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 glutamic acid-urea-lysine (GUL) moiety and a chelator that may include a radiometal. The present disclosure also relates to the use of these compounds in diagnostic imaging and in the treatment of prostate cancer.

Description

[Technical Field]

[0001] The present disclosure relates to prostate-specific membrane antigen (PSMA) ligands. In particular, the present disclosure relates to PSMA ligands having a glutamic acid-urea-lysine (GUL) moiety and a chelator that may include a radiometal.

[0002] The present disclosure also relates to the use of these compounds in the imaging and treatment of prostate cancer. [Background technology]

[0003] Prostate cancer is one of the most common cancers in the United States and Europe. In particular, metastatic prostate cancer (mCRPC) is associated with poor prognosis and reduced quality of life.

[0004] In recent years, a new trend in the development of PSMA ligand-based internal radiotherapy for treating prostate cancer has emerged, as PSMA is overexpressed in primary cancer lesions and soft tissue / bone metastatic disease, making it a suitable target for diagnostic imaging and therapy. Furthermore, PSMA expression appears to be higher in the most aggressive, castration-resistant variants of the disease, representing a patient population with high unmet medical need (Marchal et al., Histol Histopathol, 2004, Jul;19(3):715-8; Mease et al., Curr Top Med Chem, 2013, 13(8):951-62).

[0005] Among the many small molecule ligands targeting PSMA, urea-based low-molecular-weight agents are the most extensively studied. These agents have been shown to be suitable for clinical evaluation in prostate cancer and PRRT therapy (Kiess et al., QJ Nucl Med Mol Imaging, 2015;59:241-68). Some of these agents have a glutamic acid-urea-lysine (GUL) targeting scaffold. One class of molecules was created using a strategy of attaching a linker between the chelator and the GUL moiety. This approach allows urea to reach the binding site while maintaining the metal chelating site outside the binding site. Due to its demonstrated high uptake and retention and rapid renal clearance, this strategy was successful in PSMA-positive tumor xenografts (Banerjee et al., J Med Chem, 2013;56:6108-21).

[0006] However, some of these compounds still exhibit high uptake in different organs, such as the kidney, and may induce toxicity in human patients. Therefore, it is desirable to develop novel PSMA ligands with low uptake in different organs. Summary of the Invention [Means for solving the problem]

[0007] In a first embodiment, a compound of formula (I): [ka] (Wherein 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 is -NR2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 - and -(C=S)-NR 2 -, preferably W is selected from the group consisting of -(C=O)-NR 2 - and; R 2 is H or C1-C4 alkyl, preferably R 2 is H; Ch is a chelating agent optionally containing a metal or radiometal), and pharmaceutically acceptable salts thereof.

[0008] The linker between the glutamic acid-urea-lysine (GUL) moiety and the chelator Ch contains a C5 alkyl chain, which allows for low uptake of the radiolabeled molecule in different organs while maintaining a favorable tumor:kidney ratio. This low uptake indicates reduced toxicity in human patients for these types of molecules. Furthermore, a high tumor:kidney ratio suggests good visualization of the tumor when used for diagnostic imaging.

[0009] In a second aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier.

[0010] In a third aspect, the present disclosure relates to compounds of formula (I) for use as a medicament.

[0011] In a fourth aspect, the present disclosure relates to compounds of formula (I) for use in the treatment of cancer, particularly in the treatment of prostate cancer.

[0012] In a fifth aspect, the present disclosure relates to compounds of formula (I) for use in diagnostic imaging.

[0013] In a sixth aspect, the present disclosure also relates to a method of treating prostate cancer, comprising contacting cancer cells with an effective amount of a compound of formula (I).

[0014] In a fourth aspect, the present disclosure also relates to a method of diagnostic imaging comprising contacting cancer cells with an effective amount of a compound of formula (I). [Brief explanation of the drawings]

[0015] [Figure 1] 1 shows the biodistribution (mean ± SD) of 68Ga-PSMA-R2 in healthy CD-1 mice according to Example 1. [Figure 2] 1 shows the biodistribution (mean±SD) of 68Ga-PSMA-R2 in healthy CD-1 mice (bladder and kidney) according to Example 1. [Figure 3] 6 shows the biodistribution (mean±SD) of 68Ga-PSMA-R2 in athymic nude mice bearing PSMA-positive tumors (PIP) and negative (Flu) according to Example 2. [Figure 4] 6 shows the biodistribution (mean±SD) of 68Ga-PSMA-cpd2 in athymic nude mice bearing PSMA-positive tumors (PIP) and negative (Flu) according to Example 2. [Figure 5] 1 shows an efficacy study of 177Lu-PSMA-R2 and 177Lu-PSMA-617 in athymic nude mice bearing PSMA-positive tumors (PIP) according to Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition As used herein, the term "protecting group" with respect to compounds 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 protecting groups are known in the art and continue to be developed. Suitable protecting groups are described, for example, in Wutz et al. (Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley-Interscience, 2007). Protecting groups for the protection of carboxyl groups described by Wutz et al. (pages 533-643) are used in certain embodiments. In some embodiments, the protecting group is removable by treatment with acid.

[0017] Representative examples of protecting groups include, but are not limited to, benzyl, p-methoxybenzyl (PMB), t-butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr). One of ordinary skill in the art will recognize appropriate situations in which such protecting groups are required and will be able to select the appropriate protecting group for use in a particular environment.

[0018] As used herein, the term "aryl" refers to a polyunsaturated, aromatic hydrocarbyl group having one or more aromatic rings fused together, containing 6 to 10 ring atoms, wherein at least one ring is aromatic. The aromatic ring may optionally contain one to two additional rings (cycloalkyl, heterocyclyl, or heteroaryl, as defined herein) fused thereto. Suitable aryl groups include phenyl, naphthyl, and phenyl rings fused to a heterocyclyl, such as benzopyranyl, benzodioxolyl, and benzodioxanyl.

