Prostate specific membrane antigen (PSMA) ligands and uses thereof

Abstract

The present disclosure relates to prostate specific membrane antigen (PSMA) ligands. In particular, the present disclosure relates to PSMA ligands having a glutamate-urea-lysine (GUL) moiety and a chelating agent that may comprise a radioactive metal. The disclosure also relates to the use of these compounds in imaging and the treatment of prostate cancer.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080047295.1, with the application date of June 30, 2020 and the invention name “Prostate-specific membrane antigen (PSMA) ligand and its use”. Technical Field

[0002] The present disclosure relates to prostate-specific membrane antigen (PSMA) ligands. In particular, the present disclosure relates to PSMA ligands having a glutamate-urea-lysine (GUL) moiety and a chelator that may contain a radioactive metal.

[0003] The disclosure also relates to the use of these compounds in imaging and prostate cancer treatment. Background Art

[0004] Prostate cancer is one of the most prevalent cancers in the United States and Europe. In particular, metastatic prostate cancer (mCRPC) is associated with poor prognosis and decreased quality of life.

[0005] Recently, a new development stream for the treatment of prostate cancer is represented by internal radiotherapy based on PSMA ligands, as PSMA is considered a suitable target for imaging and therapy due to its overexpression in primary cancer lesions and soft tissue / bone metastatic disease. In addition, PSMA expression appears to be higher in the most aggressive castration-resistant variants of the disease, which represent a patient population with unmet medical needs. (Marchal et al., Histol Histopathol, 2004 Jul; 19(3):715-8; Mease et al., Curr Top Med Chem, 2013, 13(8):951-62).

[0006] Among the many small-molecule ligands targeting PSMA, low-molecular-weight urea-based agents are the most widely studied. These agents have demonstrated utility in clinical evaluation of prostate cancer and in PRRT therapy (Kiess et al., QJ Nucl Med Mol Imaging, 2015;59:241-68). Some of these agents utilize glutamate-urea-lysine (GUL) as a targeting scaffold. A class of molecules has been created using a strategy that attaches a linker between the chelator and GUL moieties. This approach allows the urea to reach the binding site while retaining the metal chelating moiety outside of the binding site. This strategy has been successful in xenografted PSMA-positive tumors, demonstrating high uptake and retention, as well as rapid renal clearance (Banerjee et al., J Med Chem, 2013;56:6108-21).

[0007] However, some of these compounds still show high uptake in various organs (such as the kidney), which can cause toxicity in human patients. Therefore, there is a need to develop new PSMA ligands with low uptake in various organs. Summary of the Invention

[0008] In a first aspect, the present disclosure relates to compounds having formula (I):

[0009]

[0010] in:

[0011] Z is tetrazole or COOQ, preferably Z is COOQ;

[0012] Q is H or a protecting group, preferably Q is H;

[0013] m is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably m is 4;

[0014] R is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline;

[0015] W chooses free-NR 2 -(C=O), -NR 2 -(C=S),-(C=O)-NR 2 -and-(C=S)-NR 2 -, preferably, W is -(C=O)-NR 2 -;

[0016] R 2 is H or C1-C4 alkyl, preferably R 2 It is H;

[0017] Ch is a chelating agent optionally comprising a metal or radiometal;

[0018] and pharmaceutically acceptable salts thereof.

[0019] The linker between the glutamate-urea-lysine (GUL) moiety and the chelator C comprises a C5-alkyl chain, which results in lower uptake of the radiolabeled molecule in different organs, with a good tumor-to-kidney ratio. This low uptake suggests that these types of molecules have reduced toxicity in human patients. Furthermore, when used for imaging, the high tumor-to-kidney ratio indicates good visualization of the tumor.

[0020] In a second aspect, the present disclosure relates to a pharmaceutical composition comprising a compound having formula (I) and at least one pharmaceutically acceptable carrier.

[0021] In a third aspect, the disclosure relates to compounds of formula (I) for use as medicaments.

[0022] In a fourth aspect, the disclosure relates to compounds of formula (I) for use in the treatment of cancer, particularly prostate cancer.

[0023] In a fifth aspect, the disclosure relates to compounds of formula (I) for use in imaging.

[0024] In a sixth aspect, the present disclosure also relates to a method of treating prostate cancer, comprising contacting the cancer cells with an effective amount of a compound having formula (I).

[0025] In a seventh aspect, the present disclosure also relates to a method of imaging comprising contacting a cancer cell with an effective amount of a compound having formula (I). BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 According to Example 1, 68 Biodistribution of Ga-PSMA-R2 in healthy CD-1 mice (mean ± SD).

[0027] Figure 2 According to Example 1, 68 Biodistribution of Ga-PSMA-R2 in healthy CD-1 mice (bladder and kidney) (mean ± SD).

[0028] Figure 3 The results of the present study are shown in athymic nude mice bearing PSMA positive (PIP) and negative (Flu) tumors according to Example 2. 68 Ga-PSMA-R2 biodistribution (mean ± SD).

[0029] Figure 4 The results of the present study are shown in athymic nude mice bearing PSMA positive (PIP) and negative (Flu) tumors according to Example 2. 68 Ga-PSMA-cpd 2 biodistribution (mean ± SD).

[0030] Figure 5 The results of the present study in athymic nude mice bearing PSMA-positive (PIP) tumors according to Example 3 are shown. 177 Lu-PSMA-R2 and 177 Lu-PSMA-617 efficacy study. DETAILED DESCRIPTION

[0031] definition

[0032] As used herein, the term "blocking group" with respect to a compound of formula (I) refers to a chemical substituent that can be selectively removed by readily available reagents that do not attack the regenerating or other functional groups in the molecule. Suitable blocking groups are known in the art and are being developed. Suitable blocking groups can be found in, for example, Wutz et al. ("Greene's Protective Groups in Organic Synthesis," 4th edition, Wiley-Interscience, 2007). In certain embodiments, a blocking group for protecting a carboxyl group as described by Wutz et al. (pp. 533-643) is used. In certain embodiments, the blocking group can be removed by acid treatment.

