Prostate-specific membrane antigen (PSMA) ligands and uses thereof

Abstract

To provide prostate-specific membrane antigen (PSMA) ligands, and in particular, alternative multimodal PSMA ligands suitable for use as diagnostics and / or therapeutics.SOLUTION: The present disclosure provides PSMA ligands having: a glutamate-urea-lysine (GUL) moiety; a radioisotope; and a chelating agent that can comprise a radiometal.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. Glycothamate-urea-lysine (GUL) moiety, radioisotopes, and radiometals The present invention relates to a PSMA ligand having a chelator that can include a chelator (such as a chelate or chelator complex).

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

[0003] Theragnostics is a patient management strategy that involves the integration of diagnostic and therapeutic methods.

[0004] In the context of nuclear medicine, theragnostics involves the use of diagnostic radioactive metals (e.g., positrons or gamma emitters) or therapeutic radiometals (e.g., beta emitters). This refers to the use of specific target molecules for the diagnosis and therapy of specific diseases. The present invention provides a method for detecting a target molecule having high affinity for a receptor expressed on a tumor cell, the method comprising: Radiolabeling with gallium Ga-68 for therapeutic purposes or lutetium Lu-177 for therapeutic purposes Therefore, the same molecular target compounds can be used for molecular imaging and disease diagnosis. Individualized treatment using these materials can be effectively carried out.

[0005] This use of the same target compound also allows for a more thorough approach to patient management. This diagnostic method also has several simultaneous roles, using the same molecule labeled with radionuclides for diagnostics, reproduction, monitoring, and therapy. This is because it allows for the selection of a suitable therapy or a different treatment strategy, and post-treatment follow-up. do.

[0006] For patients, theragnostics results in more effective medical care and reduces unnecessary treatments. Reduce or eliminate medical treatment and tailor therapeutic interventions to patients who will benefit most. may not respond to unnecessary treatment or may otherwise have side effects. By predicting which patients will experience this, theragnostic approach can improve efficiency. It will be not only comprehensive but also patient-centered.

[0007] For physicians, theragnostics is the optimal therapy for diagnosing and staging disease. improve their ability to select treatment options and monitor treatment effectiveness and disease progression, It is possible to safely and effectively improve predictive ability so that the above outcomes are better. do.

[0008] For payers, theragnostic approaches are associated with suboptimal diagnostics and treatments. Reduce the costs associated with diagnosis and time required to diagnose, resulting in effective individualized treatment plans. This allows patients to be treated.

[0009] Prostate cancer is one of the most prevalent cancers in the United States and Europe. Metastatic CRPC (mCRPC) is associated with poor prognosis and reduced quality of life.

[0010] Recently, PSMA ligand-based endo-radiotherapy (endo-radiotherapy) has been rapy) is an example of a new trend in development for treating prostate cancer, and PSM A is overexpressed in primary cancer lesions and in soft tissue / bone metastatic disease, PSMA expression is considered a suitable target for diagnostic imaging and therapy. The incidence appears to be even higher in the most aggressive castration-resistant variants, which is represent a patient population with high unmet medical need (March al et al.,Histol Histopathol,2004,Jul;19 (3):715-8;Mease et al.,Curr Top Med Chem ,2013,13(8):951-62).

[0011] Among the many small molecule ligands targeting PSMA, urea-based low-dose agents These agents have been the most extensively investigated in prostate cancer clinical evaluations and PR studies. Some of these agents have been shown to be suitable for RT therapy. It has glutamate-urea-lysine (GUL).

[0012] Several radiolabeled small molecule inhibitors of PSMA have been designed based on this approach (K iess AP,Banerjee SR,Mease RC,et al.Prost ate-specific membrane antigen as a target t for cancer imaging and therapy.QJ Nuc l Med Mol Imaging.2015;59:241-268)

[0013] However, in certain circumstances, the use of diagnostic radiometals can be limited (6 (Problems with availability of 8Ga and scattered production).

[0014] On the other hand, 68Ga has a physical half-life of only 68 minutes. PSMA-PET scans are preferably performed in-house to ensure sufficient tracer activity. Delivery to remote centers is difficult. As a result, large centers with many patients The center requires multiple production runs per day or multiple production units to be built simultaneously. It would require the operation of a facility, which would increase costs. To overcome these limitations, the use of 18F-labeled PSMA tracers has been proposed. Good. PET radiopharmaceutical specialty pharmacy with on-site cyclotron macy) can produce highly radioactive 18F at an affordable cost. The physical half-life of the PSMA tracer (110 min) also allows for centralized production and remote satellite 18F also has a lower positron energy than 68Ga, which may allow delivery to light centers. It has a higher energy (0.65 vs. 1.90 MeV) and theoretically provides improved spatial resolution.

