Prostate-specific membrane antigen (PSMA) ligand and use thereof

Abstract

To provide a prostate-specific membrane antigen (PSMA) ligand.SOLUTION: The present disclosure provides a PSMA ligand having a glutamic acid-urea-lysin (GUL) part, and a chelate agent capable of including radioactive metal. The present disclosure also provides use of a compound in diagnostic imaging and a compound in medical treatments for prostate cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to prostate-specific membrane antigen (PSMA) ligands. In particular, the present disclosure relates to ligands for glutamic acid. It has a guanine-urea-lysine (GUL) moiety and a chelating agent that can contain a radioactive metal. Regarding PSMA ligands.

[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, especially metastatic prostate cancer. Cancer (mCRPC) is associated with poor prognosis and reduced quality of life.

[0004] Recently, PSMA has been shown to be overexpressed in primary cancer lesions and soft tissue / bone metastatic disease. Therefore, it is believed to be an appropriate target for imaging diagnosis and therapy, and therefore, it is expected to be useful in treating prostate cancer. A new development trend for this purpose is represented by PSMA ligand-based internal radiotherapy. PSMA expression is also associated with the most aggressive, castration-resistant variants of the disease. is likely to be higher, which is likely due to the high unmet medical need of the patient population. (Marchal et al., Histol Histopathol, 2012) 004,Jul;19(3):715-8;Mease et al.,Curr To p 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 widespread. These agents are being studied extensively in clinical evaluation for prostate cancer, as well as in PR. It has been shown to be suitable for RT therapy (Kiess et al., QJ Nucl Med Mol Imaging, 2015;59:241-68). Some have used glutamate-uric acid as a targeting scaffold. One class of molecules has a chelate-lysine (GUL) moiety between the chelator and the GUL moiety. This approach allowed the binding site to be expanded. The metal chelating site is maintained in the urea-binding site, while allowing urea to reach the binding site. Due to its demonstrated high uptake and retention, and rapid renal clearance, The strategy was successful in xenograft PSMA-positive tumors (Banerjee et al. l., J Med Chem, 2013;56:6108-21).

[0006] However, some of these compounds are still highly expressed in different organs, such as the kidney. It exhibits poor uptake and can induce toxicity in human patients. It is desirable to develop novel PSMA ligands with low uptake. 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, and 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 C1-C4 alkyl, preferably R 2 is H; Ch is a chelating agent optionally containing a metal or radioactive metal, and and its acceptable salts.

[0008] The linker between the glutamic acid-urea-lysine (GUL) moiety and the chelator Ch is Low uptake of radiolabeled molecules in different organs while having a favorable tumor:kidney ratio This low uptake is a significant advantage for these types of molecules. Furthermore, the high tumor:kidney ratios suggest that the tumor-to-kidney ratios are more sensitive to the effects of steroids than those used for diagnostic imaging. This suggests good visualization of the tumor when performed.

[0009] In a second aspect, the present disclosure provides a compound of formula (I) and at least one pharmaceutically acceptable salt thereof. and an 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 provides a compound of formula (I) for use in the treatment of cancer, particularly in the treatment of prostate cancer. The present invention relates to the compound

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

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

[0014] In a fourth aspect, the present disclosure provides a method for treating cancer cells by contacting a cancer cell with an effective amount of a compound of formula (I). The present invention also relates to a diagnostic imaging method, including: [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" in reference to a compound of formula (I) refers to a group that Selective deprotection with readily available reagents that do not attack the regenerating functional groups or other functional groups in the "Protecting groups" refers to chemical substituents that can be easily removed. Suitable protecting groups are known in the art. Suitable protecting groups are described, for example, by Wutz et al. (Greene's Proc. otective Groups in Organic Synthesis,Fou 3rd Edition, Wiley-Interscience, 2007) The protection of the carboxyl group described by Wutz et al. (pages 533-643) In certain embodiments, protecting groups for the It can be removed by treatment with

[0017] Representative examples of protecting groups include, but are not limited to, benzyl, p-methoxybenzyl (P MB), t-butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydropyranyl Drofuranil (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS ), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and tri A person skilled in the art would recognize that a protecting group is required. Recognize the appropriate situations in which the protective group is used and select the appropriate protecting group to be used in a particular environment. It will be possible.