[0033] The representative example of blocking group includes but is not limited to benzyl, p-methoxybenzyl (PMB), tert-butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS) and triphenylmethyl (trityl, Tr). Those skilled in the art will recognize the appropriate situation needing blocking group, and can select appropriate blocking group to be used for particular situation.

[0034] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon radical having a single ring or multiple aromatic rings fused together, containing 6 to 10 ring atoms, at least one of which is aromatic. The aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl, or heteroaryl as defined herein) fused thereto. Suitable aryl groups include phenyl, naphthyl, and a benzene ring fused to a heterocyclyl, such as benzopyranyl, benzodioxolyl, benzodioxanyl, and the like.

[0035] As used herein, the terms "substituted aryl" and "substituted pyridine" refer to aryl or pyridine as defined above substituted with one or more substituents selected from the group consisting of halogen, -OR', -NR'R", -SR', -SiR'R"R'", -OC(O)R', -C(O)R', -C02R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(O)OR', -NR-C(NR'R"R' ”)=NR””, -NR-C(NR'R”)=NR'”, -S(O)R', -S(O)2R', -S(O)2NR'R”, -NRSO2R', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, the number of which ranges from zero to the total number of ring-opening valences on the aromatic ring system; wherein R', R", R'" and R"" can be independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. When a compound of the present disclosure contains more than one R group, for example, when more than one of these groups is present, each R group is independently selected as each R', R", R'" and R"" group.

[0036] As used herein, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain alkyl functional group having from 1 to 6 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl) and hexyl and its isomers (e.g., n-hexyl, isohexyl).

[0037] As used herein, the term "heteroalkyl" refers to a straight or branched chain alkyl functional group having 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The one or more heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the rest of the molecule.

[0038] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic group having 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0039] As used herein, the term "halogen" refers to a fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I) group.

[0040] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl is a C1-C6 alkyl as defined herein. Suitable alkoxy groups include methoxy, ethoxy, propoxy.

[0041] As used herein, the term "heteroaryl" refers to a polyunsaturated aromatic ring system having a single ring or multiple aromatic rings fused together or linked covalently, containing 5 to 10 atoms; wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl or heterocyclyl ring. Non-limiting examples of such heteroaryl groups include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxazinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0042] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or unsaturated cyclic group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S. The nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Examples of heterocycles include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperazinyl, 1-azepanyl, imidazolinyl, 1,4-dioxanyl, and the like.

[0043] Various embodiments of the present disclosure are described herein. It should be appreciated that features specified within each embodiment can be combined with other specified features to provide further embodiments.

[0044] The present disclosure includes compounds of Formula (I), (II), (III) and (IV), their stereoisomers, tautomers, enantiomers, diastereomers, racemates or mixtures thereof, and hydrates, solvates or pharmaceutically acceptable salts thereof.

[0045] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the disclosure and, which typically are not biologically or otherwise undesirable.

[0046] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other undesirable reactions when properly administered to mammals, particularly humans. Pharmaceutically acceptable carriers or excipients refer to non-toxic solid, semisolid or liquid fillers, diluents, encapsulating materials or formulation auxiliary agents of any type.

[0047] As used herein, the term "subject" refers to an animal, preferably a mammal, more preferably a human.

[0048] Compounds having formula (I)

[0049] In a first aspect, the present disclosure relates to compounds having formula (I):

[0050]

[0051] in:

[0052] Z is tetrazole or COOQ, preferably Z is COOQ;

[0053] Q is H or a protecting group, preferably Q is H;

[0054] m is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably m is 4;

[0055] R is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline;

[0056] W chooses free-NR 2 -(C=O), -NR 2 -(C=S),-(C=O)-NR 2 -and-(C=S)-NR 2 -, preferably, W is -(C=O)-NR 2 -;

[0057] R 2 is H or C1-C4 alkyl, preferably R 2 It is H;

[0058] Ch is a chelating agent optionally comprising a metal or radiometal;

[0059] and pharmaceutically acceptable salts thereof.

[0060] Compounds of formula (I) include stereoisomers of formula (Ia), (Ib), (Ic) and (Id):

[0061]

[0062] According to one embodiment, R is selected from the group consisting of aryl substituted by one or more halogens, pyridine substituted by one or more halogens, and unsubstituted isoquinoline.

[0063] According to a specific embodiment, R is selected from the group consisting of:

[0064]

[0065] wherein X is independently Br or I.

[0066] Advantageously, R is

[0067]

[0068] Ch can be selected from the group consisting of:

[0069]

[0070] and optionally contains a metal or a radioactive metal.

[0071] According to a specific embodiment, Ch is

[0072] and optionally contains a metal or a radioactive metal.

[0073] The metal or radiometal is preferably selected from metals and radiometals suitable for use in imaging methods or therapy.

[0074] According to one embodiment, Ch comprises a metal selected from the group consisting of Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho, and Sc. The metal may be selected from 68 Ga, 64 Cu, 86 Y. 90 Y. 89 Zr, 111 In, 99m Tc, 177 Lu, 153 Sm, 186 Re、 188 Re、 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc and 166 Ho is a radioactive metal.

[0075] Advantageously, Ch comprises a radioactive metal 68 Ga or 177 Lu or 225 Ac.

[0076] The compound of formula (I) is distributed in tumor-bearing animals or humans in such a manner that one hour after intravenous injection of the compound, the tumor to kidney ratio is at least 5 (at least the average of N=4).

[0077] According to one embodiment, W is -(C=O)-NR 2 -, and Ch is and optionally contains a metal or a radioactive metal.

[0078] According to one embodiment, m is 4, Z is COOQ, and Q is H.

