New integrated tumor diagnosis and treatment agent targeting prostate-specific membrane antigen

Abstract

The present invention relates to a new integrated tumor diagnosis and treatment agent targeting a prostate-specific membrane antigen; and specifically relates to a compound as shown in general formula I, or an optical isomer, pharmaceutically acceptable salt and / or solvate thereof, a preparation method therefor, and a pharmaceutical composition containing the compound, wherein j and d are 0 or 1, substituents A and B have the meanings given in the description, and X is a radionuclide. The present invention further relates to the use of the compound and the pharmaceutically acceptable salt, solvate or prodrug thereof in the treatment of cancers expressing PSMA.

Description

Novel tumor diagnosis and treatment integrated reagent targeting prostate specific membrane antigen TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and specifically relates to a novel tumor diagnosis and treatment integrated reagent targeting prostate specific membrane antigen. BACKGROUND

[0002] Prostate cancer (PCa) is the second most common cancer affecting men's health, and has been ranked first in male urological diseases for many years. With the aging of the population, the number of newly diagnosed patients is also increasing year by year. In recent years, the incidence of prostate cancer in China has shown an upward trend, and the growth is more rapid than in developed countries in Europe and the United States. According to the data of the National Cancer Center, prostate cancer has been the highest incidence of tumors in the male urinary system since 2008. How to accurately stage prostate patients as early as possible and assist with effective treatment to reduce mortality is the focus of research in this field.

[0003] According to the current guidelines, ultrasound-guided biopsy is a recognized most commonly used method for diagnosing prostate cancer. Magnetic resonance imaging (MRI) is the standard imaging method for detecting suspected early prostate cancer with negative pathological examination results. The positioning of suspected lesions by MRI can improve the coincidence rate of diagnosis. Even if MRI is used, there are still missed cases. Therefore, positron emission computed tomography (PET) imaging, which can provide additional cell biological information, has attracted widespread attention. The use of PET imaging based on choline and glucose metabolism for the diagnosis and staging of prostate cancer has been extensively studied and discussed, but the results are not satisfactory. Prostate specific membrane antigen (PSMA) is a transmembrane protein highly expressed by prostate cancer cells, and its expression level is up-regulated with tumor progression and metastasis, and its expression increases with the increase of abnormal development of prostate cancer cells. It is a highly potential target for early diagnosis, staging and treatment of PCa, and brings new hope for improving the diagnosis and treatment of prostate cancer.

[0004] PSMA is highly expressed in 95% of prostate cancer patients, and its expression level is up-regulated in castration-resistant prostate cancer (mCRPC) and metastatic prostate cancer. Therefore, PSMA can be an ideal target for the diagnosis and treatment of prostate cancer and its metastatic lesions. At present, there are a variety of molecular probes targeting PSMA in the clinical experimental stage, and common PSMA molecular probes include monoclonal antibodies, small molecule inhibitors, etc. For example, 111 In-labeled 7E11 is the first radiolabeled PSMA monoclonal antibody, and is a relatively successful drug for SPECT imaging of prostate cancer at present, but 7E11 can only bind to the intramembrane segment of PSMA, so it can only be taken up by necrotic and apoptotic cells, and the imaging sensitivity is not high. PSMA small molecule inhibitors have good cell permeability, fast blood clearance and other advantages, and mainly include three categories: 1. Phosphate, phosphite, phosphonate, phosphoramidate and other derivatives; 2. Sulfhydryl, indole-sulfhydryl, hydroxamic acid, sulfonamide derivatives; 3. Urea derivatives. At present, the urea derivative small molecule inhibitors entering the clinical experimental stage mainly include PSMA-11, PSMAI&T, PSMA-617, etc. PSMA small molecule inhibitors can be labeled with 18 F、 68 Ga for imaging of prostate cancer, and 177 Lu、 90 Y、 131 I for the treatment of prostate cancer. However, the existing PSMA-targeted PET imaging agent labeled with the nuclide Ga-68 has the problems of short half-life, limited effective utilization time, and insignificant tumor uptake in prostate cancer cell metastasis models, and the imaging effect needs to be improved.

[0005] The existing developed PSMA molecular probe tracers mainly include: 18 F-DCFPyL、 18 F-PSMA-1007, but 18 F-DCFPyL has low radiochemical yield, 18 F-PSMA-1007 has non-target uptake in the liver, and the liver uptake does not decrease significantly over time.

