable salts thereof, may be synthesized according to Scheme 1. [ka]

[0079] Scheme 1 describes the synthesis of a compound of formula (I) in which a metal chelator (M) is simultaneously coupled to two linker-PSMA urea moieties. The reaction may be carried out under standard peptide coupling conditions with an appropriate peptide coupling reagent and base, where the linker-PSMA urea group contains an amine functionality and the metal chelator contains a carboxylic acid functionality that participates in the coupling reaction.

[0080] Alternatively, compounds of formula (I) disclosed herein, or pharma- ceutically acceptable salts thereof, may be synthesized according to Scheme 2. [ka]

[0081] Scheme 2 also describes the coupling of two linker-PSMA urea moieties with a metal chelator (specifically cyclam), but in this synthetic route the amine group involved in the coupling reaction is on the metal chelator, while the carboxylic acid group is on the linker-PSMA urea moiety, and the reaction may be carried out by peptide coupling reactions and base under standard peptide coupling reaction conditions.

[0082] In one embodiment, the present invention provides a method for preparing the compound of formula (I) or its pharma- ceutically acceptable salt, comprising one or more peptide coupling steps.The method may also comprise one or more protection and deprotection steps, if appropriate.In another embodiment, the method for preparing the compound of formula (I) comprises a peptide coupling step carried out under solution phase conditions with one or more peptide coupling reagents and one or more bases.

[0083] Differences in the structure of the chelating agent, followed by the nature and location of one or more functional groups, naturally dictate the synthetic route required to obtain compounds of formula (I). For example, if the terminal group of the metal chelating agent is oxygen-based, e.g., a carboxylic acid, the protecting group (if required) and subsequent reactions must be compatible to allow coupling to obtain compounds of formula (I).

[0084] The synthetic scheme shown in scheme 2 shows the coupling of a linker-PSMA urea group with two nitrogen atoms of cyclam, where the two nitrogen atoms are adjacent to each other. The synthetic scheme disclosed herein includes modifications that allow the synthesis of positional isomers of compounds of formula (I). For example, the synthetic route and synthetic conditions in scheme 2 can be modified to produce analogous compounds of formula (I) with linker-PSMA urea groups attached to non-adjacent nitrogen atoms of cyclam.

[0085] Reference in this specification to any prior publication (or information derived therefrom) or to any matter which is publicly known is not, and should not be construed as, an acknowledgment or admission, or any form of suggestion, that that prior publication (or information derived therefrom) or public knowledge forms part of the common general knowledge in the business field to which this specification pertains.

[0086] Those skilled in the art will recognize that the invention described herein can be modified and altered other than those specifically described.It should be understood that the present invention includes all such modifications and alterations within its spirit and scope.The present invention also includes all steps, features, compositions and compounds referred to or indicated herein, individually or collectively, and includes any combination of any two or more of said steps or features. EXAMPLES

[0087] The following examples are illustrative of the present disclosure and should not be construed as in any way limiting the general nature of the disclosure set forth throughout the specification.

[0088] Example 1 Synthesis of Compounds of the Invention Various embodiments of the present invention can be prepared by techniques available in the art using readily available starting materials using the following reaction pathways and synthesis schemes. The preparation of certain compounds of the present embodiment is detailed in the following examples, but those skilled in the art will recognize that the described chemical reactions can be easily applied to prepare some other agents of the various embodiments. For example, the synthesis of compounds not exemplified can be successfully carried out by modifications obvious to those skilled in the art, such as appropriate protection of interfering groups, changing to other suitable reagents known in the art, or routine modification of reaction conditions. A list of suitable protecting groups for organic synthesis can be found in TW Greene's Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1991. Alternatively, it will be recognized that other reactions disclosed herein or known in the art can be applied to prepare other compounds of the various embodiments. Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.