[0079] According to a particular embodiment, the compound of formula (I) is a compound of formula (II):

[0080]

[0081] The compound of formula (II) may be referred to as PSMA-R2. The compound of formula (II) may contain a metal or a radioactive metal, preferably 68 Ga or 177 Lu.

[0082] According to one embodiment, the compound of formula (I) is a compound of formula (III): .

[0083]

[0084] The compound having formula (III) may be referred to as 177 Lu-PSMA-R2. Compounds of formula (III) include stereoisomers of formula (IIIa), (IIIb), (IIIc) and (IIId):

[0085]

[0086] According to another embodiment, the compound of formula (I) is a compound of formula (IV): .

[0087]

[0088] The compound having formula (IV) may be referred to as 68 Ga-PSMA-R2. Compounds of formula (IV) include stereoisomers of formula (IVa), (IVb), (IVc) and (IVd):

[0089]

[0090]

[0091] Pharmaceutical composition

[0092] The present disclosure also relates to pharmaceutical compositions comprising a compound having Formula (I) to (IV) and at least one pharmaceutically acceptable carrier.

[0093] The form, route of administration, dosage, and regimen of the pharmaceutical composition will naturally depend on the condition to be treated, the severity of the disease, the age, weight, and sex of the patient, etc.

[0094] The pharmaceutical compositions of the present disclosure can be formulated for intravenous, intramuscular, or subcutaneous administration, etc.

[0095] The pharmaceutical composition can be in the form of an aqueous solution, such as an injectable preparation containing at least one compound according to the present disclosure.

[0096] Preferably, the pharmaceutical composition contains a pharmaceutically acceptable vehicle for a formulation capable of being injected. These can be, in particular, isotonic sterile salt solutions (monosodium phosphate or disodium phosphate, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride, etc., or mixtures of these salts), or dry, especially lyophilized, compositions which, depending on circumstances after addition of sterile water or physiological saline, allow the formation of an injectable solution.

[0097] The sterile injectable solution is prepared by incorporating the active compound in the required amount into a suitable solvent with several of the other ingredients listed above (as required), followed by filtration sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization techniques which yield a powder of the active ingredient and any additional desired ingredients from its previously sterile filtered solution. After formulation, the solution will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. These formulations are readily administered in a variety of dosage forms, such as the type of injectable solution described above.

[0098] For example, for parenteral administration in an aqueous solution, the solution can be appropriately buffered and first made isotonic with a sufficient amount of saline or glucose in the liquid diluent. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, the sterile aqueous media that can be used will be known to those skilled in the art. For example, one dose can be dissolved in 1 ml of isotonic NaCl solution and then added to 1000 ml of a subcutaneous injection solution or injected at the proposed infusion site (see, for example, "Remington's Pharmaceutical Sciences", 15th Edition, pages 1035 - 1038 and 1570 - 1580). Depending on the condition of the subject being treated, the dosage will necessarily vary somewhat. In any case, the person responsible for administration will determine the appropriate dosage for the individual subject.

[0099] In a specific embodiment, the pharmaceutical composition comprises one or more excipients selected from stabilizers against radiation degradation, chelating agents, and mixtures thereof.

[0100] As used herein, "stabilizers against radiodegradation" refer to stabilizers that protect organic molecules from radiolytic degradation, for example, when gamma rays emitted from a radionuclide cleave bonds formed between atoms of the organic molecule and free radicals, those free radicals are then scavenged by the stabilizer, which prevents the free radicals from undergoing any other chemical reactions that could result in undesirable, potentially ineffective, or even toxic molecules. Therefore, these stabilizers are also referred to as "free radical scavengers" or simply "free radical scavengers." Other alternative terms for those stabilizers are "radiation stability enhancers," "radiation stabilizers," or simply "quenchers."

[0101] As used herein, "chelator" refers to a chelating agent suitable for complexing free radionuclide metal ions (not complexed with a radiolabeled peptide) in the formulation.

[0102] The dosage for administration can be adjusted according to various parameters, in particular according to the mode of administration used, the associated pathology, or alternatively the desired duration of treatment. It will be appreciated that the appropriate dosage of the compounds and compositions comprising these compounds may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit with any risks or adverse side effects of the treatments described herein.

[0103] Compounds of formula (I) to (IV) for use as medicaments

[0104] The present disclosure also relates to compounds of formula (I) to (IV) for use as medicaments. As shown in the tests provided in the examples, the compounds of formula (I) to (IV) exhibit valuable pharmaceutical properties and are therefore suitable for use in therapy.

[0105] The present disclosure also relates to compounds of Formula (I) to (IV) for use in treating cancer, particularly by targeted alpha therapy and beta radiation.

[0106] The compounds of formula (III) are particularly suitable for use as medicaments, preferably for the treatment of cancer.

[0107] As used herein, the term "cancer" has its ordinary meaning in the art and includes an abnormal state or condition characterized by rapidly proliferating cell growth. The term is intended to include all types of cancerous growths or oncogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, without regard to histopathological type or stage of invasion. The term cancer includes malignancies of various organ systems, such as those affecting the skin, lung, breast, thyroid, lymphatic, gastrointestinal, and genitourinary tracts, as well as adenocarcinomas, which include malignancies such as most colon cancers, renal cell carcinomas, prostate cancers, and / or testicular tumors, non-small cell lung cancers, small intestine cancers, and esophageal cancers.

[0108] Examples of cancer include, but are not limited to, hematological malignancies, such as B-cell lymphomas, T-cell lymphomas, non-Hodgkin's lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphomas, and myeloid neoplasms. Examples of non-hematological cancers include, but are not limited to, skin cancer, colon cancer, breast cancer, lung cancer, brain cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, colorectal cancer, bone cancer, cervical cancer, liver cancer, oral cancer, esophageal cancer, thyroid cancer, kidney cancer, stomach cancer, and testicular cancer.

[0109] In a specific embodiment, the cancer is a cancer having tumors or cells that express PSMA.