[0019] As used herein, the terms "substituted aryl" and "substituted pyridine" refer to aryl as defined above, or halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -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) means pyridine substituted with one or more substituents selected from the group consisting of R', -S(O)NR'R'', -NRSOR', -CN, -NO, -R', -N, -CH(Ph), fluoro(C1-C4)alkoxo, and fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring structure, where 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 includes multiple R groups, for example, each of the R groups is independently selected, as are each R', R'', R''', and R'''' groups when multiples of these groups are present.

[0020] As used herein, the term "alkyl," by itself or as part of another substituent, means a straight or branched chain alkyl functional group having from 1 to 6 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl).

[0021] As used herein, the term "heteroalkyl" refers to a straight-chain or branched alkyl functional group having from 1 to 6 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, and S may be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.

[0022] As used herein, the term "cycloalkyl" means a saturated or unsaturated cyclic group having 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0023] As used herein, the term "halogen" means a fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I) group.

[0024] As used herein, the term "alkoxy" refers to an -O-alkyl group, where the alkyl group is C1-C6 alkyl, as defined herein. Suitable alkoxy groups include methoxy, ethoxy, and propoxy.

[0025] As used herein, the term "heteroaryl" means a polyunsaturated, aromatic ring system having a single ring or multiple aromatic rings fused together or covalently linked, 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 heteroaryls include: furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl.

[0026] 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 optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples of heterocycles include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1-azepanyl, imidazolinyl, 1,4-dioxanyl, and the like.

[0027] Various embodiments of the present disclosure are described herein, and it will be recognized that the specified features of each embodiment may be combined with other specified features to provide further embodiments.

[0028] The present disclosure encompasses compounds of formula (I), (II), (III) and (IV), their stereoisomers, tautomers, enantiomers, diastereomers, racemates or mixtures thereof, as well as hydrates, solvates or pharmaceutically acceptable salts thereof.

[0029] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure, and which are not typically biologically or otherwise undesirable.

[0030] "Pharmaceutically" or "pharmaceutically acceptable" means molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered appropriately to a mammal, especially a human. A pharmaceutically acceptable carrier or excipient means a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.

[0031] As used herein, the term "subject" means an animal, preferably a mammal, and more preferably a human.

[0032] Compounds of formula (I) In a first aspect, the present disclosure provides a compound of formula (I): [ka] (Wherein Z is tetrazole or COOQ, preferably 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 is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 - and -(C=S)-NR 2 -, preferably W is selected from the group consisting of -(C=O)-NR2 - and; R 2 is H or C1-C4 alkyl, preferably R 2 is H; Ch is a chelating agent optionally containing a metal or radioactive metal and pharmaceutically acceptable salts thereof.

[0033] Compounds of formula (I) include those of formula (Ia), (Ib), (Ic) and (Id): [ka] Examples of the stereoisomer include:

[0034] According to one embodiment, R is selected from the group consisting of aryl substituted with one or more halogens, pyridine substituted with one or more halogens, and unsubstituted isoquinoline.

[0035] According to one specific embodiment, R is [ka] wherein X is independently Br or I. is selected from the group consisting of:

[0036] Advantageously, R is [ka] is.

[0037] Ch is [ka] and optionally including a metal or radioactive metal.

[0038] According to one specific embodiment, Ch is [ka] and optionally containing a metal or radioactive metal.

[0039] The metal or radiometal is preferably selected from metals and radiometals suitable for use in diagnostic imaging or therapy.

[0040] According to one embodiment, Ch comprises a metal selected from Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc, the metal being: 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 The radioactive metal may be selected from Ho.

[0041] Advantageously, Ch is a radioactive metal 68 Ga or 177 Lu or 225 Contains Ac.

[0042] A compound of formula (I) may be distributed in the body of a tumor-bearing animal or human such that one hour after intravenous injection of the compound, the tumor:kidney ratio is at least 5 (average value of at least N=4).

[0043] According to one embodiment, W is —(C═O)—NR 2 - and Ch is [ka] and optionally containing a metal or radioactive metal.

[0044] According to one embodiment, m is 4, Z is COOQ, and Q is H.

[0045] According to a specific embodiment, the compound of formula (I) has formula (II): [ka] is a compound of

[0046] The compound of formula (II) may be referred to as PSMA-R2. The compound of formula (II) may be coupled to a metal or radioactive metal, preferably 68 Ga or 177 It may contain Lu.

[0047] According to one embodiment, the compound of formula (I) has formula (III): [ka] is a compound of

[0048] The compound of formula (III) 177 Compounds of formula (III) may be referred to as Lu-PSMA-R2. Compounds of formula (IIIa), (IIIb), (IIIc), and (IIId): [ka] This includes stereoisomers of

[0049] According to another embodiment, the compound of formula (I) has formula (IV): [ka] is a compound of

[0050] The compound of formula (IV) 68 The compounds of formula (IV) may be referred to as Ga-PSMA-R2. Compounds of formula (IVa), (IVb), (IVc), and (IVd): [ka] This includes stereoisomers of

[0051] Pharmaceutical Composition The present disclosure also relates to pharmaceutical compositions comprising a compound of Formulas (I)-(IV) and at least one pharmaceutically acceptable carrier.

[0052] The form of the pharmaceutical composition, the route of administration, the dosage and the administration regimen will of course vary depending on the condition being treated, the severity of the disease, the age, weight and sex of the patient, etc.

[0053] The pharmaceutical compositions of the present disclosure may be formulated for intravenous, intramuscular, or subcutaneous administration.