[0006] SUMMARY

[0007] In view of the deficiencies of the prior art, the present application finds new compounds which are useful and advantageous radiopharmaceuticals and can be used in nuclear medicine as tracers, imaging agents and for treating various disease states of PSMA-expressing cancers, in particular prostate cancer. The compound probes of the present patent protection have excellent radiochemical yields through the nucleophilic substitution reaction of boronic acid with halogen, and the results of Mirco-PET imaging show that the compound probes have high tumor uptake and low non-target uptake, and have a significant downward trend over time.

[0008] The object of the present application can be achieved by the following technical solutions:

[0009] In a first aspect, the present application protects a compound represented by the general formula (I) and its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof,

[0010] Wherein:

[0011] j is an integer from 0 to 2;

[0012] d is 0 or 1;

[0013] Y is selected from C=O, S=O, a structure, preferably a C=O structure;

[0014] When the structure contains a lysine structure, then a general formula II is used:

[0015] X is a radionuclide, mainly a non-metallic radionuclide, such as 18 F, 123 I, 124 I, 125 I, 126 I, 131 I, 77 Br, 76 Br, 82 Br, 211 At, etc. X can be located at the ortho, para or meta position of the aromatic ring or aromatic heterocycle;

[0016] A is

[0017] Wherein Y1 is an alkyl group or an optionally substituted aryl group, alkylaryl group, heteroaryl group and alkylheteroaryl group, preferably a C 1-5 alkyl group, C 6-10 aryl group, alkylaryl group, heteroaryl group and alkylheteroaryl group, more preferably a C 1-3 alkyl group;

[0018] Y2 is O or NCH3;

[0019] i is an integer from 1 to 12;

[0020] m is 0 or 1 ;

[0021] l is 0 or 1 ;

[0022] n is an integer from 1 to 12, preferably an integer from 1 to 3;

[0023] B is

[0024] C, D in general formula (II) can be selected independently or simultaneously from the following (1) or (2) structures, said structure (1) is selected from (1a), (1b), (1c) and (1d) structures, said (1a), (1b), (1c) and (1d) structures are metal chelator structures or metal chelator containing structures, capable of selectively binding to a radioactive metal L; said structure (2) connects a radionuclide X through a covalent bond:

[0025] wherein R1, R2, R3and R4are independently from each other selected from H, -CH2-COOH and -CH2-C(=O)-NH2or wherein R1and R3form a -(CH2) j - bridge, non-adjacent -(CH2)r- units form a -(CH2)-NH-(CH2) j - NH-(CH2)- bridge, j is an integer from 1 to 3, wherein j is preferably 2;

[0026] wherein Z is selected from (1a), (1b), (1c) structures;

[0027] wherein r, v and q are independently from each other 0 or 1.

[0028] Particularly preferred compounds of the present application are shown in Table 1:

[0029] Table 1 is a preferred compound

[0030] In a second aspect, the present application protects a complex comprising,

[0031] (a) a radionuclide;

[0032] (b) a compound as described above or below and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0033] In a third aspect, the present application protects a pharmaceutical composition comprising a compound as described above or below or a complex as described above or below.

[0034] In a fourth aspect, the present application protects the use of a compound as described above or below, or of a complex as described above or below, or of a pharmaceutical composition as described above or below, for the following (1) or (2):

[0035] (1) the manufacture of a medicament for the treatment, amelioration or prevention of a cancer expressing PSMA and / or metastases thereof;

[0036] (2) the manufacture of a reagent for the diagnosis of a cancer, in particular a cancer expressing PSMA and / or metastases thereof.

[0037] The term "cancer expressing PSMA and / or metastases thereof" used within the meaning of the present application relates to any cancer whose cancer cells express the prostate-specific membrane antigen (PSMA) and to the respective metastases thereof. Preferably, the cancer (or cancer cells) which can be treated according to the present application is selected from the group consisting of prostate cancer, conventional renal cell carcinoma, bladder transitional cell carcinoma, testicular-embryonal carcinoma, neuroendocrine carcinoma, colon cancer, brain tumor and breast cancer.

[0038] In a particular preferred aspect of the present application, the cancer expressing PSMA is prostate cancer or breast cancer, in particular prostate cancer.