[0110] In one embodiment, the present disclosure also relates to compounds of Formula (I) to (IV) for use in treating prostate cancer.

[0111] In one embodiment, the prostate cancer is metastatic prostate cancer.

[0112] The present disclosure also relates to compounds of Formula (I) to (IV) for use in treating PSMA-expressing tumors or cells.

[0113] The PSMA-expressing tumor or cell can be selected from the group consisting of a prostate tumor or cell, a metastatic prostate tumor or cell, a lung tumor or cell, a kidney tumor or cell, a glioblastoma, a pancreatic tumor or cell, a bladder tumor or cell, a sarcoma, a melanoma, a breast tumor or cell, a colon tumor or cell, a germ cell, a pheochromocytoma, an esophageal tumor or cell, a gastric tumor or cell, and combinations thereof. In some other embodiments, the PSMA-expressing tumor or cell is a prostate tumor or cell.

[0114] Thus, the present disclosure also relates to methods of treating cancer comprising contacting cancer cells with a therapeutically effective amount of a compound having Formula (I) to (IV).

[0115] As used herein, the term "contacting" refers to any action that causes at least one compound that constitutes the therapeutic agent of the present disclosure to come into physical contact with at least one cancer cell. Contacting can include exposing one or more cells or one or more tumors to an amount of the compound that is sufficient to cause the at least one compound to come into contact with the at least one cell or tumor. The method can be implemented in vitro or ex vivo by introducing and preferably mixing the compound and one or more cells or one or more tumors in a controlled environment, such as a culture dish or tube. The method can be implemented in vivo, in which case contacting refers to exposing at least one cell or tumor in a subject to at least one compound of the present disclosure, such as by administering the compound to the subject by any suitable route.

[0116] In a specific embodiment, the cancer to be treated is a cancer having a tumor or cells that express PSMA.For example, the cancer to be treated can be prostate cancer, including metastatic prostate cancer.

[0117] The present disclosure also relates to a method of treating cancer, typically prostate cancer, comprising administering to a subject, preferably a human, in need thereof, a therapeutically effective amount of a compound having Formula (I) to (IV).

[0118] As used herein, the term "treating" includes reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of the disease, disorder, or condition to which the term applies, or one or more symptoms or manifestations of such disease, disorder, or condition. Preventing means preventing the disease, disorder, condition, or symptom, or manifestations of such, or worsening of the severity of such, from occurring. Thus, the compounds of the present disclosure can be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder, or condition.

[0119] As used herein, the term "therapeutically effective amount" of a compound refers to that amount of the compound that will elicit a biological or medical response in a subject (eg, improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease).

[0120] The present disclosure also relates to methods of treating PSMA-expressing tumors or cells, comprising contacting the PSMA-expressing tumors or cells with a therapeutically effective amount of a compound having Formula (I) to (IV).

[0121] The present disclosure also relates to the use of compounds of formula (I) to (IV) for the manufacture of a medicament.

[0122] The present disclosure also relates to the use of compounds having formula (I) to (IV) in the preparation of a medicament for treating cancer, such as prostate cancer.

[0123] The present disclosure also relates to the use of compounds having Formula (I) to (IV) in the preparation of a medicament for treating PSMA-expressing tumors or cells.

[0124] Compounds of formula (I) to (IV) for use in imaging and methods thereof

[0125] The present disclosure also relates to compounds of Formula (I) to (IV) for use in imaging, preferably in vivo imaging.

[0126] The present disclosure also relates to compounds having Formula (I) to (IV) for use in imaging PSMA-expressing tumors or cells.

[0127] The compounds of formula (IV) are particularly suitable for use in imaging, preferably for imaging of tumors or cells expressing PSMA.

[0128] In a particular embodiment, the imaging method in which the compounds of formula (I) to (IV) are used is PET (positron emission tomography) or SPECT (single photon emission computed tomography).

[0129] Thus, the present disclosure also relates to a method of imaging comprising contacting a cancer cell with an effective amount of a compound having Formula (I) to (IV).

[0130] The present disclosure also relates to a method for imaging a PSMA-expressing tumor or cell, the method comprising contacting the PSMA-expressing tumor or cell with a therapeutically effective amount of a compound having formula (I) to (IV). The method may further comprise the step of detecting a signal derived from the decay of a radioactive metal present in the compound.

[0131] The present disclosure also relates to a method for imaging PSMA-expressing tumors or cells in a subject, comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound having Formula (I) to (IV), and detecting a signal derived from the decay of a radioactive metal present in the compound.

[0132] In a specific embodiment, the present disclosure provides a method for detecting the presence of a PSMA-expressing tumor in a subject, the method comprising:

[0133] (i) administering a compound of Formula (I) to (IV), for example, as an intravenous injection in said subject;

[0134] (ii) acquiring images, typically by PET or SPECT imaging; and,

[0135] (iii) detecting the presence of a PSMA-expressing tumor in the subject.

[0136] The present disclosure also relates to compounds having formula (I) to (IV) for use in diagnosis, typically for diagnosing cancer diseases, such as PSMA-expressing cancers.

[0137] The present disclosure also relates to methods for diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells, e.g., prostate tumors or cells, in a subject, comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound having Formula (I) to (IV), and detecting a signal derived from the decay of a radioactive metal present in the compound.

[0138] Synthesis of compounds of formula (I) to (IV)

[0139] Compounds of formula (I) and (II) can be synthesized using the methods disclosed in WO 2017 / 165473.

[0140] In particular, compounds of formula (II) can be synthesized as described in Scheme 1. The modified p-bromobenzyl group of Glu-Lys urea 2 can be prepared by reductive alkylation of Glu-Lys urea 1 with p-bromobenzaldehyde in methanol in the presence of sodium cyanoborohydride. This procedure has been described in the literature (Tykvart et al. (2015) Journal of Medicinal Chemistry 58, 4357-63). Boc-6-aminohexanoic acid can then be coupled to the same ε-Lys amine of 2 using, for example, a base such as N,N-diisopropylethylamine and a coupling agent such as N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate to produce compound 3. Compound 3 can then be deprotected, for example using an acid such as trifluoroacetic acid, to yield compound 4. Finally, conjugation with commercially available DOTA-NHS ester can be performed to yield compound (II).