[0089] 1.1 Synthesis of PSMA(OtBu)2;HD-Phe-D-Phe-wCap-Lys-CO-Glu(OtBu)-OtBu Fmoc-L-Lys(Dde)-OH was attached to 2-chlorotrityl chloride resin and after Fmoc deprotection with 25% piperidine / DMF, coupled with a pre-activated solution of HL-Glu(OtBu)-OtBu and carbonyldiimidazole (3 eq.) and DIPEA (6 eq.). The Dde protecting group was removed using hydrazine / DMF and the remaining peptide was elongated using standard solid-phase peptide synthesis methods. The final Fmoc protecting group was removed and the peptide-resin was treated with 20% trifluoroethanol / DCM overnight. The resin was filtered, the supernatant concentrated under reduced pressure and the resulting residue was lyophilized from 50% ACN / water. The PSMA(OtBu)2 intermediate was obtained in 80% crude yield. MS-ESI: [M+H] + Calculated value: 867.5, Actual value: 867.5.

[0090] 1.2 Synthesis of HBED-CC-bis(tert-butyl ester) HBED-CC-bis(tert-butyl ester) was prepared as described in Makarem et al., Synlett 2008, “A Convenient Synthesis of HBED-CC-tris(tert-butyl ester)”. This method was modified to generate the symmetric bis-tert-butyl protected product; HBED-CC-bis(tert-butyl ester). Briefly, 3-(4-hydroxyphenyl)propionic acid was methyl ester protected and formylated in two steps to generate 3-(3-formyl-4-hydroxyphenyl)propionic acid methyl ester. This intermediate was reacted with ethylenediamine to form the symmetric bis-imine and reduced to generate the symmetric bis-amino derivative. Finally, the amine was N-alkylated with tert-butyl bromoacetate and the methyl ester protecting group was hydrolyzed under basic conditions. The crude product was purified by preparative RP-HPLC to give the product in 98% purity. MS-ESI: [M+H] + Calculated value: 645.3, actual value: 645.4.

[0091] 1.3 DOTA-bis(PSMA) conjugation Resin-bound PSMA(OtBu)2 was prepared as described above. The peptide-resin was treated with a DMF solution of DOTA(OtBu)2 (1.5 eq.), HATU (1.5 eq.) and DIPEA (3 eq.). After 5 h, the resin was drained, washed and treated with a DMF solution of DIC and OxymaPure for 30 min. The resin was drained, washed once and immediately treated with a DMF solution of PMSA(OtBu)2 (2 eq.) and DIPEA (4 eq.). After 4 h, the resin was drained, washed with DMF and DCM and dried. The resin was treated with a TFA solution (89.5% TFA, 3% dithiothreitol, 2.5% triisopropylsilane, 5% water) and stirred for 4 h. The resin was filtered and the crude product was precipitated from the supernatant with Et2O. The precipitate was pelleted by centrifugation and the pellet was dissolved in 50% ACN / water and lyophilized to give the crude product. The peptide was purified by preparative RP-HPLC to give the product in 99% purity. MS-ESI: [M-2H] -2 Calculated value: 937.5, Measured value: 937.5, [M-3H] -3 Calculated value: 624.6, Measured value: 625.5, [M-4H] -4 Calculated value: 468.2, actual value: 468.3.

[0092] 1.4 Conjugation of HBED-CC-bis(PSMA) Resin-bound PSMA(OtBu)2 was prepared as described above. The peptide-resin was treated with a DMF solution of HBED-CC-bis(tert-butyl ester) (1.5 eq., preparation described in section 2), HATU (1.5 eq.) and DIPEA (3 eq.). After 2 h, the resin was drained and immediately treated with a DMF solution of PMSA(OtBu)2 (2 eq.) and DIPEA (4 eq.). After 4 h, the resin was drained, washed with DMF and DCM, and dried. The resin was treated with a TFA solution (92.5% TFA, 2.5% triisopropylsilane, 5% water) and stirred for 5 h. The resin was filtered and the crude product was precipitated from the supernatant with Et2O. The precipitate was pelleted by centrifugation, and the pellet was dissolved in 50% ACN / water and lyophilized to give the crude product. The peptide was purified by preparative RP-HPLC to give the product in 98% purity. MS-ESI:[M+2H] +2 Calculated value: 1003.5, Measured value: 1004.2, [M+3H] +3 Calculated value: 669.3, actual value: 669.6.