[0015] However, the development of alternative PSMA ligands is always desirable because of the need for diagnostic methods. and / or the development of alternative and diverse PSMA ligands suitable for use as therapeutics would be beneficial. Because it can become. Summary of the Invention

[0016] In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently 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; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C6~C 10 Consists of aryl and heteroaryl containing 5 to 10 ring atoms wherein said aryl and heteroaryl are substituted one or more times by X; X is -ZY; Z is a bond or C1-C6 alkylene, preferably Z is a bond; Y is a radioisotope; L is C1 to C6 alkylene, C3 to C6 cycloalkylene, and C6 to C 10 Arele a linker selected from the group consisting of alkylene, cycloalkylene, and Arylene includes -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2 R',-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''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR one or more substituents selected from "R", -NRSO2R', -CN, and -NO2 , optionally replaced by a number ranging from zero to (2m'+l), where m' is R', R'', R''', and R'''' are the total number of carbon atoms in the group. each independently represents hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl may refer to alkyl, aryl, and heteroaryl; 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)-N R 2 - and; Each occurrence of L and W can be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or radioactive metal. and pharmaceutically acceptable salts thereof.

[0017] The compounds of formula (I) are chelating agents that can contain radioisotopes and radiometals. The fact that the PSMA ligand may be labeled via a variety of modalities means that For example, the compounds of formula (I) can be used in imaging in nuclear medicine. Radioactive halogens and metals used for diagnostic or therapeutic purposes may be included.

[0018] In a second aspect, the present disclosure provides a compound of formula (I) and at least one pharmaceutically acceptable salt thereof The present invention relates to a pharmaceutical composition comprising a carrier.

[0019] In a third aspect, the disclosure relates to a compound of formula (I) for use as a medicament. do.

[0020] In a fourth aspect, the present disclosure provides a method for treating cancer, particularly prostate cancer, comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of: It relates to compounds of formula (I).

[0021] In a fifth aspect, the disclosure relates to a compound of formula (I) for use in diagnostic imaging. Regarding.

[0022] In a sixth aspect, the present disclosure also provides a method for treating prostate cancer, comprising administering to cancer cells with an effective amount of a compound of formula (I).

[0023] In a seventh aspect, the present disclosure also provides a method for diagnostic imaging, comprising: effectively detecting cancer cells; and contacting the compound of formula (I) with an amount of the compound of formula (I) and determining the decay of the radioisotope present in the compound. and detecting a signal resulting from the breakdown. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition As used herein, the term "protecting group" in reference to compounds of formula (I) means a protecting group that is Selected by readily available reagents that do not attack the resulting functional group or other functional groups in the molecule. Suitable protecting groups are known in the art and are not intended to be limiting unless otherwise specified. Suitable protecting groups are described, for example, in Wutz et al. Greene's Protective Groups in Organic Sy nthesis, Fourth Edition”, Wiley-Interscien ce, 2007). The protecting group for the carboxyl group is As described in Wutz et al. (pp. 533-643), In some embodiments, the protecting group is converted to a protecting group by treatment with acid. It can be removed by

[0025] Representative examples of protecting groups are benzyl, p-methoxybenzyl (PMB), tertiary butyl (t- Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl Tetrahydropyranyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), Benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (T ES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl Those skilled in the art will recognize the appropriate conditions under which protecting groups are required. and be able to select the appropriate protecting group for use in a particular situation. Deaf.

[0026] As used herein, the term "alkyl" refers to any group, either alone or as part of another substituent. As a moiety, it refers to a linear or branched alkyl functional group having 1 to 12 carbon atoms. The alkyl group is 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) Includes.

[0027] Alkylene refers to a divalent alkyl as defined above.

[0028] As used herein, the term "cycloalkyl" refers to a group having 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, ... Includes cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] Cycloalkylene refers to a divalent cycloalkyl as defined above.

[0030] As used herein, the term "aryl" refers to a group in which at least one ring is aromatic. A single ring or multiple aromatic rings fused together containing 6 to 10 ring atoms, which are of the aromatic ring group The aromatic ring may optionally have a ring fused thereto. 1 to 2 additional rings (cycloalkyl, heterocyclyl, as defined herein) Suitable aryl groups include benzopyranyl, benzyl, benzophenone ... Heterocyclyls, such as benzodioxolyl, benzodioxanil, and the like Examples include phenyl, naphthyl, and phenyl rings fused to a phenyl ring.

[0031] Arylene refers to a divalent aryl as defined above.

[0032] Alkyl, cycloalkyl, and aryl monovalent and divalent derivative groups include -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -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''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', - With one or more substituents selected from -CN and -NO2, the range is from zero to (2m'+l). and m' is the total number of carbon atoms in such a group. R', R'', R''', and R'''' are each independently hydrogen, alkyl, or , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl It may also refer to a rule.