[0141] Compounds of formula (I) and (II) can be radiolabeled using methods commonly used in the field of radiolabeling. Specifically, the method described in WO 2017 / 165473 can also be used. 177 The compound of formula (II) is radiolabeled with Lu to form a compound of formula (III). The method described in WO 024013 can also be used. 68 The compound of formula (II) is radiolabeled with Ga to form the compound of formula (IV).

[0142] Scheme 1: Synthesis of compounds of formula (II)

[0143]

[0144] Examples

[0145] Example 1: Distribution in healthy animals (Study using 68 Ga-PSMA-R2

[0146] Biodistribution studies were performed in healthy CD-1 mice using Ga-labeled PSMA-R2, which was administered intravenously at a dose of 120-150 μCi (4.44-5.55 MBq). Animals (3 or 4 / group) were sacrificed at specific time points after intravenous injection, and organs were harvested, weighed, and evaluated in a gamma counter. Figure 1 and Figure 2 Calculated %ID / g values are reported.

[0147] 68 The uptake of Ga-PSMA-R2 in the kidney and bladder indicated that the radiotracer was excreted through the renal system ( Figure 2 Very low liver uptake was recorded (0.74% at 30 minutes decreasing to 0.21% at 4 hours), indicating minimal excretion via the hepatobiliary system ( Figure 1 Although slightly higher radiotracer uptake was recorded in the blood and other organs (e.g., adrenal glands, lungs, thyroid gland) at the earliest time point (30 min), %ID values decreased rapidly at later time points ( Figure 1 Low uptake of the radiotracer was detected in the remaining organs (intestine, pancreas, muscle, bone) at all time points (including the earliest at 30 minutes).

[0148] Example 2: In vivo distribution in tumor models (study using 68 Ga-PSMA-R2)

[0149] Athymic male nude mice bearing PC-3 PSMA-positive and PSMA-negative tumor xenografts were injected with approximately 4.5 MBq of 68 Ga-PSMA-R2 was then evaluated for biodistribution and imaging studies. Tumor and organ uptake was determined using a gamma counter at four time points (30 minutes, 1 hour, 2 hours, and 4 hours post-injection (pi). To assess receptor specificity, additional groups of animals were simultaneously injected with an excess of unlabeled PSMA-R2 (40 nmol). The results are shown in Figure 2. Figure 3 shown.

[0150] use 68 The same study was performed on Ga-PSMA-cpd2 (comparative compound having the formula:

[0151]

[0152] The results are as follows Figure 4 shown.

[0153] 68 Ga-PSMA-R2 and 68 The tumor uptake, kidney uptake, salivary gland uptake, and tumor to kidney ratio of Ga-PSMA-cpd2 are summarized in Table 1 .

[0154] Table 1: 68 Ga-PSMA-R2 and 68 Comparison of Ga-PSMA-cpd2

[0155] <![CDATA[ 68 Ga-PSMA-R2]]> <![CDATA[ 68 Ga-PSMA-cpd2]]> Tumor uptake 29％(1h) 36％(1h) Renal uptake 6％(1h) 13％(1h) Tumor-to-kidney ratio 5(1h) 3(1h) salivary glands 0.81％(0.5h) 0.95％(0.5h)

[0156] These results showed that compared with the comparative compound 68 Compared with Ga-PSMA-cpd2, after 1 hour, 68 The renal uptake and salivary gland uptake of Ga-PSMA-R2 were low. 68 In the case of Ga-PSMA-R2, the ratio was higher in tumor than in kidney.

[0157] This shows that 68 Compared with Ga-PSMA-cpd2, 68 Ga-PSMA-R2 may have lower toxicity. 68 In the case of Ga-PSMA-R2, the high ratio of tumor to kidney after 1 hour indicated better visualization of the tumor, as the optimal imaging time point was 45 minutes to 1 hour.

[0158] Example 3: In vivo efficacy in mice in a PC3-PIP PSMA-positive model

[0159] Efficacy studies were performed in a prostate cancer model using Lu-labeled PSMA-R2).

[0160] Mice bearing PC3-PIP (PSMA-positive) tumors were injected once with 111 MBq of 177 Lu-PSMA-R2, 177 Lu-PSMA-617 (included as a reference compound), or with saline (control).

[0161] Tumor volume was expressed as absolute value (mm 3 ) or relative to the volume measured at the time of the first injection.

[0162] The results of absolute tumor volume showed that compared with the control group, 177 Lu-PSMA-R2 and 177 The tumor volume of the Lu-PSMA-617 group was significantly reduced (p<0.001) (see Figure 5 A).

[0163] Similarly, when the data are expressed as relative volumes, it is found that177 LuPSMA-R2 and 177 The tumor volumes of both Lu-PSMA-617 groups were significantly reduced compared with those of the control group (p<0.001) (see Figure 5 B).

[0164] No differences in tumor volume were observed between the two treatment groups when expressed as absolute or relative volumes. Figure 5 In CF, the absolute and relative tumor volumes of the two subgroups treated at two-day intervals are shown.

[0165] These results indicate that 177 Lu-PSMA-R2 effectively reduced the tumor size of PSMA-positive tumors in mice. 177 Lu-PSMA-R2 thus exhibits valuable pharmaceutical properties and can therefore be used in therapy.

[0166] Example 4: Safety Pharmacology

[0167] Behavioral Irwin test and effects on body temperature after a single intravenous administration in rats

[0168] The purpose of this study was to evaluate the 175 Possible effects of Lu-PSMA-R2 (at doses of 0.2, 0.6, and 2.0 mg / kg) on general behavioral parameters in rats after intravenous administration.