[0054] The pharmaceutical composition may take the form of an aqueous solution, such as an injectable dosage form, comprising at least one compound according to the present disclosure.

[0055] Preferably, the pharmaceutical composition contains pharmaceutically acceptable excipients for injectable formulations, which may in particular be isotonic, sterile, saline solutions (monosodium phosphate or disodium phosphate, sodium, potassium, calcium or magnesium chloride, etc., or mixtures of such salts), or dry, in particular lyophilized compositions which, upon addition of sterile water or saline, constitute an injectable solution, depending on the case.

[0056] Sterile injectable solution is prepared by incorporating the active compound in the required amount in a suitable solvent together with some of the other ingredients listed above that are required, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other required ingredients from the ingredients listed above.For the preparation of sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains the powder of active ingredient plus the desired additional ingredients from its solution that has been previously sterilized and filtered.When formulated, the solution is administered in a manner compatible with the dosage formulation and in an amount that is therapeutically effective.The formulation can be easily administered in a variety of dosage forms, such as the above-mentioned type of injectable solution.

[0057] For parenteral administration in aqueous solution, the solution may be, for example, a suitably buffered liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, sterile aqueous media that can be used will be known to those skilled in the art in light of the present disclosure. For example, a dosage can be dissolved in 1 mL of isotonic NaCl solution and added to 1000 mL of subcutaneous infusion fluid or injected at the proposed injection site (see, e.g., Remington's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. In any event, the appropriate dose for the individual subject will be determined by the person administering the dosage.

[0058] In certain embodiments, the pharmaceutical composition comprises one or more excipients selected from stabilizers against radiolysis, sequestering agents, and mixtures thereof.

[0059] As used herein, "radiolytic stabilizer" refers to a stabilizer that protects organic molecules against radiolysis, e.g., when gamma rays emitted from a radionuclide cleave bonds between atoms of an organic molecule, forming radicals, which are then removed by the stabilizer, thereby preventing the radicals from undergoing other chemical reactions that could result in undesirable, potentially ineffective, or even toxic molecules. Thus, these stabilizers are also called "free radical scavengers" or, simply, "radical scavengers." Other alternative terms for these stabilizers are "radiostability enhancers," "radiolytic stabilizers," or simply "quenchers."

[0060] As used herein, "sequestering agent" means a chelating agent suitable for complexing free radionuclide metal ions in the formulation (not complexed with the radiolabeled peptide).

[0061] The dosage used for administration can be adapted as a function of various parameters of the relevant pathology, in particular as a function of the administration form used, and alternatively as a function of the intended duration of treatment. It will be understood that the appropriate dosage of the compounds and compositions containing the compounds may vary from patient to patient. Determining the optimal dosage generally requires balancing the level of therapeutic benefit against any risk or adverse side effects of the treatments described herein.

[0062] Compounds of formula (I) to (IV) for use as drugs The present disclosure also relates to compounds of formulas (I)-(IV) for use as medicaments. The compounds of formulas (I)-(IV) exhibit useful pharmaceutical properties as shown in the tests provided in the examples and are therefore indicated for therapy.

[0063] The present disclosure also relates to compounds of formulae (I)-(IV) for use in the treatment of cancer, particularly by targeted alpha therapy and by beta radiation.

[0064] The compounds of formula (III) are particularly suitable for use as drugs, preferably for use in the treatment of cancer.

[0065] As used herein, the term "cancer" has its common meaning in the art and includes an abnormal state or condition characterized by rapidly proliferating cell proliferation. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues, or malignant cancerous cells, tissues, or organs, regardless of invasive histopathological type or stage. The term cancer includes malignant diseases of various organ systems, such as diseases affecting the skin, lung, breast, thyroid, lymphatic system, gastrointestinal tract, and genitourinary tract, as well as adenocarcinomas, including most colon cancers, renal cell carcinoma, prostate cancer, and / or testicular tumors, non-small cell carcinoma of the lung, small intestine cancer, and esophageal cancer.

[0066] Examples of cancers include, but are not limited to, hematological malignancies such as B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, non-Hodgkin's lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasms, 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.

[0067] In a specific embodiment, the cancer is a cancer having PSMA-expressing tumors or cells.

[0068] In specific embodiments, the present disclosure also relates to compounds of Formulas (I)-(IV) for use in the treatment of prostate cancer.

[0069] In a specific embodiment, the prostate cancer is metastatic prostate cancer.

[0070] The present disclosure also relates to compounds of Formulas (I)-(IV) for use in treating PSMA-expressing tumors or cells.

[0071] The PSMA-expressing tumor or cell can be selected from the group consisting of prostate tumor or cells, metastatic prostate tumor or cells, lung tumor or cells, kidney tumor or cells, glioblastoma, pancreatic tumor or cells, bladder tumor or cells, sarcoma, melanoma, breast tumor or cells, colon tumor or cells, germ cell, pheochromocytoma, esophageal tumor or cells, gastric tumor or cells, and combinations thereof. In some other embodiments, the PSMA-expressing tumor or cell is a prostate tumor or cell.

[0072] Accordingly, the present disclosure also relates to a method of treating cancer, comprising contacting cancer cells with a therapeutically effective amount of a compound of Formulas (I)-(IV).

[0073] As used herein, the term "contacting" refers to any procedure that brings at least one compound, including a therapeutic agent of the presently disclosed subject matter, into physical contact with at least one cancer cell. Contacting can include exposing the cell or tumor to a compound in an amount sufficient to bring the at least one compound into contact with the at least one cell or tumor. This method can be performed in vitro or ex vivo by introducing, preferably mixing, the compound and the cell or tumor in a controlled environment, such as a culture dish or tube. This method can be performed 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 presently disclosed subject matter, for example, by administering the compound to the subject via any suitable route.