[0039] The compounds according to the present application are used as radioimaging agents or radiopharmaceuticals, different radionuclides are complexed with the chelating agent or form a substituted aryl group.

[0040] Illustrative radionuclides include alpha emitters: 149 Tb, 153 Gd, 211 At, 213 Bi, 223 Ra, 225 Ac, 230 U; beta ﹣ emitters: 47 Sc, 64 Cu, 90 Y, 152 Tb, 153 Sm, 161 Tb, 177 Lu, 186 Re, 188 Re, 203 Pb, 212 Pb; nuclides for PET imaging: 18 F, 44 Sc, 45 Ti, 52 Mn, 52 Fe, 59 Fe, 60 Cu, 6l Cu, 62 Cu,64 Cu, 66 Cu, 67 Cu, 66 Ga, 68 Ga, 82 Rb, 86 Y, 89 Zr, 152 Tb, 155 Gd, 157 Gd; for SPECT imaging: 67 Ga, 99m Tc, 111 In, 131 I, 153 Sm, 155 Tb, 165 Er, 191 Pt.

[0041] The complexes of the compounds according to the application can contain one or more than one radionuclide, preferably one radionuclide. These radionuclides are preferably suitable for use as radioimaging agents or for use as therapy for proliferating cells, such as cancer cells expressing PSMA, in particular prostate cancer cells expressing PSMA. According to the application, they are referred to as "metal complexes" or "radiopharmaceuticals".

[0042] The preferred imaging method is positron emission tomography (PET).

[0043] The synthesis procedures of the compounds of the present application are known to the person skilled in the art. Preferred syntheses of the compounds of the present application are described in detail in the examples section.

[0044] Advantages of the present application:

[0045] The present application finds new compounds which are useful and advantageous radiopharmaceuticals and can be used in nuclear medicine as tracers, imaging agents and for the treatment of disease states expressing PSMA, in particular prostate cancer tumors. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 is a Mirco-PET imaging of ZT-1 ;

[0047] Figure 2 is an imaging effect of ZT-4, ZT-7. DETAILED DESCRIPTION

[0048] The application will be further described in connection with the following embodiments. The following description is only the preferred embodiments of the application and is not intended to limit the application in other forms. Any skilled person in the art can modify the disclosed technical content to obtain equivalent embodiments. Any modification or equivalent change to the following embodiments without departing from the technical essence of the application falls within the protection scope of the application.

[0049] Example 1

[0050] I. Materials and methods

[0051] All commercially available chemicals are of analytical grade and used without further purification. In vitro experiments were performed in triplicate, and at least three independent sets of data were obtained for each experiment.

[0052] II. Synthesis of molecular probes

[0053] I. Synthesis of general intermediates:

[0054] 1.1 Synthesis of intermediate 3

[0055] The starting material 1 was dissolved in super dry dimethyl sulfoxide (DMSO), and the purchased intermediate 2 was added. Condensation reaction occurred under the action of 2-succinimidyl-1,1,3,3-tetramethyl uronium tetrafluoroborate (TSTU) and diisopropylethylamine (DIPEA). Intermediate 3 was obtained by semi-preparative high performance liquid purification; ESI-MS (m / z): 317.11 [M+H] + .

[0056] 1.2 Synthesis of intermediate 5

[0057] The starting material 1 was dissolved in super dry DMSO, and DIPEA was added dropwise. After half an hour, the purchased intermediate 4 was added. After half an hour of reaction, the reaction was monitored to the end point, and trifluoroacetic acid was added dropwise. Intermediate 5 was obtained by semi-preparative high performance liquid purification; ESI-MS (m / z): 383.24 [M+H] + .

[0058] 1.3 Synthesis of intermediate 13

[0059] Intermediate 13 is synthesized from L-di-tert-butyl glutamate hydrochloride as a starting material and can be directly used for the synthesis of ZT-1, ZT-2, and ZT-3. The preparation process is shown in the following flowchart:

[0060] The raw material L-dit-butyl glutamate hydrochloride and 4-dimethylamino pyridine (DMAP) were cooled to 0°C under nitrogen protection, and dichloromethane (DCM) and triethylamine (TEA) were added in sequence. After stirring for 5 min, N, N'-carbonyldiimidazole (CDI) was added, and after being raised to room temperature, it was stirred overnight. After dilution with DCM, it was washed with saturated sodium bicarbonate solution, water and saturated brine in sequence, dried and purified by column chromatography to obtain intermediate 7. At 70°C, methyl trifluoromethanesulfonate and triethylamine were added to a solution of intermediate 7 in 1,2-dichloroethane (DCE). After stirring for 30 min, intermediate 8 was added, and after being raised to room temperature, it was stirred overnight. The reaction solution was concentrated and dried, and intermediate 9 was obtained by column chromatography purification; ESI-MS (m / z): 621.54 [M+H] + .