[0169] Table 2: Experimental design of behavioral Owen test

[0170]

[0171] The following parameters were assessed: mortality, body weight, clinical signs, and Owen's test.

[0172] Owen's test was performed at the following time intervals after administration: 5, 15, 30 minutes and 1, 2 and 24 hours.

[0173] Single intravenous administration at doses of 0.2, 0.6, and 2.0 mg / kg 175 Lu-PSMA-R2 did not produce any effects on behavioral, neurological, or autonomic parameters in rats in the Irvine study up to 24 hours after administration. No deaths occurred during the study, and no clinical signs were observed during the 6-day observation period.

[0174] The study results are summarized in Table 10.

[0175] Evaluation of the effects of a single intravenous administration on respiration in freely conscious rats

[0176] The purpose of this study was to evaluate the efficacy of 0.2, 0.6, and 2.0 mg / kg by whole body plethysmography following intravenous administration according to the study design detailed in Table 3 175 The potential effects of LuPSMA-R2 on respiratory function in conscious rats.

[0177] Table 3: Experimental design of the study evaluating the effects on respiratory function

[0178]

[0179] Inspiratory time, expiratory time, peak inspiratory flow, peak expiratory flow, tidal volume, relaxation time, minute volume, respiratory rate and enhanced pauses were recorded continuously from about 1 hour before administration to 4 hours after administration. The number of breaths and gender parameters of the rats were reported before administration and 5, 15 and 30 minutes after administration and 1, 1.5, 2, 3 and 4 hours after administration. Clinical signs were recorded on the administration day.

[0180] The study results are summarized in Table 10.

[0181] Effects of intravenous administration on cardiovascular function in conscious miniature pigs

[0182] The purpose of this study is to investigate 175 Potential effects of Lu-PSMA-R2 on cardiovascular function in conscious, telemetered male minipigs after intravenous administration at doses of 0.058, 0.175, and 0.583 mg / kg. The experimental design is shown in Table 4.

[0183] The test article or vehicle was administered intravenously into the external auricular vein at a fixed injection rate of 4 mL / min. The dose was administered to each animal at a dose volume of 1 mL / kg body weight.

[0184] Each animal received vehicle or one of three doses of the test article at 7-day intervals according to the crossover design described in Table 4.

[0185] Table 4: Experimental design of studies evaluating effects on cardiovascular function in male minipigs

[0186]

[0187] Systolic, diastolic and mean blood pressure (SBP, DBP and MBP), heart rate (HR), body temperature and II-lead electrocardiogram were recorded continuously from 1 hour before administration to 24 hours after administration. Hemodynamic and electrocardiographic data were reported before administration and at 5, 15, 30 minutes and 1, 2, 4, 8 and 24 hours after administration.

[0188] The study results are summarized in Table 10.

[0189] Single and repeated dose toxicity studies

[0190] Single and repeated dose toxicity studies have been conducted using Lu-PSMA-R2 solution. 175 Lu-PSMA-R2 (as 177 The results were performed on a surrogate of Lu-PSMA-R2).

[0191] Test object 175 Lu-PSMA-R2 is contained in acetate buffer 175 Solutions of Lu-PSMA-R2 and unlabeled PSMA-R2, wherein PSMA-R2 is present at a nominal concentration of 1 mg / mL, partially in the free form (PSMA-R2) and partially complexed with Lu-175, with the ratio of the two components being approximately 1:1. The dose is expressed as the sum of the free form and the Lu-175 labeled form.

[0192] Single-dose toxicity studies in rats and minipigs and a 2-week repeated-dose toxicity study in rats have been completed.

[0193] Single-dose toxicity study in rats

[0194] This study aimed to evaluate the 175 Toxicity after acute intravenous injection of Lu-PSMA-R2 at 2 or 4 mg / kg.

[0195] Two groups of 30 animals (1:1 male:female ratio) were dosed at 2 and 4 mg / kg, respectively. A control group with identical characteristics was treated with vehicle (Table 5).

[0196] Table 5: Experimental design of single-dose toxicity study in rats

[0197]

[0198] Signs of response to treatment at all doses were assessed 30, 120, and 240 minutes after injection, as well as 24 hours later. On day 2, 10 rats / sex / group were sacrificed. The remaining 5 animals / sex / group were observed daily for 14 days.

[0199] Body weights were recorded on the day of treatment group assignment, day 1 (injection day), day 8, and day 15. Food consumption was measured on day 2 and weekly thereafter. At the end of treatment, urine samples were collected for urinalysis. Blood samples drawn at sacrifice were screened for clinical pathology on day 2 and day 15. After dissection, organs were weighed and tissues were analyzed microscopically (more than 50 different tissues were analyzed).

[0200] The results of the study are summarized in Table 10. They show that a single intravenous administration of the test article at dose levels of 2 and 4 mg / kg 175Lu-PSMA-R2 (approximately 480 and 960 times the expected human dose based on mg / kg scaling, considering that the human body weighs 60 kg) did not cause signs of toxicity and was therefore well tolerated in rats.

[0201] Single-dose toxicity study in miniature pigs

[0202] According to the experimental design detailed in Table 6, the After a single intravenous bolus administration in miniature pigs 175 Toxicity and toxicokinetic characteristics of Lu-PSMA-R2.

[0203] A two-week treatment-free period was allowed after administration.

[0204] All animals were dosed intravenously. Plasma samples were collected on day 1 for toxicokinetic analysis.

[0205] Table 6: Experimental design of single-dose toxicity study in minipigs

[0206]

[0207] Mortality, clinical signs, body weight, food consumption, clinical pathology investigation, ophthalmoscopy, ECG evaluation and macroscopic observation were indexed at necropsy. Selected organs were then weighed and tissues were collected.

[0208] In addition, plasma samples were collected on day 1 for toxicokinetic analysis.