[0018] As used herein, the term "aryl" refers to a heterocyclic group containing 6 to 10 ring atoms. and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 At least one ring is aromatic. The aromatic ring may optionally have one or more rings fused thereto. and two further rings (cycloalkyl, heterocyclyl or heterocyclic, as defined herein). Suitable aryl groups include benzopyranyl, benzodioxo phenyl, naphthyl and phenyl fused to heterocyclyl, such as phenyl, naphthyl and benzodioxanyl; An example is a phenyl ring.

[0019] As used herein, the terms "substituted aryl" and "substituted pyridine" refer to the groups defined above. Aryl or halogen as defined, -OR', -NR'R'', -SR', -SiR' R''R''', -OC(O)R', -C(O)R', -CO2R', -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)alkoxo, and fluoro(C1-C4) and one or more substituents selected from the group consisting of alkyl, aryl, arylsulfonic acid ... R' and R'' are substituted pyridines up to the total number of open valences on the structure. R''' and R'''' are hydrogen, alkyl, heteroalkyl, cycloalkyl, heteroalkyl, The compounds of the present disclosure may be independently selected from cycloalkyl, aryl, and heteroaryl. If the compound contains more than one R group, each R', R'', R' when more than one of these groups is present Similarly to the R'' and R'''' groups, for example, each of the R groups is independently selected.

[0020] As used herein, the term "alkyl" means any group by itself or as part of another substituent. As a moiety, it means a linear or branched alkyl functional group having 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, Examples include:

[0021] As used herein, the term "heteroalkyl" refers to a group of 1 to 6 carbon atoms and O, and 1 to 4 heteroatoms selected from the group consisting of N, Si, and S. means a branched alkyl functional group, the nitrogen and sulfur atoms of which may be optionally oxidized, and The heteroatoms O, N and S may optionally be quaternized. It may be located at any interior position of the alkyl 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" refers to a group having 3 to 6 carbon atoms. It means a saturated or unsaturated cyclic group. Suitable cycloalkyl groups include cyclopropyl, Examples include cyclobutyl, cyclopentyl and cyclohexyl.

[0023] As used herein, the term "halogen" includes fluoro (-F), chloro (-C It refers to a bromo (-1), bromo (-Br), or iodo (-I) group.

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

[0025] As used herein, the term "heteroaryl" refers to a heteroaryl containing 5 to 10 atoms. polyunsaturated having one or more aromatic rings fused together or covalently linked; means an aromatic ring structure, in which at least one ring is aromatic and at least one ring atom is The heteroatoms are selected from N, O and S. The nitrogen and sulfur heteroatoms are optionally The nitrogen heteroatom may be optionally quaternized and the ring may be oxidized. It may be fused to a chloroalkyl or heterocyclyl ring. Non-limiting examples of such heteroaryls include: Examples include: furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl. aryl, 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, benzimidazolyl benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnamoyl Examples include quinolinyl, quinazolinyl and quinoxalinyl.

[0026] As used herein, the term "heterocyclyl" or "heterocycloalkyl" means a saturated or unsaturated cyclic group having 5 to 10 ring atoms, and at least one ring atom is a heteroatom selected from N, O and S. The nitrogen and sulfur heteroatoms are optionally The nitrogen heteroatom may be optionally quaternized. Examples of heterocycles include, but are not limited to, However, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, Trihydrothienyl, piperazinyl, 1-azepanyl, imidazolinyl, 1,4-dioxinyl Sanil and others.

[0027] Various embodiments of the present disclosure are described herein. It will be appreciated that features of the invention may be combined with other specified features to provide further embodiments. Hello.

[0028] The present disclosure relates to compounds of formula (I), (II), (III) and (IV), their stereoisomers, Tautomers, enantiomers, diastereomers, racemates or mixtures thereof, and It includes hydrates, solvates or pharmaceutically acceptable salts.

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

[0030] "Pharmaceutically" or "pharmaceutically acceptable" means a substance that is suitable for administration to mammals, particularly humans. A molecular entity that does not elicit an adverse, allergic, or other harmful response when administered and compositions. A pharmaceutically acceptable carrier or excipient is a non-toxic solid, semi-solid, Or it means a liquid filler, diluent, encapsulating material or compounding aid of any kind.