[0061] In a 100 mL round-bottom flask, ammonium formate was added to a solution of intermediate 9 in ethanol, and 12% Pd-C was added, and the suspension was stirred overnight at room temperature. The mixture was filtered through diatomite, and the filtrate was concentrated and dried to obtain intermediate 10 without further purification.

[0062] Intermediate 11 was dissolved in super-dry DMSO, and DIPEA was added dropwise. After the addition was completed, the reaction solution was blown three times with a pipette. After half an hour, intermediate 10 dissolved in super-dry DMSO was added dropwise to the reaction system, and after half an hour of reaction, the reaction was monitored to the end point, and trifluoroacetic acid was added, and PSMA-Tz (intermediate 12) was obtained by semi-preparative high performance liquid purification. Then reacted with intermediate 3 at room temperature for 5-10 min to obtain the product intermediate 13; ESI-MS (m / z): 804.24 [M+H] + .

[0063] 1.4 Preparation of intermediate 18

[0064] Intermediate 18 is an important intermediate and can be used for the synthesis of ZT-7, ZT-8 and ZT-9. The preparation process is shown in the following flow chart:

[0065] Intermediate 10 was dissolved in super dry DMSO, TSTU, DIPEA was added, and the reaction was allowed to proceed for 0.5 h to give intermediate 15. DOTA reagent was added, and the reaction was allowed to proceed for 2 h, and the reaction was monitored to the end point. Ammonium formate was added to the reaction in ethanol, and 12% Pd-C was added, and the mixture was stirred at room temperature overnight. The mixture was filtered through celite, and the filtrate was concentrated to dryness to give intermediate 16. Intermediate 11 was dissolved in super dry DMSO, and DIPEA was added dropwise. After the addition was complete, the reaction was blown with a pipette three times. After half an hour, intermediate 16 dissolved in super dry DMSO was added dropwise to the reaction, and the reaction was allowed to proceed for half an hour. The reaction was monitored to the end point, and trifluoroacetic acid was added dropwise. Purification by semi-preparative HPLC gave intermediate 17. Intermediate 17 was reacted with intermediate 3 at room temperature for 5-10 min to give product intermediate 18; ESI-MS (m / z): 1348.33 [M+H] + .

[0066] 1.5 Preparation of intermediate 19

[0067] Intermediate 19 is an important intermediate and can be used for the synthesis of ZT-4, ZT-5, ZT-6. The preparation process is shown in the following flow chart:

[0068] Intermediate 5 was dissolved in super dry DMSO, and DIPEA was added dropwise. After the addition was complete, the reaction was blown with a pipette three times. After half an hour, intermediate 10 dissolved in super dry DMSO was added dropwise to the reaction, and the reaction was allowed to proceed for half an hour. The reaction was monitored to the end point, and trifluoroacetic acid was added dropwise. Purification by semi-preparative HPLC gave intermediate 19; ESI-MS (m / z): 684.26 [M+H] + .

[0069] I I. For 18 F imaging and therapy

[0070] Description of ZT-1

[0071] Dimethylformamide was added to dissolve intermediate 13, pyridine, and copper (II) trifluoromethanesulfonate, respectively. Pyridine, copper, and intermediate 13 were mixed together, and the precursor solution was injected into an aqueous solution of Na 18 F at 25°C for 10 min. HPLC-retention time: 12.34 min; ESI-MS (m / z): 778.51 [M+H] + .

[0072] Description of ZT-4

[0073] Dimethylformamide was added to intermediate 19, pyridine and copper (II) trifluoromethanesulfonate, respectively. After dissolution, pyridine, copper and intermediate 19 were mixed together and the precursor solution was injected into a solution of Na 18 HPLC-retention time: 12.21 min; ESI-MS (m / z): 644.71 [M+H] + .