[0033] As used herein, the term "halogen" includes fluoro (-F), chloro (-F), (-Cl), bromo (-Br), or iodo (-I) groups.

[0034] As used herein, the term "heteroalkyl" refers to a heteroalkyl group having 1 to 6 carbon atoms. and a straight chain having 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S. refers to a chain or branched alkyl functional group, wherein the nitrogen and sulfur atoms may optionally be oxidized; The nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be heteroatoms. Any interior position of the alkyl group or the position at which the alkyl group is attached to the remainder of the molecule may be placed in

[0035] As used herein, the term "heteroaryl" refers to a heterocyclic group, either a single ring or a ring containing two or more heterocyclic rings. Polycyclic aromatic compounds containing 5 to 10 atoms with multiple aromatic rings fused or covalently bonded refers to an unsaturated aromatic ring system in which at least one ring is aromatic and at least one ring is The atoms are heteroatoms selected from N, O, and S. The nitrogen and sulfur heteroatoms are It may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Such rings may be fused to an aryl, cycloalkyl, or heterocyclyl ring. Non-limiting examples of heteroaryls such as furanyl, thiophenyl, pyrrolyl, pyrazo aryl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl (oxatriazolyl), thiatriazolyl, Lysinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl , dioxinyl, thiazinyl, triazinyl Indolyl, indolyl, isoindolyl, benzofuranyl, isoben Zofranil, benzothiophenyl, isobenzothiophenyl phenyl), indazolyl, benzimidazolyl, benzoxazolyl, purinyl, Benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and and quinoxalinyl.

[0036] As used herein, the term "heterocycloalkyl" refers to a heterocyclic group having 5 to 10 alkyl groups. refers to a saturated or unsaturated cyclic group having ring atoms, at least one of which is selected from the group consisting of N, O, and The heteroatoms are selected from the group consisting of nitrogen, sulfur, and arsenic. The nitrogen and sulfur heteroatoms are optionally oxidized. The nitrogen heteroatom may be optionally quaternized. Examples of heterocycles are tetrahydrogen, tetrahydropyridyl, piperidinyl, morpholinyl, Tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1-azepanyl, imidazoline Including, but not limited to, zolinyl, 1,4-dioxanyl, and the like. stomach.

[0037] Various embodiments of the present disclosure are described herein. The features described may be combined with other specific features to provide further embodiments. will be recognized.

[0038] The present disclosure relates to compounds of formula (I), (II), (III), and (IV), their stereoisomers, isomers, tautomers, enantiomers, diastereomers, racemates, or mixtures thereof, and It also includes hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0039] The term "pharmaceutically acceptable salts" refers to compounds that retain the biological effectiveness and properties of the compounds of the present disclosure. and generally refers to salts that are not biologically or otherwise undesirable.

[0040] "Pharmaceutically" or "pharmaceutically acceptable" means a substance that is suitable for administration to a mammal, particularly a human. Molecular entities that do not cause adverse, allergic, or other untoward reactions when administered Pharmaceutically acceptable carriers or excipients refer to non-toxic solid, semi-solid or or a liquid filler, diluent, encapsulating agent, or formulation aid of any type.

[0041] As used herein, the term "subject" refers to an animal, preferably a mammal, more preferably a mammalian animal. Preferably, it refers to a human.

[0042] Compounds of formula (I) In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently 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; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C6~C 10Consists of aryl and heteroaryl containing 5 to 10 ring atoms wherein said aryl and heteroaryl are substituted one or more times by X; X is -ZY; Z is a bond or C1-C6 alkylene, preferably Z is a bond; Y is a radioisotope; L is C1 to C6 alkylene, C3 to C6 cycloalkylene, and C6 to C 10 Arele a linker selected from the group consisting of alkylene, cycloalkylene, and Arylene includes -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2 R',-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''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR one or more substituents selected from "R", -NRSO2R', -CN, and -NO2 , optionally replaced by a number ranging from zero to (2m'+l), where m' is R', R'', R''', and R'''' are the total number of carbon atoms in the group. each independently represents hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl may refer to alkyl, aryl, and heteroaryl; 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)-N R 2 - and; Each occurrence of L and W can be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or radioactive metal. and pharmaceutically acceptable salts thereof.

[0043] Compounds of formula (I) include those of formulas (Ia), (Ib), (Ic), and (Id): [ka] This includes stereoisomers of

[0044] The phrase "each occurrence of L and W can be the same or different" refers to the variable " When "n" is 2 or 3, one "L" group can be a C1-C6 alkylene. The other "L" group can be a C3-C6 cycloalkylene or arylene. In other embodiments, each "L" group may be, for example, a C1-C6 alkylene. Similarly, if "n" is 2 or 3, then one "W The group is —(C═O)—NR 2 - and the other "W" group can be -(C=S)- NR 2 - or in other embodiments, each "W" can be, for example, -(C=O )-NR 2 -It can be.