[0074] In certain embodiments, the cancer to be treated is a cancer having PSMA-expressing tumors or cells. For example, the cancer to be treated can be prostate cancer, including metastatic prostate cancer.

[0075] The present disclosure also relates to a method of treating cancer, generally prostate cancer, comprising administering to a subject, preferably a human, in need thereof a therapeutically effective amount of a compound of Formulas (I)-(IV).

[0076] As used herein, the term "treating" includes reversing, alleviating, inhibiting, or preventing or reducing the likelihood of progression of the disease, disorder, or condition to which such term applies, or reversing, alleviating, inhibiting one or more symptoms or manifestations of such disease, disorder, or condition. Prevention means preventing the occurrence of a disease, disorder, or condition, or a symptom or manifestation of such disease, disorder, or condition, or preventing the severity of such disease, disorder, or condition from worsening. Thus, the compounds of the present disclosure can be administered prophylactically to prevent or reduce the onset or recurrence of a disease, disorder, or condition.

[0077] As used herein, the term "therapeutically effective amount" of a compound means an amount of compound that elicits a biological or medical response in a subject, e.g., relieves symptoms, alleviates the condition, slows or delays the progression, or prevents the disease.

[0078] The present disclosure relates to a method of treating a PSMA-expressing tumor or cell, comprising contacting the PSMA-expressing tumor or cell with a therapeutically effective amount of a compound of Formulas (I)-(IV).

[0079] The present disclosure also relates to the use of the compounds of formulae (I) to (IV) for the manufacture of a medicament.

[0080] The present disclosure also relates to the use of compounds of Formulae (I)-(IV) for the manufacture of a medicament for the treatment of cancer, such as prostate cancer.

[0081] The present disclosure also relates to the use of compounds of Formulas (I)-(IV) for the manufacture of a medicament for the treatment of PSMA-expressing tumors or cells.

[0082] Compounds of formula (I) to (IV) for use in diagnostic imaging and methods thereof The present disclosure also relates to compounds of Formulas (I)-(IV) for use in diagnostic imaging, preferably in in vivo diagnostic imaging.

[0083] The present disclosure also relates to compounds of Formulas (I)-(IV) for use in diagnostic imaging of PSMA-expressing tumors or cells.

[0084] The compounds of formula (IV) are particularly suitable for use in diagnostic imaging, preferably for the diagnostic imaging of PSMA-expressing tumours or cells.

[0085] In a specific embodiment, the imaging method in which the compounds of Formulae (I)-(IV) are used is PET (positron emission tomography) or SPECT (single photon emission computed tomography).

[0086] Accordingly, the present disclosure also relates to a diagnostic imaging method comprising contacting cancer cells with an effective amount of a compound of Formulas (I)-(IV).

[0087] The present disclosure also relates to a method for imaging PSMA-expressing tumors or cells, comprising contacting the tumors or cells with an effective amount of a compound of Formulas (I)-(IV), which may further comprise detecting a signal derived from the decay of a radiometal present in the compound.

[0088] The present disclosure also relates to a method of imaging a PSMA-expressing tumor or cell in a subject, comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound of Formulas (I)-(IV) and detecting a signal derived from the decay of a radioactive metal present in the compound.

[0089] In a specific embodiment, the present disclosure provides a method for detecting the presence or absence of a PSMA-expressing tumor in a subject, comprising: (i) administering to said subject a compound of Formula (I)-(IV), for example by intravenous infusion; (ii) acquiring an image, typically by PET or SPECT imaging; and (iii) detecting the presence or absence of a PSMA-expressing tumor in said subject; The present invention provides a method comprising:

[0090] The present disclosure also relates to compounds of Formulas (I)-(IV) for use in diagnosis, typically for the diagnosis of cancer diseases, such as PSMA-expressing cancers.

[0091] The present disclosure also relates to a method of diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells, such as prostate tumors or cells, in a subject, comprising administering to said subject, preferably a human, a therapeutically effective amount of a compound of Formulas (I)-(IV) and detecting a signal derived from the decay of a radioactive metal present in said compound.

[0092] Synthesis of compounds of formulas (I) to (IV) Compounds of formula (I) and (II) can be synthesized using the methods disclosed in WO 2017 / 165473.

[0093] In particular, compounds of formula (II) can be synthesized as disclosed 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 the presence of sodium cyanoborohydride in methanol. This procedure has been described in the literature (Tykvartetal. (2015) Journal of medicinal chemistry 58, 4357-63). The aliphatic linker, Boc-6-aminohexanoic acid, can then be coupled onto 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 give compound 3. Compound 3 can then be deprotected using an acid such as trifluoroacetic acid to give compound 4. Finally, conjugation with commercially available DOTA-NHS ester can be carried out to give compound (II).

[0094] The compounds of formula (I) and (II) can be radiolabeled using methods commonly used in the field of radiolabeling. In particular, the compounds of formula (II) can be radiolabeled using the methods described in WO 2017 / 165473. 177 Compounds of formula (II) can also be radiolabeled with Lu to form compounds of formula (III). 68 It can also be radiolabeled with Ga to form compounds of formula (IV).

[0095] Scheme 1: Synthesis of compounds of formula (II) [ka] [Example]

[0096] Example 1: Biodistribution in healthy animals 68 (Study conducted on Ga-PSMA-R2) Biodistribution studies were performed in healthy CD-1 mice using Ga-labeled PSMA-R2 administered intravenously at doses of 120–150 μCi (4.44–5.55 MBq). At specific time points after intravenous injection, animals (3 or 4 / group) were sacrificed, and organs were collected, weighed, and evaluated in a gamma counter. Calculated ID% / g values ​​are reported in Figures 1 and 2.