[0031] As used herein, the term "subject" refers to an animal, preferably a mammal, more preferably a Or rather means 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, and 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 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 aryl substituted with one or more halogens, one or A compound selected from the group consisting of pyridines substituted with multiple halogens, and unsubstituted isoquinolines. do.

[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 a metal suitable for use in diagnostic imaging or therapy. The metals are selected from metals of the genus and radioactive metals.

[0040] According to one embodiment, Ch is Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb , Ac, Bi, Al, Ga, Re, Ho and Sc. , 68 Ga, 64 Cu, 86 Y, 90 Y, 89 Zr, 111 In, 99m Tc, 177 L u, 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 From Ho It can be the radioactive metal of choice.

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

[0042] Compounds of formula (I) exhibit tumor:kidney ratios of at least 1 hour after intravenous injection of the compound. 5 (average of at least N=4) in the body of tumor-bearing animals or humans. It can be done.

[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 a metal or is a 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 Lu-PSMA-R2. The compounds have the 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 compound of formula (IV) may be referred to as Ga-PSMA-R2. are represented by the formulae (IVa), (IVb), (IVc) and (IVd): [ka] This includes stereoisomers of:

[0051] Pharmaceutical Composition The present disclosure provides compounds of formula (I)-(IV) and at least one pharmaceutically acceptable carrier. and a pharmaceutical composition comprising the compound.

[0052] The form of the pharmaceutical composition, the route of administration, the dosage and the administration regimen will of course depend on the patient's condition being treated. The dosage will vary depending on the condition, 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] Pharmaceutical compositions include at least one compound according to the present disclosure in the form of an aqueous solution, e.g. It can be in an injectable form.

[0055] Preferably, the pharmaceutical composition is pharmaceutically acceptable for injectable formulations. These contain excipients, particularly isotonic, sterile, saline solution (monosodium phosphate or disodium phosphate, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride etc., or a mixture of such salts), or sterile water or saline, depending on the case, It may also be a dry, especially a lyophilized, composition from which an injectable solution may be constituted, if necessary.

[0056] Sterile injectable solutions may be prepared by adding, as appropriate, any of the other ingredients listed above, along with the required amount. The active compound is prepared by incorporating the required amount in an appropriate solvent, followed by filtered sterilization. Generally, the dispersion medium contains a base and other required ingredients from those listed above. Dispersions are prepared by incorporating the various sterilized active ingredients into the appropriate sterile vehicle. In the case of sterile powders for the preparation of injectable sterile solutions, the preferred preparation method is vacuum drying and and freeze-drying technology, which allows the powder of the active ingredient plus any desired additions from its previously sterile-filtered solution. Once formulated, solutions may be administered in a manner compatible with the dosage formulation and therapeutically effective. The formulations are administered in various dosage forms, such as the injectable solution types described above. It is easily administered in a dosage form.

[0057] For parenteral administration in an aqueous solution, for example, the solution may be diluted with sufficient saline or glucose. The diluent may be a suitably buffered, liquid diluent that has first been made isotonic with water. Certain aqueous solutions of are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Sterile aqueous media that can be used will be known to those of skill in the art in light of the present disclosure. For example, one dosage can be dissolved in 1 mL of isotonic NaCl solution and administered subcutaneously. It can be added to 1000 mL of infusion fluid or injected at the infusion presentation site (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. The person administering the drug will, in any event, determine the appropriate dose for the individual subject.

[0058] In certain embodiments, the pharmaceutical composition contains stabilizers against radiolysis, sequestering agents, The composition comprises one or more excipients selected from the group consisting of steroids, anti-inflammatory drugs ...

[0059] As used herein, a "radiolytic stabilizer" refers to an organic compound that is resistant to radiolysis. It means a stabilizer that protects molecules, for example, when gamma rays emitted from a radioactive nuclide are released from an organic molecule. When radicals are formed, they are then transferred to the stabilizers. and thereby remove unwanted, potentially ineffective, or toxic substances. This prevents the radicals from undergoing other chemical reactions that could result in molecules that are The stabilizers are also called "free radical scavengers" or simply "radical scavengers" Other alternative terms for these stabilizers are "radiation stability enhancers," "radiolytic stabilizers," "Stabilizers" or simply "quenchers."