[0045] According to one embodiment, L is selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene, and and C6~C 10 arylene, wherein said alkylene, Cycloalkylene and arylene include -OR', ═O, ═NR', -NR'R'', - Halogen, -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', and one or more substituents selected from zero to (2 m' is the number of carbon atoms in such a group, is the total number of atoms. R', R'', R''', and R'''' are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0046] According to one embodiment, L is -OR', =O, =NR', -NR'R'', -halogen , -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', and one or more substituents selected from zero to (2m'+l ) C3-C6 alkylene optionally substituted with a number ranging from R', R are linkers formed by the reaction of R with m', and m' is the total number of carbon atoms in such a group. R''', R''', and R''', are each independently hydrogen, alkyl, heteroaryl, refers to alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl Good too.

[0047] Typically, the radioisotope Y is a radioactive halogen, 18 F, 34 Cl, 75 Br , 76Br, 77 Br, 123 I, 124 I, 125 I, 131 I, and 211 From At Preferably, Y is selected from the group consisting of: 18 F or 211 At.

[0048] According to one embodiment, R is selected from the group consisting of: [ka] p is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and preferably p is , 1; Preferably, R is [ka] is selected from More preferably, R is [ka] is.

[0049] Advantageously, R is [ka] is.

[0050] Ch is selected from the group consisting of: [ka] Optionally, it comprises a metal or a radioactive metal.

[0051] According to a particular embodiment, Ch is [ka] and optionally comprising a metal or a radioactive metal.

[0052] The metal or radiometal is preferably suitable for use in diagnostic imaging or in therapy. The metals are selected from radioactive metals and radioactive metals.

[0053] 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 Lu , 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 B i, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc, and 166 Select from Ho The radioactive metal may be selected from the group consisting of:

[0054] Advantageously, Ch is a radioactive metal 68 Ga or 177 Contains Lu.

[0055] According to one embodiment, W is —(C═O)—NR 2 - and Ch is [ka] and optionally comprising a metal or a radioactive metal.

[0056] According to one embodiment, m is 4, Z is COOQ, and Q is H.

[0057] According to one embodiment, R is [ka] and Ch is [ka] and optionally comprising a metal or a radioactive metal.

[0058] According to a particular embodiment, the compound of formula (I) has formula (II): [ka] and L is -OR', ═O, ═NR', -NR'R'', -halogen, -O C(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' with one or more substituents ranging from zero to (2m'+l) a alkylene group selected from the group consisting of C3 to C6 alkylene optionally substituted in a range of R', R'', R are the carbon atoms in the alkyl group, and m' is the total number of carbon atoms in such a group. R''' and R'''' are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, It may refer to cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0059] Advantageously, the compound of formula (II) is preferably 68 Ga, 67 Ga, 177 Lu, and 176The metal or radioactive metal is selected from Lu.

[0060] According to a particular embodiment, the compound of formula (II) is 68 Ga or 67 Contains Ga.

[0061] According to another particular embodiment, the compound of formula (II) is 177 Lu or 176 Contains Lu nothing.

[0062] According to certain embodiments, the compound of formula (I) has formula (III): [ka] and optionally containing a metal or a radioactive metal.

[0063] The compounds of formula (III) are represented by the formulae (IIIa), (IIIb), (IIIc), and (II Id): [ka] This includes stereoisomers of

[0064] Advantageously, the compound of formula (III) is preferably 68 Ga, 67 Ga, 177 Lu, and Beauty 176 Lu.

[0065] According to a particular embodiment, the compound of formula (III) is 68 Ga or 67 Contains Ga.

[0066] According to another particular embodiment, the compound of formula (III) is 177 Lu or 176 Lu include.

[0067] According to one embodiment, the compound of formula (I) has formula (IV): [ka] is a compound of

[0068] Compounds of formula (IV) include those of formulas (IVa), (IVb), (IVc), and (IVd): [ka] This includes stereoisomers of

[0069] According to another embodiment, the compound of formula (I) has formula (V): [ka] is a compound of

[0070] Compounds of formula (V) include those of formulas (Va), (Vb), (Vc), and (Vd): [ka] This includes stereoisomers of

[0071] Pharmaceutical Composition The present disclosure also provides a method for producing a compound of Formula (I)-(V) and at least one pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions comprising the carrier.

[0072] The pharmaceutical composition comprises i) a PSMA-binding ligand, ii) optionally a linker, and iii) It can further include a compound containing a chelating agent that optionally contains a metal or radiometal. .