[0097] in the kidneys and bladder 68 Ga-PSMA-R2 uptake indicated that the radiotracer was excreted through the renal system (Figure 2). The reported liver uptake was very low (0.74% at 30 min, decreasing to 0.21% at 4 h), indicating minimal excretion through the hepatobiliary system (Figure 1). At the earliest time point (30 min), slightly higher radiotracer uptake was recorded in the blood and other organs, such as the adrenal glands, lungs, and thyroid, but the ID% values ​​rapidly decreased at later time points (Figure 1). At all time points (including the earliest time point, 30 min), low radiotracer uptake was detected in the remaining organs (intestine, pancreas, muscle, and bone).

[0098] Example 2: Biodistribution in tumor models ( 68 (Study conducted on Ga-PSMA-R2) Approximately 4.5 MBq of IgG was administered to male athymic nude mice bearing PC-3 PSMA-positive and PSMA-negative tumor xenografts. 68 Ga-PSMA-R2 was injected into the mice and subsequently evaluated for biodistribution and imaging studies. Tumor and organ uptake was determined using a gamma counter at four time points (30 min, 1 h, 2 h, and 4 h) post-injection (pi). To assess receptor specificity, an additional group of animals was co-injected with excess unlabeled PSMA-R2 (40 nmol). The results are shown in Figure 3.

[0099] The same study, 68 Ga-PSMA-cpd2, the formula: [ka] The results are shown in Figure 4.

[0100] 68 Ga-PSMA-R2 and 68 For Ga-PSMA-cpd2, tumor uptake, kidney uptake, salivary gland uptake, and tumor:kidney ratio are summarized in Table 1.

[0101] [Table 1]

[0102] From these results, it can be seen that after 1 hour, the kidney uptake and salivary gland uptake of the comparative compound were 68 Compared with Ga-PSMA-cpd2, 68 The tumor:kidney ratio was low for Ga-PSMA-R2. 68 High in the case of Ga-PSMA-R2.

[0103] From this, 68 Compared with Ga-PSMA-cpd2 68This suggests that Ga-PSMA-R2 may have low toxicity. Furthermore, the high tumor:kidney ratio at 1 hour suggests that the optimal imaging time point is between 45 minutes and 1 hour. 68 This suggests that tumor visualization is superior with Ga-PSMA-R2.

[0104] Example 3: In vivo efficacy in mice in a PC3-PIP PSMA-positive model Lu-labeled PSMA-R2 was used to conduct efficacy studies in prostate cancer models.

[0105] PC3-PIP (PSMA positive) tumor-bearing mice were included as a reference compound. 177 Lu-PSMA-R2, 177 A single injection of 111 MBq of Lu-PSMA-617 or saline (control) was administered.

[0106] Tumor volumes are expressed as absolute values ​​(mm 3 ) or relative to the volume measured at the time of the first injection.

[0107] The absolute tumor volume results showed that, compared with the control group, 177 Lu-PSMA-R2 and 177 It can be seen that tumor volume was significantly reduced in the Lu-PSMA-617 group (p<0.001) (see Figure 5A).

[0108] Similarly, if the data are expressed as relative volumes, 177 LuPSMA-R2 group and 177 Tumor volumes from both Lu-PSMA-617 groups were found to be significantly reduced compared to the control group (p<0.001) (see Figure 5B).

[0109] No differences were observed between the tumor volumes of the two treatment groups when expressed as absolute or relative volumes. Figures 5C-F show the absolute and relative tumor volumes of the two subgroups treated 2 days apart.

[0110] From these results, 177 Lu-PSMA-R2 was found to be effective in reducing tumor size of PSMA-positive tumors in mice. 177 Lu-PSMA-R2 exhibits useful drug properties and can therefore be adapted for therapeutic use.

[0111] Example 4: Safety Pharmacology Effects on Irwin behavioral observation test and body temperature following a single intravenous administration in rats The purpose of this study was to determine the effect of doses of 0.2, 0.6, and 2.0 mg / kg on general behavioral parameters in rats after intravenous administration according to the study design in Table 2. 175 The objective of this study was to evaluate the possible effects of Lu-PSMA-R2.

[0112] [Table 2]

[0113] The following parameters were assessed: mortality, body weight, clinical signs and Irwin test.

[0114] Irwin tests were performed at the following intervals after administration: 5, 15, 30 minutes, and 1, 2 and 24 hours.

[0115] at doses of 0.2, 0.6 and 2.0 mg / kg 175 A single intravenous administration of Lu-PSMA-R2 did not induce any effects on behavioral, neurological, or autonomic parameters in an Irwin study in rats up to 24 hours after administration. No deaths occurred during the study, and no clinical signs were observed during the 6-day observation period.

[0116] The results of the study are summarized in Table 10.

[0117] Effects on respiration in unrestrained conscious rats after a single dose The purpose of this study was to assess the effects of whole-body plethysmography on respiratory function in conscious rats after intravenous administration, according to the study design detailed in Table 3. 175 The objective of this study was to evaluate the possible effects of LuPSMA-R2 0.2, 0.6, and 2.0 mg / kg.

[0118] [Table 3]

[0119] Inspiratory time, expiratory time, peak inspiratory flow, peak expiratory flow, tidal volume, pause time, minute ventilation, respiratory rate, and enhanced pause were continuously recorded from approximately 1 hour before dosing until 4 hours after dosing. Respiratory rate and sex parameters of the rats were reported before dosing and at 5, 15, and 30 minutes and 1, 1.5, 2, 3, and 4 hours after dosing. Clinical signs were recorded on the day of dosing.