[0074] Description of ZT-7

[0075] Dimethylformamide was added to intermediate 18, pyridine and copper (II) trifluoromethanesulfonate, respectively. After dissolution, pyridine, copper and intermediate 18 were mixed together and the precursor solution was injected into a solution of Na 18 HPLC-retention time: 12.56 min; ESI-MS (m / z): 1293.86 [M+H] + .

[0076] III. Probes for 131 Imaging and therapy

[0077] Description of ZT-2

[0078] In a reaction vial was added a solution of intermediate 13 in acetonitrile containing triethylamine, followed by a solution of Cu2O and 1,10-phenanthroline in acetonitrile, followed by a solution of Na 131 HPLC-retention time: 12.73 min; ESI-MS (m / z): 891.86 [M+H] + .

[0079] Description of ZT-5

[0080] In a reaction vial was added a solution of intermediate 19 in acetonitrile containing triethylamine, followed by a solution of Cu2O and 1,10-phenanthroline in acetonitrile, followed by a solution of Na 131 HPLC-retention time: 12.31 min; ESI-MS (m / z): 757.12 [M+H] + .

[0081] Description of ZT-8

[0082] In a reaction vial was added a solution of intermediate 18 in acetonitrile containing triethylamine, followed by a solution of Cu2O and 1,10-phenanthroline in acetonitrile, followed by a solution of Na 131H2O at 25 °C for 1 h. HPLC-retention time: 12.56 min; ESI-MS (m / z): 1406.42 [M+H] + .

[0083] IV. For 211 At imaging and treatment of the synthesis of the probe

[0084] Description of ZT-3

[0085] In a reaction bottle, 7% sodium bicarbonate solution of intermediate 13 was added, mixed with 211 At aqueous solution. To the mixture, 0.1 mol / L KI solution was added, and the mixture was allowed to stand at room temperature for 30 min. HPLC-retention time: 12.99 min; ESI-MS (m / z): 971.36 [M+H] + .

[0086] Description of ZT-6

[0087] In a reaction bottle, 7% sodium bicarbonate solution of intermediate 19 was added, mixed with 211 At aqueous solution. To the mixture, 0.1 mol / L KI solution was added, and the mixture was allowed to stand at room temperature for 30 min. HPLC-retention time: 12.21 min; ESI-MS (m / z): 837.45 [M+H] + .

[0088] Description of ZT-9

[0089] In a reaction bottle, 7% sodium bicarbonate solution of intermediate 18 was added, mixed with 211 At aqueous solution. To the mixture, 0.1 mol / L KI solution was added, and the mixture was allowed to stand at room temperature for 30 min. HPLC-retention time: 12.31 min; ESI-MS (m / z): 1485.15 [M+H] + .

[0090] V. Mirco-PET imaging

[0091] The inoculated nude mice with human prostate cancer cells (LNCaP) were placed in a narcotic box, and pre-anesthetized with isoflurane-oxygen mixed gas with a volume fraction of 3% for 5-10 min. The mice were placed on the scanning bed, the limbs were fixed with medical adhesive tape, and the anesthesia was maintained using isoflurane-oxygen mixed gas. The position was adjusted so as to be located at the center of the field of view of the micro-PET scanner. The physiological saline diluted 18F-labeled ZT-1 solution, determine the radioactivity, record the determination time. After the tail vein injection into the tumor-bearing mice, record the injection time, and then determine the residual radioactivity in the insulin syringe, record the determination time. 30, 90, 180 min after the injection of the probe, 10 min static scanning is carried out, and the acquisition mode is three-dimensional mode. Three-dimensional ordered subset expectation maximization (3D OSEM) algorithm is used for image reconstruction, and the results are shown in Figure 1. As shown in Figure 1, ZT-1 maintains high tumor uptake in mice: 0.5 h is 19.34 ± 2.15% ID / g, 1.5 h is 21.34 ± 4.32% ID / g, 3 h is 19.52 ± 4.73% ID / g, at the same time, the non-target uptake of the kidney and liver is small, and is rapidly metabolized over time. Therefore, ZT-1 has clear tumor edge contour and good imaging quality in small animal-PET / CT imaging. As shown in Figure 2, ZT-4 and ZT-7 both show excellent imaging effect. Similarly, other compounds of the present application also show excellent imaging effect.