[0073] According to one embodiment, the pharmaceutical composition further comprises a compound of formula (I') which is a compound of formula (I). and Y is a halogen and is not a radioisotope. The formula below: [ka] (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently 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; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C6~C 10 Consists of aryl and heteroaryl containing 5 to 10 ring atoms wherein said aryl and heteroaryl are substituted one or more times by X; X is -ZY; Z is a bond or C1-C6 alkylene, preferably Z is a bond; Y is a halogen; L is C1 to C6 alkylene, C3 to C6 cycloalkylene, and C6 to C 10 Arele a linker selected from the group consisting of alkylene, cycloalkylene, and Arylene includes -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2 R',-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''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR one or more substituents selected from "R", -NRSO2R', -CN, and -NO2 , optionally replaced by a number ranging from zero to (2m'+l), where m' is R', R'', R''', and R'''' are the total number of carbon atoms in the group. each independently represents hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl may refer to alkyl, aryl, and heteroaryl; 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)-N R 2 - and; Each occurrence of L and W can be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or radioactive metal. and pharmaceutically acceptable salts thereof.

[0074] The form of the pharmaceutical composition, the route of administration, the dosage and the regimen will, of course, depend on the condition to be treated, It depends on the severity of the disease, the patient's age, weight, and sex, etc.

[0075] The pharmaceutical compositions of the present disclosure are intended for intravenous, intramuscular, or subcutaneous administration and the like. It can be formulated.

[0076] Pharmaceutical compositions include aqueous solutions, e.g., injectable preparations, containing at least one compound according to the present disclosure. The composition may take the form of a pharmaceutical preparation.

[0077] Preferably, the pharmaceutical composition is a pharmaceutically acceptable carrier for an injectable formulation. These contain vehicles, particularly isotonic, sterile, saline solution (monosodium phosphate or or disodium, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride sodium, and other similar or mixtures of such salts) or, as the case may be, sterilized Drying, especially freeze-drying, which allows the preparation of an injectable solution upon addition of water or saline. It may also be a dry composition.

[0078] Sterile injectable solutions can be prepared by dissolving 1,2,4-trimethylbenzoic acid in an appropriate solvent with any other ingredients listed above. It is prepared by incorporating the active compound in the required amount, and then optionally sterilized. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a basic dispersion medium and the various sterilized active ingredients as enumerated above. by incorporating the compound into a sterile vehicle containing the required other ingredients from In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is The method comprises the step of: adding the active ingredient and any additional desired ingredients to a solution of the active ingredient in ... The vacuum drying and freeze drying techniques yield powders of the formula. They will be administered in a manner compatible with and in such amount as is therapeutically effective. It is easily administered in a variety of dosage forms, such as an injectable solution.

[0079] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered and contain a liquid diluent. The agent may first be made isotonic with sufficient saline or glucose. The solutions are particularly 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 is dissolved in 1 ml of isotonic NaCl solution and injected subcutaneously into 1000 ml of It may be added to the therapeutic fluid or injected into the intended site of injection (e.g. "Remington's Pharmaceutical Sciences" 15 th 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. It will be determined.

[0080] In certain embodiments, the pharmaceutical composition may contain stabilizers against radiolysis, buffers, and mixtures thereof.

[0081] As used herein, a "radiolytic stabilizer" refers to a compound that stabilizes, for example, a compound that stabilizes against radiation. Gamma rays emitted from radionuclides break the bonds between atoms in organic molecules, forming radicals. refers to stabilizers that protect organic molecules from radiolysis when they are used in a chemical reaction, and then Does the cal result in unwanted, potentially ineffective or even toxic molecules? The radicals are captured by stabilizers that prevent them from undergoing any other chemical reactions they might undergo. Therefore, these stabilizers are also called "free radical scavengers" or "free radical scavengers" for short. They are also called "radical scavengers." Another alternative term for these stabilizers is "radical scavengers." These are known as "radiolytic stabilizers," "radiolytic stabilizers," or simply "quenchers."

[0082] As used herein, a "metal ion sequestering agent" refers to a metal ion sequestering agent that sequesters free radionuclides in a formulation. This refers to a chelating agent suitable for complexing with specific metal ions (it does not complex with radiolabeled peptides).

[0083] Buffers include acetate buffers, citrate buffers, and phosphate buffers.

[0084] The dose used for administration will vary as a function of various parameters, in particular the dosage used. as a function of the mode, the pathology involved, or alternatively, the desired duration of treatment. The appropriate dosage of the compounds and compositions containing the compounds may vary from patient to patient. It will be appreciated that determining optimal dosages may be accomplished using the methods described herein. the level of therapeutic benefit relative to any risks or adverse side effects of the proposed treatment; The dosage level selected generally involves a balancing act. Route of administration, time of administration, rate of excretion of the compound, duration of treatment, and combinations used Other drugs, compounds, and / or materials, as well as the patient's age, sex, weight, condition, and health status This may depend on a variety of factors, including, but not limited to, the nature of the condition, and previous medical history.