[0120] The results of this study are summarized in Table 10.

[0121] Effects on cardiovascular function in conscious minipigs after intravenous administration The purpose of this study was to determine the effect of benzodiazepine on telemetered cardiovascular function in conscious male minipigs after intravenous administration of 0.058, 0.175, and 0.583 mg / kg. 175 The purpose of this study was to investigate the potential effects of Lu-PSMA-R2. The experimental design is shown in Table 4.

[0122] Test item or vehicle was administered intravenously into the external auricular vein at a fixed infusion rate of 4 mL / min. The dose was administered to each animal in a dosing volume of 1 mL / kg body weight.

[0123] Following the crossover design described in Table 4, each animal received one of three doses of vehicle or test item at 7-day intervals.

[0124] [Table 4]

[0125] Systolic, diastolic, and mean blood pressures (SBP, DBP, and MBP), heart rate (HR), body temperature, and lead II electrocardiogram were recorded continuously from 1 hour before dosing through 24 hours after dosing. Hemodynamic and electrocardiogram data were reported before dosing and at 5, 15, and 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing.

[0126] The results of this study are summarized in Table 10.

[0127] Single and repeated dose toxicity studies Single and repeat dose toxicity studies were performed with Lu-PSMA-R2 solution. 177 As a substitute for Lu-PSMA-R2, 175 Preclinical toxicity studies were conducted on Lu-PSMA-R2.

[0128] Test items 175 Lu-PSMA-R2 in acetate buffer 175 The solution contained Lu-PSMA-R2 and unlabeled PSMA-R2, with the PSMA-R2 at a nominal concentration of 1 mg / mL, which was partially present in the free form (PSMA-R2) and partially present in the Lu- 175 The ratio of the two is approximately 1:1. 175 Expressed as the sum of Lu-labeled forms.

[0129] Single-dose toxicity studies in rats and minipigs, and a 2-week repeated-dose toxicity study in rats were conducted.

[0130] Single-dose toxicity study in rats The purpose of this study was to determine the efficacy and safety of 2 or 4 mg / kg of cyclosporine in Sprague Dawley (SD) rats immediately after acute intravenous infusion. 175 The objective of this study was to evaluate the toxicity of Lu-PSMA-R2.

[0131] Two groups of 30 animals (1:1 male:female ratio) were administered 2 and 4 mg / kg, respectively. A control group of identical characteristics was treated with vehicle (Table 5).

[0132] [Table 5]

[0133] Signs of response to treatment at all doses were assessed at 30, 120, and 240 minutes (pi), and 24 hours later. On day 2, 10 rats / sex and 10 rats / group were sacrificed. The remaining 5 rats / sex / group were observed daily for 14 days.

[0134] Treatment group assignment, body weights were recorded on days 1 (injection day), 8, and 15. Food intake was measured on day 2 and weekly thereafter. At the end of treatment, urine samples were collected for urinalysis. Blood samples taken at sacrifice on days 2 and 15 were screened for clinical pathology. After necropsy, organs were weighed and tissues were processed for microscopic analysis (more than 50 different tissues were analyzed).

[0135] The results of the study are summarized in Table 10. The results show that the dose levels of the test item at 2 and 4 mg / kg (approximately 480 and 960 times the intended human dose on a mg / kg scale, assuming a human body weight of 60 kg) 175 A single intravenous administration of Lu-PSMA-R2 did not induce any signs of toxicity, suggesting that it was well tolerated in rats.

[0136] Single-dose toxicity study in minipigs According to the experimental design detailed in Table 6, after a single bolus i.v. 175 The toxicity and toxicokinetic profile of Lu-PSMA-R2 was investigated in Göttingen minipigs.

[0137] After administration, a 2-week treatment-free period was given.

[0138] All animals were dosed intravenously. Plasma samples were collected on day 1 for toxicokinetic analysis.

[0139] [Table 6]

[0140] Mortality, clinical signs, body weight, food consumption, clinical pathology, ophthalmoscopy, ECG evaluation, and gross observations were indexed at necropsy, after which selected organs were weighed and tissues were collected.

[0141] Additionally, plasma samples were collected on day 1 for toxicokinetic analysis.

[0142] The results of the study are summarized in Table 10. The results show that the dose levels of the test item at 0.175, 0.583, and 1.754 mg / kg (approximately 42,140 and 420 times the intended human dose on a mg / kg scale, assuming a human body weight of 60 kg) were 175 It is suggested that a single intravenous administration of Lu-PSMA-R2 did not induce any signs of toxicity in minipigs, and it can therefore be concluded that the test item is well tolerated by minipigs at these doses.

[0143] Repeated-dose toxicity study in rats The purpose of this study was to evaluate the efficacy and safety of benzodiazepine in rats after daily intravenous administration and after recovery from treatment-related effects during a two-week recovery period. 175 The objective of this study was to investigate the toxicity of Lu-PSMA-R2 (main group).

[0144] The doses tested were 0.13, 0.39, and 1.29 mg / kg / day, which are approximately 31, 93, and 310 times the predicted human dose of PSMA-R2.

[0145] Each main treatment group consisted of 10 male and 10 female rats. Five additional males and five additional females were included in groups 1 and 4 to be sacrificed after two weeks of recovery. Two satellite groups for pharmacokinetics (low and mid dose) had nine male and nine female animals, and one group (high dose) contained 12 male and 12 female animals. One additional group (control) contained three male and three female animals.

[0146] The experimental design is diagrammed in Tables 7 and 8.