[0209] The results of the study are summarized in Table 10. They show that a single intravenous administration of the test article at dose levels of 0.175, 0.583 and 1.754 mg / kg 175 Lu-PSMA-R2 (approximately 42, 140, and 420 times the expected human dose, based on mg / kg scaling, considering a body weight of 60 kg) did not cause any signs of toxicity in the minipigs. Therefore, it can be concluded that these amounts of the test substance were well tolerated by the minipigs.

[0210] Repeated-dose toxicity study in rats

[0211] The purpose of this study is to investigate 175 Toxicity of Lu-PSMA-R2 in rats after 2 weeks of daily intravenous administration and recovery from any treatment-related effects within a 2-week recovery period (main group).

[0212] The doses tested were 0.13, 0.39, and 1.29 mg / kg / day, approximately 31, 93, and 310 times the expected human dose of PSMA-R2.

[0213] Each main treatment group consisted of 10 male and 10 female rats. After 2 weeks of recovery in Groups 1 and 4, an additional 5 male and 5 female rats were sacrificed. Two satellite toxicokinetic groups (low-dose and mid-dose) consisted of 9 male and 9 female animals, and one group (high-dose) included 12 male and 12 female animals. Another group (control) included 3 male and 3 female animals.

[0214] The experimental design is shown in Tables 7 and 8.

[0215] Table 7: Experimental design of repeated dose toxicity study in rats - main groups.

[0216]

[0217] Table 8: Experimental design of repeated-dose toxicity study in rats - satellite group for TK evaluation

[0218]

[0219] In this study, the 175 Toxicity and toxicokinetics of Lu-PSMA-R2 in Sprague Dawley rats following daily intravenous administration for 2 weeks at doses of 0.13, 0.39, and 1.29 mg / kg / day. A 2-week treatment-free period was allowed for recovery from any treatment-related effects or persistent adverse effects observed during the 2-week dosing period for the control and high-dose groups.

[0220] No signs of toxicological significance were noted during routine clinical observations. Body weight and food consumption were unaffected by treatment. No treatment-related abnormalities were observed on ophthalmoscopy. No toxicologically relevant findings were found on clinical pathology. No evidence of treatment-related effects was found at autopsy, organ weights, or histopathology.

[0221] Toxicokinetic assessments demonstrated that all animals treated at all three dose levels were exposed to the test article. Generally, exposure was roughly dose-proportional. Exposure was similar in males and females. Across all genders and dose levels, the drug was eliminated with a half-life of approximately 0.4-0.8 hours. Clearance was dose-independent, demonstrating linear kinetics. No accumulation was observed following daily dosing from day 1 to day 14.

[0222] According to the results obtained in this study, no toxic effects were observed in the treated mixed groups compared to the control. Therefore, 1.29 mg / kg / day can be considered as the NOAEL (no observed adverse effect level), which is 310 times higher than the foreseeable human dose.

[0223] The study results are summarized in Table 10.

[0224] Repeated-dose toxicity study in miniature pigs

[0225] The objectives of this study were to investigate the toxicity and toxicokinetic profile of LuPSMA-R2 following 2 weeks of daily intravenous administration in minipigs, as well as recovery from any treatment-related effects during a 2-week recovery period.

[0226] The doses tested were: 0.058, 0.175, and 0.583 mg / kg / day, approximately 14, 42, and 140 times the expected human dose of PSMA-R2.

[0227] Each group consisted of 3 male and 3 female miniature pigs. Groups 1 and 4 included 2 additional animals of each sex, which were sacrificed after 2 weeks of recovery. The experimental design is summarized in Table 9.

[0228] All animals were dosed intravenously once daily for 14 consecutive days.

[0229] Table 9: Experimental design of the repeated-dose toxicity study in minipigs

[0230]

[0231] Body weight and food intake were not affected by treatment. Physical examinations performed did not reveal significant changes in any animal. No treatment-related abnormalities were detected on ophthalmoscopy and electrocardiography. Clinical pathology (i.e., hematology, coagulation, blood chemistry, and urinalysis) as well as macropathology, terminal body weight, and absolute and relative organ weights did not show significant or treatment-related changes at any dose, and there were no treatment-related histopathological modifications.

[0232] Toxicokinetic evaluation showed that all animals treated at the three dose levels were exposed to the test article. On day 1, the estimated 175 The half-lives of Lu-PSMA-R2 were 0.71 and 0.63 hours, respectively. These values were confirmed on day 14. Plasma clearance was independent of dose, showing linear kinetics. The increase in systemic exposure (in terms of Cmax and AUC0-tlast) was roughly dose-proportional. No relevant accumulation was observed after daily administration from day 1 to day 14.

[0233] The results of this study indicated that 0.583 mg / kg / day could be considered the NOAEL for this study.

[0234] The results of the safety pharmacology and toxicology studies are summarized in Table 10.

[0235] Table 10: Summary of results obtained in safety pharmacology and toxicology studies

[0236]

[0237]

[0238]

[0239] Genotoxicity Studies: Bacterial Mutagenesis Assays

[0240] Tested the test article 175 The ability of Lu-labeled PSMA-R2 solution to induce gene mutations in test strains of Salmonella typhimurium and Escherichia coli, as measured by reversion of auxotrophic strains to prototrophy. Five test strains, TA1535, TA1537, TA98, TA100, and WP2 uvrA, were used. Experiments were performed in the absence and presence of metabolic activation using liver S9 fractions from rats pretreated with phenobarbital and 5,6-benzoflavone.

[0241] The test substances were used as solutions in sodium acetate buffer and all concentrations in this report are expressed with respect to the active ingredient. 175 Lu-labeled PSMA-R2 solutions were tested in toxicity assays at the maximum feasible concentration of 1000 μg / plate and four lower concentrations spaced approximately half-logarithmically: 316, 100, 31.6, and 10.0 μg / plate. No precipitation of the test substance was observed at the end of the incubation period at any concentration. No toxicity or associated increase in the number of revertants was observed in any of the tested strains at any dose level, in the absence or presence of S9 metabolism.