[0085] Compounds of formula (I) to (V) for use as pharmaceuticals and methods thereof The present disclosure also relates to compounds of formulas (I)-(V) for use as pharmaceuticals. Compounds (I) to (V) are effective as shown in the tests provided in the Examples. They exhibit beneficial pharmaceutical properties and are therefore desirable for therapy.

[0086] The present disclosure also provides methods for treating cancer, particularly by targeted alpha therapy or by beta radiation. The present invention also relates to compounds of formulae (I)-(V) for use in treating atopic dermatitis.

[0087] The compounds of formula (IV) are particularly suitable for use as medicines, preferably for treating cancer. It is suitable for use in

[0088] As used herein, the term "cancer" refers to a cancer that is a common form of cancer in the art. An abnormal situation or condition characterized by significant and rapidly proliferating cell growth The term includes all types of tumors, regardless of histopathological type or stage of invasion. Cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or It is meant to include organs. The term cancer includes cancers of the skin, lung, breast, thyroid, lymphatic system, digestive Malignant tumors of various organ systems, including those affecting the colon, urinary tract, and genitourinary tract, as well as most colon Cancer, renal cell carcinoma, prostate and / or testicular cancer, non-small cell lung cancer, cancer of the small intestine, and cancer of the esophagus (o This includes adenocarcinomas, including malignant tumors such as cancer of the esophagus.

[0089] Examples of cancers include hematological malignancies such as B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, non-Hodgkin lymphomas, and leukemias. Kin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small Stromal lymphoma (SLL), mantle cell lymphoma (MCL), NK cell lymphoid neoplasia Examples of non-hematological cancers include, but are not limited to, cutaneous, myeloid lineage neoplasms. 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, Not limited to these.

[0090] In certain embodiments, the cancer is a cancer having PSMA-expressing tumors or cells.

[0091] In certain embodiments, the present disclosure also provides a compound of the formula ( It also relates to compounds I) to (V).

[0092] In certain embodiments, the prostate cancer is metastatic prostate cancer.

[0093] The present disclosure also provides methods of treating PSMA-expressing tumors or cells using methods of formula (I)-(III) V)

[0094] The PSMA-expressing tumor or cell may be selected from the group consisting of: prostate tumor or cells, metastatic prostate tumors or cells, lung tumors or cells, kidney tumors or cells, glioblastoma, pancreatic tumors or cells, bladder tumors or cells, sarcoma, melanoma, breast tumors or cells, colon tumors or cells, Germ cells, pheochromocytoma, esophageal tumors or cells, gastric tumors or cells, and combinations thereof. In some other embodiments, the PSMA-expressing tumor or cells are prostate tumors or cells.

[0095] Thus, the present disclosure also provides a method for treating cancer, comprising: treating cancer cells with a therapeutically effective The present invention also relates to a method of treating a cancer, comprising contacting a patient with an amount of a compound of Formula (I)-(V).

[0096] In certain embodiments, the cancer to be treated is a cancer having a PSMA-expressing tumor or cells. be.

[0097] The cancer to be treated is preferably prostate cancer, typically prostate cancer, including metastatic prostate cancer. It can be said that:

[0098] The present disclosure also provides a method for treating cancer in a subject in need thereof, comprising: administering to said subject, preferably a human subject, a therapeutically effective amount of a compound of formula (I)-(V). The present invention also relates to a method comprising:

[0099] As used herein, the term "contacting" refers to the treatment of the subject matter of the present disclosure. At least one compound containing a drug is brought into physical contact with at least one cancer cell. Contacting refers to any treatment that involves administering at least one of at least one compound to a subject. exposing the cell or tumor to the compound in an amount sufficient to result in contact with the cell or tumor; The method may include culturing the cells in a controlled environment, such as in a culture dish or tube. In vitro or in vitro assays are performed by introducing and preferably mixing the compound and cells or tumors into the The method can be performed ex vivo. The method can be performed in vivo. In this case, contacting may involve administering the compound to the subject via any suitable route. At least one compound of the presently disclosed subject matter is administered to a subject at least once a day, such as by administering to the subject a steroid hormone, ... or a steroid hormone. This means exposing a single cell or tumor to the compound. Typically, the compound is administered intravenously. It is administered as follows.