[0093] 1.5 Binding of NOTA-bis(PSMA) NOTA-(OH)3 was activated with HBTU (2 equiv.) and DIPEA (4 equiv.) in DMF for 30 min, then treated with PSMA(OtBu)2 (2 equiv. relative to NOTA, preparation described in section 1) and DIPEA (2 equiv. relative to NOTA) in DMF. The reaction was stirred for 2 h, concentrated under reduced pressure, and the resulting residue was treated with TFA solution (92.5% TFA, 2.5% triisopropylsilane, 5% water) with stirring for 4 h. The product was precipitated with Et2O, pelleted by centrifugation, and the pellet was dissolved in 50% ACN / water and lyophilized to give the crude product. The peptide was purified by preparative RP-HPLC to give the product in 99% purity. MS-ESI: [M+H] + Calculated value: 1776.9, Measured value: 1776.8, [M+2H] +2 Calculated value: 889.0, actual value: 889.0.

[0094] Example 2 Radiolabeling procedure 2.1 68Preparation of Ga-HBED-CC-bis(PSMA) The HBED-bisPSMA compound was dissolved in water in saline (0.9%, Baxter), HEPES (Sigma Aldrich), ethanol (Merck) and ascorbic acid (Sigma) at room temperature. 68 The filtered solution was clear, colorless, and free of particulates. 68 Ga-HBED-bisPSMA was produced in >95% yield (radio-HPLC, FIG. 1) and >95% radiochemical yield (radio-ITLC).

[0095] 2.2 64 Cu-DOTA-bis(PSMA) and 64 Preparation of Cu-NOTA-bis(PSMA) To an Eppendorf was added 120 µL of 0.25 M sodium acetate solution (pH 5.5; Huayi), 20 µL of ethanol (Merck), 20 µL of 0.5% (w / v) gentisic acid (Huayi) aqueous solution and 80 µL (50 µg) of precursor compound (approximately 0.6 mg / mL). 64 CuCl2 (Austin Health) was volumetrically dispensed into Eppendorfs with a target activity of 200MBq. The solution was incubated at 45°C for 20 minutes. 64 Cu-DOTA-bisPSMA and 64 The radiochemical purity of the solution of Cu-NOTA-bisPSMA was >99%.

[0096] Example 3 68 Ga or 64 Biodistribution studies on compounds of the invention that form complexes with Cu 3.1 Experimental protocol Thirty-two male NSG mice were inoculated subcutaneously with 6 million human PSMA-expressing prostate cancer (LNCaP) cells in PBS:Matrigel (1:1) in the right flank. Mice were weighed and tumor volumes were measured twice weekly using electronic calipers. Tumor volumes (mm 3 ) was calculated as length x width x height x π / 6.

[0097] Fifty-one days after inoculation, 10 mice were randomized into group 1 for biodistribution study and then divided into two subgroups matched by tumor volume (tumor volume range: 143–774 mm). 3 , subgroup mean value 355mm 3 and 368mm 3 On the same day, HBED-CC-bis(PSMA) 68 The cells were labeled with Ga and injected into the tail vein of group 1 mice.

[0098] On day 58, eight mice each were randomized into groups 2 and 3 for the biodistribution study, which were then divided into two subgroups with corresponding tumor volumes (group 2 - tumor volume range: 36-510 mm 3 , subgroup mean value 231 mm 3 and 237mm 3 Group 3 - Tumor volume range: 51-429 mm 3 , subgroup mean value 190mm 3 and 212mm 3 On the same day, bis(PSMA) conjugated with NOTA and bis(PSMA) conjugated with DOTA were 64 They were labeled with Cu and injected into mice in groups 2 and 3, respectively.

[0099] On each day for all three groups, two matched subgroups of n=5 (or 4) were harvested for tissue biodistribution and blood by cardiac puncture at 1 or 3 hours post-injection.