[0147] [Table 7]

[0148] [Table 8]

[0149] In this study, after 2 weeks of daily intravenous administration at doses of 0.13, 0.39, and 1.29 mg / kg / day, 175 The toxicity and toxicokinetic profile of Lu-PSMA-R2 was investigated in SD rats. Control and high-dose groups were given a 2-week treatment-free period to allow for recovery from treatment-related effects or persistence of adverse effects identified during the 2-week dosing phase.

[0150] No signs of toxicological significance were recorded during daily clinical observations. Body weight and food consumption were unaffected by treatment. Ophthalmoscopic examination revealed no treatment-related abnormalities. Clinical pathology revealed no findings of toxicological relevance. Necropsy, organ weights, or histopathological examination revealed no evidence of treatment-related effects.

[0151] Toxicokinetic evaluation showed that all animals treated at three dose levels were exposed to the test item. In general, exposure was approximately dose-proportional. Exposure was similar in males and females. The drug was eliminated with a half-life of approximately 0.4 to 0.8 hours, considering both genders and all dose levels. Clearance was dose-independent, suggesting linear kinetic behavior. No accumulation was observed after daily dosing from Day 1 to Day 14.

[0152] Based on the results obtained in this study, no toxic effects were observed in the treated mixed group when 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 expected human dose.

[0153] The results of the study are summarized in Table 10.

[0154] Repeated-dose toxicity study in minipigs The objective of this study was to investigate the toxicity and toxicokinetics of LuPSMA-R2 in minipigs after daily intravenous administration and after recovery from treatment-related effects during a 2-week recovery period.

[0155] The doses tested were 0.058, 0.175, and 0.583 mg / kg / day, which are approximately 14, 42, and 140 times the predicted human dose of PSMA-R2.

[0156] Each group contained 3 male and 3 female minipigs. Groups 1 and 4 contained 2 additional animals / sex to be sacrificed after 2 weeks of recovery. The experimental design is summarized in Table 9.

[0157] All animals received the drug intravenously once daily for 14 consecutive days.

[0158] [Table 9]

[0159] Body weight and food intake were unaffected by treatment. Physical examinations performed revealed no overt changes in any of the animals. No treatment-related biochemical abnormalities were detected by ophthalmoscopy and electrocardiography. Clinical pathology (i.e., hematology, aggregation, blood chemistry, and urinalysis), as well as gross pathology, terminal body weight, and absolute and relative organ weights, revealed no significant or treatment-related changes at any dose, with no histopathology treatment-related changes.

[0160] Toxicokinetic evaluation showed that all animals treated at the three dose levels were exposed to the test item. 175 The half-lives of Lu-PSMA-R2 were 0.71 and 0.63 hours in male and female minipigs, respectively, considering the mean values ​​by sex. These values ​​were observed on day 14. Plasma clearance was dose-independent, suggesting linear kinetic behavior. The increase in systemic exposure (in terms of Cmax and AUC0-tlast) was approximately dose-proportional. No relevant accumulation was observed after daily dosing from day 1 to day 14.

[0161] The results of this study indicate that 0.583 mg / kg / day can be considered the NOAEL for this study.

[0162] The results of the safety pharmacology and toxicity studies are summarized in Table 10.

[0163] [Table 10]

[0164] [Table 11]

[0165] Genotoxicity studies: bacterial mutation assays Test items for their ability to induce gene mutations in test strains of Salmonella typhimurium and Escherichia coli, as measured by reversion of auxotrophic strains to prototrophic strains. 175 Lu-labeled PSMA-R2 solutions were examined. Five test strains, TA1535, TA1537, TA98, TA100, and WP2uvrA, were used. Experiments were performed in both the absence and presence of metabolic activation using liver S9 fractions from rats pretreated with phenobarbital and 5,6-benzoflavone.

[0166] Test items were used as solutions in sodium acetate buffer, and all concentrations in this report are expressed in terms of the active ingredient. 175 Lu-labeled PSMA-R2 solutions were assayed in toxicity studies at the maximum feasible concentration of 1000 μg / plate and at four lower concentrations at approximately half-log intervals: 316, 100, 31.6, and 10.0 μg / plate. At the end of the incubation period, no precipitation of the test item was observed at any concentration. Neither toxicity nor an associated increase in the number of revertants was observed in the test strains at any dose level, in the absence or presence of S9 metabolism.

[0167] Based on the results obtained in the preliminary toxicity studies, the test item was assayed in all test strains using the plate incorporation method in the main assay at the following dose levels: 1000, 500, 250, 125, and 62.5 μg / plate. At the end of the incubation period, no precipitation of the test item was observed at any concentration. Neither toxicity nor an associated increase in the number of revertants was observed in the test strains at any dose level in the absence or presence of S9 metabolism. Due to the clear negative results, further experiments were not undertaken.

[0168] Test items 175It is concluded that Lu-labeled PSMA-R2 solution does not induce reversion in Salmonella typhimurium or Escherichia coli in the presence or absence of S9 metabolism under the reported experimental conditions.

[0169] In vitro stability in plasma The stability of PSMA-R2 ligands 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 37°C for 30, 60, and 120 minutes at a final concentration of 10 μg / mL. Samples were analyzed by LC-MS / MS.

[0170] PSMA-R2 showed good stability in human plasma with 85% recovery after 2 hours.

[0171] Plasma protein binding studies After incubation of the compound in human, mouse, and rat plasma at two different concentrations: 1 and 5 μg / mL, PSMA-R2 and 175 Plasma protein binding of Lu-PSMA-R2 was determined by ultrafiltration, and the results (percentage of unbound fraction) are reported in Table 11.