[0100] As used herein, the term "treating" refers to the treatment to which such term applies. a disease, disorder, or condition that is associated with a condition or one or more of such diseases, disorders, or conditions Reversing, alleviating, inhibiting or preventing the progression of symptoms or signs Preventing includes preventing or reducing the likelihood of a disease, disorder, condition, or other to prevent the occurrence of symptoms or signs of, or a worsening of the severity of, such Thus, the compounds of the present disclosure may be used to prevent the onset or recurrence of a disease, disorder, or condition. It can be administered prophylactically to prevent or reduce.

[0101] As used herein, the term "therapeutically effective amount" of a compound refers to a will induce a biological or medical response in the animal, e.g., ameliorate the symptoms, alleviate the condition, compounds that may reduce, slow or delay disease progression, or prevent disease Refers to the amount of

[0102] The present disclosure also provides a method for the manufacture of a medicament for the treatment of cancer, preferably prostate cancer, comprising administering to a subject a compound of formula (I): or a compound of formula (I) to (V) and at least one pharmaceutically acceptable salt thereof The present invention also relates to the use of pharmaceutical compositions comprising such carriers.

[0103] The present disclosure also provides a method for treating a PSMA-expressing tumor or cell, comprising administering to a subject a compound of formula (I) or a compound of formula (I) to (V) and at least one pharmaceutically acceptable salt thereof The present invention also relates to the use of pharmaceutical compositions comprising such carriers.

[0104] Compounds of formula (I)-(V) for use in diagnostic imaging and methods thereof The present disclosure also provides a method for the treatment of a pulmonary arthritis, comprising administering to a subject a subject having a pulmonary arthritis, the method ... The present invention also relates to compounds of formula (I) to (V).

[0105] The present disclosure also provides methods for treating a PSMA-expressing tumor or cell, such as a prostate tumor or cell, in a subject. Also relates to compounds of formulae (I)-(V) for use in diagnostic imaging.

[0106] The compounds of formula (V) are particularly suitable for use in diagnostic imaging, preferably for the treatment of PSMA-expressing tumors. Or it is suitable for use in diagnostic imaging of cells.

[0107] In certain embodiments, the imaging modality in which the compounds of Formulae (I)-(V) are used is PE T (positron emission tomography) or SPECT (single photon emission computed tomography )

[0108] Thus, the present disclosure also provides a method for diagnostic imaging, comprising treating cancer cells with an effective amount of a compound represented by formula (I): The present invention also relates to a method comprising contacting a compound of formula (V) with a compound of formula (V).

[0109] The present disclosure also provides a method for imaging a PSMA-expressing tumor or cell, comprising: contacting the A-expressing tumor or cells with a therapeutically effective amount of a compound of formula (I)-(V). The method also relates to a method comprising: and detecting a signal resulting from the decay of the isotope and / or radioactive metal. It can include.

[0110] The present disclosure also provides methods for in vivo imaging of PSMA-expressing tumors or cells in a subject. The method comprises administering to said subject, preferably a human, a therapeutically effective amount of a compound of formula (I) to ( V) and administering the radioisotope and / or radioactive material present in said compound and detecting a signal resulting from the decay of the radioactive metal.

[0111] In certain embodiments, the present disclosure provides a method for determining the presence or absence of a PSMA-expressing tumor in a subject. 1. A method for detecting (i) administering to said subject a compound of Formula (I)-(V), for example, as an intravenous injection; To do; (ii) acquiring images, typically by PET or SPECT imaging; and (iii) detecting the presence or absence of a PSMA-expressing tumor in the subject. Provide the law.

[0112] The present disclosure also provides methods for the treatment of cancer disorders, typically PSMA-expressing cancers, for use in diagnostic methods. The present invention also relates to compounds of formulae (I)-(V) for use in diagnosing a disorder.

[0113] The present disclosure also provides a method for treating cancer cells or PSMA-expressing tumors or cells in a subject, such as a prostate cancer cell. A method for diagnosing and / or detecting a tumor or cell, comprising: administering to a subject, or a human, a therapeutically effective amount of a compound of formula (I)-(V); The signal obtained from the decay of radioactive isotopes and / or radioactive metals present in the compound is detected. The present invention also relates to a method for producing the same, comprising:

[0114] Synthesis of Compounds of Formulas (I) to (V) Compounds of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea was synthesized by cyanohydrin in methanol. In the presence of sodium borohydride, p-nitrobenzaldehyde stimulated the synthesis of Glu-L ys can be prepared by reductive alkylation of urea 1. This type of procedure is (Tykvart et al. (2015) Journal of medicinal chemistry 58,4357-63). , an aliphatic linker, Boc-5-aminovaleric acid, is linked to two identical ε-Lys amines, e.g. , a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N '-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] pyridinium 3-oxide hexafluorophosphate) to form a bond to produce compound 3. Compound 3 can then be reacted with, for example, a trifluoro Deprotection can be performed using an acid such as acetic acid to yield compound 4. Conjugation with available DOTA-NHS ester was performed to yield compound 5. Finally, compound (III) can be reacted with 18 F - Using a nitro group can be obtained by substituting

[0115] The compounds of formula (I), (II) and (III) are commonly used in the field of radiolabeling. In particular, compounds of formula (III) can also be radiolabeled using methods described in Using the method described in WO 2017 / 165473, To form a compound of formula (IV): 177 It can also be radiolabeled with Lu. Compound (III) is also described in WO 024013. to form a compound of formula (V) using a method 68 Radiolabeling with Ga It is also possible.