[0060] As used herein, a "sequestering agent" refers to a compound that sequesteres free radionuclide metal ions in a formulation. (not complexed with radiolabeled peptide) ).

[0061] The dose used for administration is a function of various parameters of the pathology involved, in particular: It should be adapted as a function of the form of administration used, and in turn as a function of the desired duration of treatment. It is understood that the appropriate dosage of the compounds and compositions containing the compounds may vary from patient to patient. It will be understood that determining the optimal dosage will generally depend on the risk or deleterious effects of the treatments described herein. This requires balancing the level of therapeutic benefit against adverse side effects.

[0062] Compounds of formula (I) to (IV) for use as drugs The present disclosure also relates to compounds of formulas (I) to (IV) for use as medicaments. Compound (IV) exhibits useful pharmaceutical properties as shown in the tests provided in the Examples, however This is indicated for treatment.

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

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

[0065] As used herein, the term "cancer" has its general meaning in the art. The term includes an abnormal condition or symptom characterized by aggressive and rapidly proliferating cell proliferation. All types of cancer growth or oncogenic processes, regardless of histopathological type or stage Cancer is meant to include cancerous processes, metastatic tissues, or malignant cancerous cells, tissues, or organs. The term refers to malignant diseases of various organ systems, e.g., skin, lung, breast, thyroid, lymphatic system, stomach Diseases affecting the intestinal and genitourinary tract, as well as most colon cancers, renal cell carcinoma, prostate cancer and / or It includes adenocarcinomas, including malignancies such as testicular cancer, non-small cell carcinoma of the lung, small intestine cancer, and esophageal cancer.

[0066] Examples of cancer include, but are not limited to, hematological malignancies, such as B-cell lymphoid neoplasms, T-cell Alveolar lymphoid neoplasms, non-Hodgkin's lymphoma (NHL), B-NHL, T-NHL, chronic lymphoma Myeloid leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) Non-hematological cancers include lymphoid neoplasms, NK cell lymphoid neoplasms, and myeloid neoplasms. These include, but are not limited to, skin cancer, colon cancer, breast cancer, lung cancer, brain cancer, prostate cancer, head and neck cancer, pancreatic cancer, Visceral 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 with PSMA-expressing tumors or cells. .

[0068] In a specific embodiment, the present disclosure provides 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 relates to compounds of formula (I)-(IV) for use in treating PSMA-expressing tumors or cells. It also relates to things.

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

[0072] Thus, the present disclosure provides a method for treating cancer cells by contacting the cancer cells with a therapeutically effective amount of a compound of Formulas (I)-(IV). The present invention also relates to a method of treating cancer, comprising:

[0073] As used herein, the term "contact" refers to contacting a small amount of a substance with a therapeutic agent of the presently disclosed subject matter. bringing at least one compound into physical contact with at least one type of cancer cell, Contacting refers to the manipulation of at least one type of cell or tumor with at least one The method may include exposing the cell or tumor to a sufficient amount of the compound to allow contact of the compound with the cell or tumor. This method involves introducing a compound and cells or tumors in a controlled environment, such as a culture dish or tube. In vitro or ex vivo The method can be performed in vivo. In this case, contacting refers to contacting at least one compound of the presently disclosed subject matter in a subject. Exposing at least one type of cell or tumor, e.g., via any suitable route means administering a compound to a subject.

[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 provides a method of treating cancer, generally prostate cancer, in a subject in need thereof, preferably The present invention also relates to a method comprising administering to a subject, or a human, a therapeutically effective amount of a compound of formula (I)-(IV). do.