[0172] [Table 12]

[0173] From this result, 175 Lu-PSMA-R2 was confirmed to be a non-highly binding compound, and 175The unbound fractions of Lu-labeled or unlabeled PSMA-R2 range from approximately 25% to 45%. Protein-binding results for rat plasma and minipig plasma are in the same range. Mouse exhibits lower protein binding compared to other species, with unbound fractions ranging from 70% to 86%. In general, results are quite similar across all species at the two different concentrations tested. The present invention includes the following aspects. [1] Formula (I): [ka] (Wherein 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 is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 - and -(C=S)-NR 2 -, preferably W is selected from the group consisting of -(C=O)-NR 2 - and; R 2 is H or C 1 ~C 4 alkyl, preferably R 2 is H; Ch is a chelating agent optionally containing a metal or radioactive metal and pharmaceutically acceptable salts thereof. [2] Formula (Ia), (Ib), (Ic) or (Id): [ka] The compound of formula (I) according to [1], [3] The compound of formula (I) according to [1] or [2], wherein R is selected from the group consisting of aryl substituted with one or more halogens, pyridine substituted with one or more halogens, and unsubstituted isoquinoline. [4] R,

change

change

change

[10] Formula (II):

change

[11] Formula (III):

change

[10] , wherein

[12] Formula (IV):

change

[10] , wherein

[13] A pharmaceutical composition comprising a compound of formula (I) according to any one of [1] to [9], a compound of formula (II) according to

[10] , a compound of formula (III) according to

[11] , or a compound of formula (IV) according to

[12] , and at least one pharmaceutically acceptable carrier.

[14] A compound of formula (I) according to any one of [1] to [9], a compound of formula (II) according to

[10] , a compound of formula (III) according to

[11] , or a compound of formula (IV) according to

[12] , which is used as a drug.

[15] The compound described in

[14] is used for the treatment of cancer.

[16] The compound according to

[14] or

[15] , which is used in the treatment of prostate cancer.

[17] A compound of formula (I) according to any one of [1] to [9], a compound of formula (II) according to

[10] , a compound of formula (III) according to

[11] , or a compound of formula (IV) according to

[12] , which is used in diagnostic imaging.

[18] In diagnosis, a compound of formula (I) according to any one of [1] to [9], a compound of formula (II) according to

[10] , a compound of formula (III) according to

[11] , or a compound of formula (IV) according to

[12] is used in the diagnosis of cancer diseases, such as PSMA-expressing cancers.

[19] A method for treating cancer, comprising contacting cancer cells with a therapeutically effective amount of a compound of formula (I) described in any one of [1] to [9], a compound of formula (II) described in

[10] , a compound of formula (III) described in

[11] , or a compound of formula (IV) described in

[12] .

[20] An imaging diagnostic method comprising contacting the cancer cells with an effective amount of a compound of formula (I) according to any one of [1] to [9], a compound of formula (II) according to

[10] , a compound of formula (III) according to

[11] , or a compound of formula (IV) according to

[12] .

[21] A method for diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells in a subject, comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound of formula (I) as defined in any of [1] to [9], a compound of formula (II) as defined in

[10] , a compound of formula (III) as defined in

[11] , or a compound of formula (IV) as defined in

[12] , and detecting a signal derived from the decay of a radioactive metal present in the compound.

Claims

1. Formula (II): 【Chemistry 1】 A compound of the formula: In formula (II), 【Chemistry 2】 Optionally, the chelating agent of claim 1 comprises a metal or a radioactive metal, or a compound, or a pharmaceutically acceptable salt thereof.

2. 2. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the chelating agent comprises a metal selected from Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc.

3. The metal is 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 3. The compound of formula (II) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the radioactive metal is selected from the group consisting of:

4. Formula (III): 【Transformation 3】 4. A compound of formula (II) according to any one of claims 1 to 3, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

5. Formula (IV): 【Chemistry 4】 4. A compound of formula (II) according to any one of claims 1 to 3, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of formula (II) as defined in any one of claims 1 to 3, a compound of formula (III) as defined in claim 4, or a compound of formula (IV) as defined in claim 5, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

7. A compound of formula (II) according to any one of claims 1 to 3, a compound of formula (III) according to claim 4, or a compound of formula (IV) according to claim 5, or a pharmaceutically acceptable salt thereof, for use as a drug.

8. 10. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

9. 9. A compound according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer.

10. A compound of formula (II) according to any one of claims 1 to 3, a compound of formula (III) according to claim 4, or a compound of formula (IV) according to claim 5, or a pharmaceutically acceptable salt thereof, for use in diagnostic imaging.

11. A compound of formula (II) as defined in any one of claims 1 to 3, a compound of formula (III) as defined in claim 4, or a compound of formula (IV) as defined in claim 5, or a pharmaceutically acceptable salt thereof, for use in diagnosis, typically in the diagnosis of cancer diseases such as PSMA-expressing cancers.

12. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 1 to 3, a compound of formula (III) according to claim 4, or a compound of formula (IV) according to claim 5, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for use in a method for treating cancer, comprising contacting cancer cells with a therapeutically effective amount of a compound of formula (II) as defined in any one of claims 1 to 3, a compound of formula (III) as defined in claim 4, or a compound of formula (IV) as defined in claim 5, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 1 to 3, a compound of formula (III) according to claim 4, or a compound of formula (IV) according to claim 5, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for use in an imaging diagnostic method, comprising contacting cancer cells with an effective amount of a compound of formula (II) according to any one of claims 1 to 3, a compound of formula (III) according to claim 4, or a compound of formula (IV) according to claim 5, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 1 to 3, a compound of formula (III) according to claim 4, or a compound of formula (IV) according to claim 5, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for use in 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 (II) as defined in any one of claims 1 to 3, a compound of formula (III) as defined in claim 4, or a compound of formula (IV) as defined in claim 5, or a pharmaceutically acceptable salt thereof, and detecting a signal derived from the decay of a radioactive metal present in the compound.

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