[0242] Based on the results obtained in the preliminary toxicity tests, the test article was tested in the primary assay using the plate incorporation method with all test strains at the following dose levels: 1000, 500, 250, 125, and 62.5 μg / plate. No precipitation of the test article was observed at the end of the incubation period at any concentration. No toxicity or associated increase in the number of revertants was observed in any of the test strains at any dose level, either in the absence or presence of S9 metabolism. Due to the clearly negative results obtained, no further experiments were performed.

[0243] It was concluded that under the reported experimental conditions, in the absence or presence of S9 metabolism, the test substances 175 Lu-labeled PSMA-R2 solution did not induce reverse mutation in Salmonella typhimurium or Escherichia coli.

[0244] In vitro stability in plasma

[0245] The stability of the PSMA-R2 ligand was evaluated in vitro after incubation with plasma from four different species (mouse, rat, minipig, and human). PSMA-R2 was incubated in different matrices at a final concentration of 10 μg / mL at 37°C for 30, 60, and 120 minutes. Samples were analyzed by LC-MS / MS.

[0246] PSMA-R2 showed good stability in human plasma, with a recovery rate of 85% after 2 hours.

[0247] Plasma protein binding studies

[0248] PSMA-R2 and 175 Plasma protein binding of Lu-PSMA-R2 has been determined by ultrafiltration after incubation of the compound at two different concentrations, 1 and 5 μg / mL, in human, mouse, rat, and minipig plasma. The results (percentage of the unbound fraction) are reported in Table 11.

[0249] Table 11: PSMA-R2 plasma protein binding results expressed as a percentage of the unbound fraction

[0250]

[0251] Results support 175 Lu-PSMA-R2 is a non-highly bound compound. 175 The unbound fraction for both Lu-labeled and unlabeled PSMA-R2 ranged from approximately 25% to 45%. Results for protein binding in rat plasma and minipig plasma were within the same range. Mice exhibited lower protein binding compared to the other species, with unbound fractions ranging from approximately 70% to 86%. Generally speaking, results were very similar across all species at the two different concentrations tested.

Claims

1. A compound having formula (I): in: Z is tetrazole or COOQ, preferably Z is COOQ; Q is H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably m is 4; R is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; W chooses free-NR 2 -(C=O), -NR 2 -(C=S),-(C=O)-NR 2 -and-(C=S)-NR 2 - Preferably, W is -(C=O)-NR 2 -; R 2 is H or C1-C4 alkyl, preferably R 2 It is H; Ch is a chelating agent optionally comprising a metal or radiometal; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 having formula (I), wherein the compound is a compound having formula (Ia), (Ib), (Ic) or (Id):

3. The compound of formula (I) according to claim 1 or 2, wherein R is selected from the group consisting of aryl substituted by one or more halogens, pyridine substituted by one or more halogens, and unsubstituted isoquinoline.

4. The compound of formula (I) according to claims 1 to 3, wherein R is selected from the group consisting of: wherein X is independently Br or I.

5. A compound of formula (I) according to any one of claims 1 to 4, wherein R is 6. The compound of formula (I) according to any one of claims 1 to 5, wherein Ch is selected from the group consisting of: and optionally contains a metal or a radioactive metal.

7. The compound of formula (I) according to any one of claims 1 to 6, wherein Ch comprises a metal selected from the group consisting of Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc.

8. The compound of formula (I) according to claim 7, wherein the metal is selected from 68 Ga, 64 Cu, 86 Y. 90 Y. 89 Zr, 111 In, 99m Tc, 177 Lu, 153 Sm, 186 Re、 188 Re、 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc and 166 Ho is a radioactive metal.

9. The compound of formula (I) according to any one of claims 1 to 8, wherein the compound is distributed in a tumor-bearing animal or human such that one hour after intravenous injection of the compound, the tumor to kidney ratio is at least 5.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein the compound is a compound of formula (II):

11. The compound of formula (I) according to any one of claims 1 to 10, wherein the compound is a compound of formula (III):

12. The compound of formula (I) according to any one of claims 1 to 10, wherein the compound is a compound of formula (IV):

13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9, a compound of formula (II) according to claim 10, a compound of formula (III) according to claim 11 or a compound of formula (IV) according to claim 12, and at least one pharmaceutically acceptable carrier.

14. A compound of formula (I) according to any one of claims 1 to 9, a compound of formula (II) according to claim 10, a compound of formula (III) according to claim 11 or a compound of formula (IV) according to claim 12 for use as a medicament.

15. The compound for use according to claim 14, for use in the treatment of cancer.

16. A compound for use according to claim 14 or 15 for use in the treatment of prostate cancer.

17. A compound of formula (I) according to any one of claims 1 to 9, a compound of formula (II) according to claim 10, a compound of formula (III) according to claim 11 or a compound of formula (IV) according to claim 12 for use in imaging.

18. A compound of formula (I) according to any one of claims 1 to 9, a compound of formula (II) according to claim 10, a compound of formula (III) according to claim 11 or a compound of formula (IV) according to claim 12 for use in diagnosis, typically for use in the diagnosis of cancer disorders, such as PSMA-expressing cancers.

19. A method of treating cancer, comprising contacting cancer cells with a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 9, a compound of formula (II) according to claim 10, a compound of formula (III) according to claim 11, or a compound of formula (IV) according to claim 12.

20. A method of imaging comprising contacting cancer cells with an effective amount of a compound of formula (I) according to any one of claims 1 to 9, a compound of formula (II) according to claim 10, a compound of formula (III) according to claim 11, or a compound of formula (IV) according to claim 12.

21. A method for diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells in a subject, the method comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 9, a compound of formula (II) according to claim 10, a compound of formula (III) according to claim 11 or a compound of formula (IV) according to claim 12, and detecting a signal derived from the decay of a radioactive metal present in the compound.

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