[0076] As used herein, the term "treating" refers to treating a disease, disorder, or To reverse, reduce, inhibit or prevent the progression of the condition to which such term applies or reducing the severity or severity of one or more symptoms of such disease, disorder or condition. Prevention includes the prevention, mitigation or inhibition of the onset or progression of a disease, disorder or condition. to prevent the symptoms or manifestations of such disease, disorder or condition from occurring or to prevent such It means preventing the severity of a disease, disorder, or condition from worsening. The compounds of the present invention are used to prophylactically prevent or reduce the onset or recurrence of a disease, disorder, or condition. can be administered to

[0077] As used herein, the term "therapeutically effective amount" of a compound refers to a therapeutically effective amount of a compound that is effective in treating a subject's biological or physiological condition. induces a medical response, e.g., relieves symptoms, alleviates the condition, slows or delays progression The term "amount of a compound that causes or prevents a disease" refers to the amount of a compound that causes or prevents a disease.

[0078] The present disclosure provides a method of treating a PSMA-expressing tumor or cell, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) ) to (IV) do.

[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 relates to a method for producing a medicament for the treatment of cancer, such as prostate cancer, comprising administering to a subject a compound of formula (I)-(IV) The present invention also relates to the use of the compounds.

[0081] The present disclosure provides a method for producing a medicament for treating a PSMA-expressing tumor or cell, comprising administering to a subject a compound of formula (I) ... The present invention also relates to the use of compounds of formula (IV).

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

[0083] The present disclosure provides compounds of formula (I) to (I) for use in diagnostic imaging of PSMA-expressing tumors or cells. V)

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

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

[0086] Thus, the present disclosure provides a method for treating cancer by contacting cancer cells with an effective amount of a compound of Formulas (I)-(IV). The present invention also relates to a diagnostic imaging method, comprising:

[0087] The present disclosure provides a method for treating a PSMA-expressing tumor or cell by contacting the tumor or cell with an effective amount of a compound of Formulas (I)-(IV). The present invention also relates to a method for imaging PSMA-expressing tumors or cells, comprising: The method further comprises detecting a signal derived from the decay of a radioactive metal present in said compound. The method may include the step of:

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

[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. A method of: (i) administering to said subject a compound of formula (I) to (IV), for example by intravenous infusion; process; (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 provides diagnostic methods for PSMA-expressing cancers, such as those typically used in the diagnosis of cancer diseases. It also relates to compounds of formulae (I) to (IV).

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

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

[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 reacts with cyanohydrin in methanol. Glu-Lys urea was synthesized by p-bromobenzaldehyde in the presence of sodium borohydride. 1 can be prepared by reductive alkylation. This procedure is described in the literature (Tyk vartetal.(2015)Journal of medicinal chem Then, an aliphatic linker, Bo c-6-aminohexanoic acid can be prepared by, for example, reacting a base (such as N,N-diisopropylethylamine) with ) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl) 1-[bis(dimethylamino)methylene]- 1H-1,2,3-Triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate) on the same ε-Lys amine of 2 to give compound 3. Compound 3 can then be deprotected using an acid such as trifluoroacetic acid to give Compound 4 can be obtained. Finally, conjugation with commercially available DOTA-NHS ester is carried out to give compound 4. Compound (II) can be obtained.

[0094] The compounds of formula (I) and (II) can be radiolabeled using methods commonly used in the field of radiolabeling. In particular, the method described in WO 2017 / 165473 can be used The compound of formula (II) can be prepared by the method described above. 177 Lu to form a compound of formula (III) Compounds can also be formed using the methods described in WO 024013. and a compound of formula (II) 68 It can also be radiolabeled with Ga to form a compound of formula (IV) This can be done.

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

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

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

[0098] Example 2: Biodistribution in tumor models ( 68 Studies performed on Ga-PSMA-R2 ) PC-3 PSMA-positive and PSMA-negative tumor xenograft-bearing males Approximately 4.5MBq of 68 Injection of Ga-PSMA-R2 followed by Biodistribution and imaging studies were evaluated at four time points (3 hr post injection (pi)). At 0 min, 1 h, 2 h, and 4 h, tumor and organ counts were measured using a gamma counter. To assess receptor specificity, additional groups of animals were injected with excess unlabeled P SMA-R2 (40 nmol) was co-injected. 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 Tumor uptake of Ga-PSMA-cpd2 , 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 G Compared with a-PSMA-cpd2, 68 It can be seen that the level is low in Ga-PSMA-R2. Furthermore, the tumor:kidney ratio was 68 High in the case of Ga-PSMA-R2.