[0100] Biodistribution tissues were excised, weighed, and counted using a Capintec (Captus 4000e) gamma counter. Data were analyzed using Prism 9 for Windows (GraphPad).

[0101] 3.2 Results The results of biodistribution are shown in FIG. 68The injected activity of Ga-HBED-CC-bis(PSMA) was targeted to be 6 MBq per mouse, with the actual mean injected activity being 6.17 MBq. 64 Cu-DOTA-bis(PSMA) and 64 The injected activity of Cu-NOTA-bis(PSMA) was targeted to be 5 MBq per mouse, with actual mean injected activities of 5.25 MBq and 5.04 MBq, respectively.

[0102] Radiolabeled PSMA ligands exhibited distinct biodistribution profiles and biodistribution kinetics across two time points between gallium radiolabeled HBED-CC-bis(PSMA) and two copper radiolabeled DOTA-bis(PSMA) and NOTA-bis(PSMA) compounds, respectively. 68 Ga-HBED-CC-bis(PSMA) showed the highest tumor uptake. Mean %ID / g was consistent within groups for each organ / time point.

Claims

1. Formula (I): 【Chemistry 1】 wherein M is: Table 1 wherein each linker may be the same or different and is a residue of a metal chelator selected from the group consisting of: Table 2 or one or more fragments thereof] or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof.

2. Formula (Ia): 【Chemistry 2】 wherein M is: Table 3 【change】 is a residue of a metal chelating agent selected from the group consisting of or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof.

3. 3. The compound of claim 1 or 2, wherein the metal chelator forms a complex with an ion of a metal selected from the group consisting of Cu, Ga, Lu, F, Tc, In, Zr, Y, Rb, Ac, Rd, Re, Sm, Lu, Sc, Zr, Y, Ac, As, Ra, and I.

4. 4. The compound of claim 3, wherein the ion is a radionuclide.

5. The compound of claim 4 which forms a complex with a Cu radionuclide.

6. Cu radionuclide ６０ Cu, ６１ Cu, ６２ Cu, ６４ Cu and ６７ 6. The compound of claim 5, wherein the compound is selected from the group consisting of Cu.

7. The compound of claim 4 which is complexed with a Ga radionuclide.

8. Ga radioactive nuclide ６８ The compound of claim 7, wherein the compound is Ga.

9. 5. The compound of claim 4, which is complexed with a Lu radionuclide.

10. Lu radionuclide １７７ 10. The compound of claim 9, wherein Lu is

11. ９０ Y. １１１ In, １７７ Lu, １８８ Re, ２１１ As, ２１２ Pb and ２２５ 5. The compound of claim 4, complexed with a radionuclide selected from the group consisting of Ac.

12. The following structure: 【Transformation 3】 2. The compound of claim 1, wherein

13. 13. The compound of claim 12, complexed with a radionuclide.

14. A composition comprising a compound of claim 1 or 2 and one or more pharmaceutically acceptable excipients.

15. A cancer radioimaging agent containing the compound described in claim 4.

16. 16. The radioimaging agent of claim 15, wherein the cancer is characterized by overexpression of PSMA.

17. 17. The radioimaging agent of claim 16, wherein the cancer is prostate cancer.

18. A radioactive pharmaceutical for cancer treatment, comprising the compound described in claim 4.

19. 20. The radiopharmaceutical for treating cancer of claim 18, wherein the cancer is characterized by overexpression of PSMA.

20. 20. The radiopharmaceutical for cancer treatment of claim 19, wherein the cancer is prostate cancer.

21. 10. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for radioimaging of cancer.

22. 22. The use of claim 21, wherein the cancer is characterized by overexpression of PSMA.

23. 23. The use according to claim 22, wherein the cancer is prostate cancer.

24. 10. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for treating cancer.

25. 25. The use of claim 24, wherein the cancer is characterized by overexpression of PSMA.

26. 26. The use of claim 25, wherein the cancer is prostate cancer.

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