[0116] Scheme 1: Synthesis of compounds of formula (III) [ka] The present invention includes the following embodiments. [Claim 1] Formula (I): [ka] (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently 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; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C 6 ~C 10 selected from the group consisting of aryl and heteroaryl containing 5 to 10 ring atoms, wherein said aryl and heteroaryl are substituted one or more times by X; X is -ZY; Z is a bond or C 1 ~C 6 alkylene, preferably Z is a bond; Y is a radioisotope; L is C 1 ~C 6 Alkylene, C 3 ~C 6 Cycloalkylene, and C 6 ~C 10 a linker selected from the group consisting of arylene, wherein the alkylene, cycloalkylene, and arylene are selected from the group consisting of: -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -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'')═NR'''', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NRSO 2 R', -CN, and -NO 2 optionally substituted with one or more substituents ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 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; Each occurrence of L and W can be the same or different; R 2 is H or C 1 ~C 4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or radioactive metal. and pharmaceutically acceptable salts thereof. [Claim 2] The compound has formula (Ia), (Ib), (Ic), or (Id):

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Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Z is tetrazole or COOQ; Q is independently H or a protecting group selected from benzyl, p-methoxybenzyl, tert-butyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and triphenylmethyl; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6; R is 【Chemistry 61】 and L is a linker selected from the group consisting of C 1 -C 6 alkylene, C 3 -C 6 cycloalkylene, and C 6 -C 10 arylene, wherein the alkylene, cycloalkylene, and arylene are selected from the group consisting of -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO 2 R', -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'')═NR'''', -S(O)R', -S(O) 2 R', -S(O) 2 optionally substituted with one or more substituents selected from NR'R'', -NRSO 2 R', -CN, and -NO 2 in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such group; R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; W is selected from the group consisting of —NR 2 —(C═O), —NR 2 —(C═S), —(C═O)—NR 2 —, and —(C═S)—NR 2 —; Each occurrence of L and W can be the same or different; R 2 is H or C 1 -C 4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is 【Chemistry 20】 and optionally containing a metal or radioactive metal. and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein the compound has formula (Ia), (Ib), (Ic), or (Id): 【Chemistry 2】 2. The compound of formula (I) according to claim 1, which is a compound of formula (I):

3. The compound of formula (I) of claim 1, wherein L is a linker selected from the group consisting of C3-C6 alkylene optionally substituted with one or more substituents selected from -OR', =O, =NR', -NR'R'', -halogen, -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' in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such group.

4. The compound of formula (I) of claim 1, wherein R', R'', R''', and R'''' may each independently represent hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein Ch comprises a metal selected from Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho, and Sc.

5. The compound of formula (I) according to claim 4, 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.

6. The compound of formula (II): 【Chemistry 81】 6. A compound of formula (I) according to any one of claims 1 to 5, wherein L is a linker selected from the group consisting of C3-C6 alkylene optionally substituted with one or more substituents selected from: -OR', =O, =NR', -NR'R'', -halogen, -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' in a number ranging from zero to (2m'+1), and m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

7. The following moiety in formula (II): 【Chemistry 20】 The compound of formula (II) according to claim 6, wherein comprises 68 Ga or 67 Ga.

8. The following moiety in formula (II): 【Chemistry 20】 The compound of formula (II) according to claim 6, wherein comprises 177 Lu or 176 Lu.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and at least one pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, wherein the composition further comprises a compound comprising i) a PSMA-binding ligand, ii) optionally a linker, and iii) a chelating agent optionally comprising a metal or a radioactive metal.

11. A compound according to any one of claims 1 to 8 for use as a pharmaceutical.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in the treatment of cancer.

13. The pharmaceutical composition of claim 12 for use in the treatment of prostate cancer.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in diagnostic imaging.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in a diagnostic method.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in a method for treating cancer, the method comprising contacting cancer cells with a therapeutically effective amount of the compound.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in a method for diagnostic imaging, the method comprising administering an effective amount of the compound to a subject and detecting a signal resulting from the decay of the radioisotope and / or the radiometal present in the compound.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 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 a therapeutically effective amount of the compound to the subject and detecting a signal resulting from the decay of the radioisotope and / or radiometal present in the compound.

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