[0103] From this, 68 Compared with Ga-PSMA-cpd2 68 Ga-PSMA-R2 poison Furthermore, the high tumor:kidney ratio at 1 hour indicates that optimal Because the time for imaging diagnosis is 45 minutes to 1 hour, 68 In the case of Ga-PSMA-R2, tumor This suggests that tumor visualization is better.

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

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

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

[0107] The absolute tumor volume results showed that, compared with the control group, 177 Lu-PSMA-R2 and 177 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 Lu -Tumor volumes from both PSMA-617 groups were significantly reduced compared to the control group It was found that the effect was significantly greater than that of the control group (p<0.001) (see Figure 5B).

[0109] The difference between the tumor volumes of the two treatment groups, when expressed as absolute or relative volume, was In Figure 5C-F, the two subgroups treated at 2-day intervals showed no significant difference. Absolute and relative tumor volumes are shown.

[0110] From these results, 177 Lu-PSMA-R2 inhibits PSMA-positive mice It can be seen that the present invention is effective in reducing the tumor size of ovarian tumors. 177 Lu-PSM A-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 evaluate the efficacy of intravenous administration in rats in general clinical trials according to the study design in Table 2. On the dynamic parameters at doses of 0.2, 0.6 and 2.0 mg / kg 175 Lu-P The aim was to evaluate the possible effects of SMA-R2.

[0112] [Table 2]

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

[0114] Irwin test at the following intervals after administration: 5, 15, 30 minutes, and 1, 2, and 24 hours was carried out.

[0115] at doses of 0.2, 0.6 and 2.0 mg / kg 175 A single injection of Lu-PSMA-R2 Intravenous administration did not significantly affect behavior, neurological, or neurological outcomes in rats in an Irwin study up to 24 hours after administration. did not induce any effects on autonomic parameters. No deaths occurred during the study. 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 evaluate the systemic toxicity of cyclosporine after intravenous administration according to the study design detailed in Table 3. plethysmography of the respiratory function of conscious rats 175 LuPSMA-R 2 The objective of this study was to evaluate the possible effects of 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, minutes Ventilation, respiratory rate, and improved resting were continuously recorded from approximately 1 hour before administration until 4 hours after administration. The respiratory rate and sex parameters of the rats were recorded before administration and at 5, 15 and 24 hours after administration. Clinical signs were reported on the day of administration. It was recorded.

[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 evaluate the efficacy and safety of 100 mg / kg i.v. After administration, the effect of benzodiazepine on telemetered cardiovascular function in conscious male minipigs was 175 Lu- The purpose of this study was to investigate the potential effects of PSMA-R2. The experimental design is shown in Table 4.

[0122] Test item or vehicle 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, subjects received either vehicle or test item at 7-day intervals. Each animal received one of three doses of fluticasone.

[0124] [Table 4]

[0125] From 1 hour before administration to 24 hours after administration, systolic blood pressure, diastolic blood pressure and mean blood pressure (SBP , DBP and MBP), heart rate (HR), body temperature and lead II electrocardiogram were continuously recorded. Hemodynamic and electrocardiogram data were collected before administration and at 5, 15, and 30 minutes, as well as at 1, 2, and 30 minutes after administration. Reported at 4, 8 and 24 hours.

[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 Lu- As a substitute for PSMA-R2, 175 Preclinical toxicology studies on Lu-PSMA-R2 went.

[0128] Test items 175 Lu-PSMA-R2 in acetate buffer 175 Lu-PSMA- A solution containing R2 and unlabeled PSMA-R2, with a nominal concentration of 1 mg of PSMA-R2. / mL, which exists partly in the free form (PSMA-R2) and partly in the Lu- 175 and some duplicates The ratio of the two is about 1:1. The dose is 175 Lu-labeled combination It is expressed as a total.

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

[0130] Single-dose toxicity study in rats The purpose of this study was to identify Sprague Dawley rats (S D) In ​​rats, immediately after acute intravenous infusion of 2 or 4 mg / kg 175 Lu-PSMA The objective of this study was to evaluate the toxicity of -R2.

[0131] Two groups of 30 animals (male:female ratio 1:1) 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). On the second day, 10 rats per sex and 10 rats per group were sacrificed. The remaining 5 animals / sex / group were observed daily for 14 days.