[0092] The protection scope of the present application is not limited to the above embodiments. Changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the present application are included in the present application, and are protected by the appended claims.

Claims

1. A compound represented by the general formula (I) and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein: j is an integer of 0 to 2; d is 0 or 1; Y is selected from C=0, S=0, structure; When the structure contains a lysine structure, then the general formula II is used: X is a radionuclide, preferably a non-metal radionuclide, such as 18 F, 123 I, 124 I, 125 I, 126 I, 131 I, 77 Br, 76 Br, 82 Br, or 211 one or more of At; X can be located at the ortho, para or meta position of the aromatic or heteroaromatic ring; A is wherein Y1is alkyl or optionally substituted aryl, alkylaryl, heteroaryl and alkylheteroaryl; Y2is O or NCH3; i is an integer of 1 to 12; m is 0 or 1; l is 0 or 1; n is an integer of 1 to 12; B is C, D in general formula (II) can be selected from the following (1), (2) structures respectively or simultaneously, the structure (1) includes (1a), (1b), (1c) or (1d): wherein R1, R2, R3and R4are independently from each other selected from H, -CH2-COOH and -CH2-C(=0)-NH2or wherein R1and R3form a -(CH2) j - a bridge, the non-adjacent -(CH2)r- units form a -(CH2)-NH-(CH2) j - a -NH-(CH2)- bridge, j is an integer from 1 to 3, wherein j is preferably 2; wherein Z is selected from the structures of (1a), (1b), (1c); wherein r, v and q are each independently of the others 0 or 1.

2. The compound according to claim 1, and stereoisomers, pharmaceutically acceptable salts, solvates thereof or prodrugs thereof, characterized in that, said Y is selected from the structure of C=O; Preferably, Y1is selected from C 1-5 alkyl, C 6-10 aryl, alkylaryl, heteroaryl and alkylheteroaryl, preferably C 1-3 alkyl; Preferably, n is an integer of 1 to 3.

3. A compound as shown by any one of the following: and stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, 4. A complex comprising (a) and (b) (a) a radionuclide; (b) a compound as claimed in any one of claims 1 to 3, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

5. The complex according to claim 4, wherein The radionuclides include alpha emitters, beta ﹣ emitters, positron emitters for PET imaging, and gamma emitters for SPECT imaging; preferably, the alpha nuclides are selected from one or more of 149 Tb, 153 Gd, 211 At, 213 Bi, 223 Ra, 225 Ac, 230 U. beta ﹣ the nuclide is selected from one or more of 47 Sc, 64 Cu, 90 Y, 152 Tb, 153 Sm, 161 Tb, 177 Lu, 186 Re, 188 Re, 203 Pb, 212 Pb. The radionuclide for PET imaging is selected from the group consisting of 18 F, 44 Sc, 45 Ti, 52 Mn, 52 Fe, 59 Fe, 60 Cu, 6l Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 66 Ga, 68 Ga, 82 Rb, 86 Y, 89 Zr, 152 Tb, 155 Gd, 157 Gd. The radionuclide for SPECT imaging is selected from one or more of 67 Ga, 99m Tc, 111 In, 131 I, 153 Sm, 155 Tb, 165 Er, 191 Pt.

6. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 3, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof or a complex as claimed in claim 4 or 5.

7. Use of a compound as claimed in any one of claims 1 to 3, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a complex as claimed in claim 4 or 5, or a pharmaceutical composition as claimed in claim 6, in (1) or (2): (1) the manufacture of a medicament for the treatment, amelioration or prevention of a cancer expressing PSMA and / or metastases thereof; (2) the manufacture of a reagent for the diagnosis of a cancer, in particular a cancer expressing PSMA and / or metastases thereof. said cancer expressing PSMA and / or metastases thereof relates to any cancer expressing prostate-specific membrane antigen by its cancer cells and the respective metastases thereof. said cancer is selected from one or more of prostate cancer, conventional renal cell carcinoma, bladder transitional cell carcinoma, testicular-embryonal carcinoma, neuroendocrine carcinoma, colon cancer, brain tumor and breast cancer.

8. Use according to claim 7, characterized in that, said cancer expressing PSMA is prostate cancer or breast cancer; 9. Use according to claim 8, characterized in that, preferably prostate cancer.

10. Use according to claim 9, characterized in that, ​ ​

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