[0134] Treatment group assignment, body weights were recorded on days 1 (injection day), 8, and 15. was measured on day 2 and weekly thereafter. At the end of treatment, urine samples were collected for urinalysis. On days 2 and 15, blood samples taken at sacrifice were screened for clinical pathology. After dissection, 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 indicated that dose levels 2 and 4 mg / kg (human Assuming a body weight of 60 kg, this corresponds to approximately 480 mg / kg of the intended human dose. and 960 times) 175 A single intravenous administration of Lu-PSMA-R2 Therefore, no signs of toxicity were induced, suggesting that it was well tolerated in rats. can be.

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

[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 intake, clinical pathology, ophthalmoscopy, ECG evaluation, and The rats were then weighed and tissues were collected. Ta.

[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 showed that dose levels of 0.175, 0.583 and and 1.754 mg / kg (assuming a human body weight of 60 kg, on a mg / kg scale) , which are approximately 42, 140, and 420 times the intended human dose) 175 Lu - A single intravenous administration of PSMA-R2 did not induce any signs of toxicity in minipigs. Therefore, the test item was not found to be toxic to minipigs at these doses. It can be concluded that the drug is well tolerated.

[0143] Repeated-dose toxicity study in rats The purpose of this study was to evaluate the effects of treatment after daily intravenous administration and during a two-week recovery period. in rats after recovery from 175 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 is the PSM A-R2 are approximately 31, 93, and 310 times the predicted human dose.

[0145] Each main treatment group consisted of 10 male and 10 female rats. Group 1 and 4, which included five more males and five females to be sacrificed after two weeks of recovery. Two satellite groups for pharmacokinetics (low and mid dose) consisted of 9 male and 1 female animals. One group (high dose) contained 12 male and 12 female animals. One additional group (control) contained three male and three female animals. is.

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

[0147] [Table 7]

[0148] [Table 8]

[0149] In this study, doses of 0.13, 0.39, and 1.29 mg / kg / day were administered every 2 weeks. After intravenous administration, 175 Toxicity and toxicokinetic profile of Lu-PSMA-R2 The control and high-dose groups were given a 2-week treatment-free period. recovery from treatment-related effects observed during the 2-week dosing phase; or adverse effects persist.

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

[0151] Toxicokinetic evaluation demonstrated that all animals treated at the three dose levels were resistant to the test item. In general, the exposure was approximately dose-proportional. The drug was similar in both sexes and at all dose levels. The clearance was dose-independent, with a half-life of approximately 0.4 to 0.8 hours. No accumulation was observed after daily dosing from day 1 to day 14, suggesting linear kinetic behavior. It wasn't done.

[0152] Based on the results obtained in this study, the treated No toxic effects were observed in the mixed group. The date can be considered as the NOAEL (No Observed Adverse Effect Level), which is the expected This is 310 times higher than the human dose.

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

[0154] Repeated-dose toxicity study in minipigs The purpose of this study was to evaluate the effects of treatment after daily intravenous administration and during a two-week recovery period. To investigate the toxicity and toxicokinetics of LuPSMA-R2 in minipigs after recovery from use. And so it was.

[0155] The doses tested were 0.058, 0.175, and 0.583 mg / kg / day, which is a PS Approximately 14, 42, and 140 times the predicted human dose of MA-R2.

[0156] Each group contained 3 male and 3 female minipigs. Group 1 and 4 included two additional animals / sex to be sacrificed after two weeks of recovery. The results are 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 not affected by treatment. Physical examination performed revealed that all animals Treatment-related biochemical abnormalities were not observed by ophthalmoscopy and No electrocardiogram was detected. Clinical findings (i.e., hematology, coagulation, blood chemistry, and urine fraction) Histopathological analysis was performed based on gross pathology, terminal body weight, and absolute and relative organ weights. No significant or treatment-related changes were evident at any dose. It didn't work.

[0160] Toxicokinetic evaluation showed that all animals treated at the three dose levels were exposed to the test article. On the first day, an estimated 175 Lu-PSMA-R2 half-life by gender Considering the mean values ​​of 0.71 and 0.72 for male and female minipigs, respectively. These values ​​were confirmed on day 14. Plasma clearance was dose-independent. The increased systemic exposure (Cmax and AUC0-t The effect of daily dosing on days 1 through 14 was approximately dose-proportional. No subsequent associated accumulation was identified.

[0161] Based on the results of this study, 0.583 mg / kg / day was considered the NOAEL for this study. It shows what can be done.

[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 Salmonella typhimurium, as determined by reversion of an auxotrophic strain to a prototrophic strain. (Salmonella typhimurium) and Escherichia coli The test items were evaluated for their ability to induce gene mutations in test strains of M 175 Lu-labeled PSMA-R2 solutions were tested. Five test strains, TA1535, TA15 37, TA98, TA100, and WP2uvrA were used. Metabolic activity was measured using liver S9 fractions from rats pretreated with 5,6-benzoflavone. Experiments were performed both in the absence and presence of nitrite.

[0166] All tests in this report were carried out using test items as solutions in sodium acetate buffer. All concentrations are expressed in terms of active ingredient. 175 Lu-labeled PSMA-R2 solution The solution was tested in toxicity tests at the maximum feasible concentration of 1000 μg / plate and approximately half At four lower concentrations in logarithmic intervals: 316, 100, 31.6, and 10.0 μg / plate At the end of the incubation period, the test items were assayed for precipitation at all concentrations. Neither toxicity nor the associated increase in the number of revertants was observed in the absence or presence of S9 metabolism. In its presence, no adverse effects were observed in the test strains at any dose level.

[0167] Based on the results obtained in the preliminary toxicity studies, the plate incorporation method was used in the primary assay. The following dose levels were used: 1000, 500, 250, 125, and 62.5 μg / ml. Test items were assayed in all test lines at the same rate. Incubation period At the end of the experiment, no precipitation of the test items was observed at any concentration. No associated increase in strain numbers was observed at either dose level in the absence or presence of S9 metabolism. No further testing was undertaken due to the clear negative results. I didn't touch it.

[0168] Test items 175 Lu-labeled PSMA-R2 solution was found to be a potent inhibitor of S9 metabolism under the reported experimental conditions. In the presence or absence of Salmonella typhimurium Does not induce reverse mutations in Bacillus subtilis or Escherichia coli It can be concluded that:

[0169] In vitro stability in plasma Incubated with plasma from four different species (mouse, rat, minipig, and human) After in vitro infusion, the stability of the PSMA-R2 ligand was evaluated. The test was performed at 37°C in a matrix containing 10 μg / mL of ATP for 30, 60, and 120 minutes. The samples were analyzed by LC-MS / MS.

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

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

[0172] [Table 12]

[0173] From this result, 175 Lu-PSMA-R2 is non-highly bonded It was confirmed that the compound 175 Lu-labeled or unlabeled PSMA The unbound fraction of -R2 ranges from approximately 25% to 45%. The results for minipig plasma are in the same range. Mouse plasma exhibits lower protein binding compared to other species. In general, in all species tested, the unbound fraction ranged from 70 to 86%. The results at the two different concentrations tested are quite similar.

Claims

1. Formula (I): 【Chemistry 1】 wherein Z is COOQ; Q is H; m is 4; R is 【Chemistry 2】 and W is -(C=O)-NR ２ - and; R ２ is H; Ch is any of the following, optionally including metals or radioactive metals: 【Transformation 3】 and a chelating agent selected from the group consisting of or a pharmaceutically acceptable salt thereof.

2. Formula (Ia), (Ib), (Ic) or (Id): 【Chemistry 4】 2. The compound of formula (I) according to claim 1, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

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

4. The compound of formula (I) of claim 3, or a pharmaceutically acceptable salt thereof, wherein the metal is a radioactive metal selected from 68Ga, 64Cu, 86Y, 90Y, 89Zr, 111In, 99mTc, 177Lu, 153Sm, 186Re, 188Re, 67Cu, 212Pb, 225Ac, 213Bi, 212Bi, 212Pb, 67Ga, 203Pb, 47Sc, and 166Ho.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is 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.

6. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

7. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use as a drug.

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

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 (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in diagnostic imaging.

11. A compound of formula (I) according to any one of claims 1 to 4, 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 (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer, comprising contacting a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, with cancer cells.

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