Functionalized bisaminothiol derivatives, complexes having these bisaminothiol derivatives, and the use of said complexes for diagnostic and therapeutic purposes.

Abstract

The present invention relates to a compound of general formula I [wherein A is a chelator selected from the group consisting of A1, A2, A3 and A4; k is independently 0, 1 or 2 at each occurrence; m is independently 1, 2, 3, 4 or 5 at each occurrence; n is independently 0, 1, 2 or 3 at each occurrence; p is independently 1, 2 or 3 at each occurrence; q is independently 1, 2 or 3 at each occurrence; u is independently 0 or 1 at each occurrence; X and Y are substituted or unsubstituted amino acids; L is a bifunctional linker selected from the group consisting of L1, L2 and L3 (where v, x and y are independently 0, 1, 2 or 3, and z is 0, 1, 2, 3, 4 or 5), and R is H, methyl or ethyl]. TIFF2025517989000061.tif143170

Description

[Technical Field]

[0001] This invention relates to functionalized bisaminothiol derivatives. Furthermore, this invention relates to complexes of these functionalized bisaminothiol derivatives with metals, particularly radioactive metals. Moreover, this invention relates to the use of such complexes, in particular their use in the diagnosis and treatment of diseases involving prostate-specific membrane antigen (PSMA). [Background technology]

[0002] In personal medicine, radiolabeled agents used to target disease-specific biological structures for the diagnosis and subsequent treatment of that disease are called theranostics. This approach is used to locate and then eliminate metastatic diseases.

[0003] Compared to normal prostate epithelial cells, expression of prostate-specific membrane antigen (PSMA) is increased in human prostate cancer and its metastatic malignancies. This highly specific expression of PSMA on the cell surface is characteristic of localized and metastatic prostate cancer. Furthermore, PSMA expression has been observed in the neovascularization of several non-prostate solid malignancies (Chang et al., Clin Cancer Res 1999, 5, 2674) (Non-patent Literature 1).

[0004] Therefore, PSMA is an attractive target for the diagnosis, staging, detection of recurrence, and treatment of prostate cancer (and other diseases in which PSMA is upregulated) using radiolabeled compounds. Such molecules typically include a pharmacophore for PSMA binding, a linker structure for optimizing pharmacological properties, and a chelator or prosthetic group for incorporating the appropriate radionuclide. In recent years, mainly, 68 Ga-PSMA-11, 18 F-DCFPyL and 18 Including F-PSMA-1007 18 F and 68Ga-labeled radiopharmaceuticals are used for prostate cancer PET imaging.

[0005] 99m Tc, with its longer half-life (t 1 / 2 = 6.01 h), low radiotoxicity, and 99 Mo / 99m Tc-generator for widespread and decentralized availability, is a common isotope in nuclear medicine for SPECT imaging. Due to similar coordination chemistry, technetium and rhenium are a theranostic pair, 99m when labeled with Tc for SPECT imaging, 186 Re (t 1 / 2 = 89.25 h) or 188 Re (t 1 / 2 = 17.02 h) allows the use of the same PMSA ligand for radioligand therapy (RLT).

[0006] Initial 99m Tc-labeled PSMA ligands had slow distribution, high liver uptake, and slow clearance from the body. 99m The slow pharmacokinetic properties of Tc-labeled tracers require late imaging times to achieve sufficient tumor-to-background ratios (Werner et al., EJNMMI Research 2020, 10, 45 (Non-Patent Document 2); Vallabhajosula et al., J Nucl Med 2014, 55, 1791 (Non-Patent Document 3)). This results in longer waiting times for patients between tracer injection and SPECT image acquisition. In the case of therapeutic administration, slow clearance can lead to high uptake in off-target organs and thus harmful effects due to radiotoxicity.

[0007] Known PSMA ligands containing the HYNIC chelate moiety require a coligand to stabilize the technetium complex in biological systems and prevent oxidation by oxygen. The choice of coligand can affect the complex shape, the number of PSMA ligands coordinating to a single Tc atom, and ultimately, the biodistribution of the radiolabeled compound. The hydrazine moiety of HYNIC is a potent nucleophile, which can lead to undesirable byproducts during radiolabeling or when applied to biological systems. The formation of stable complexes between rhenium and HYNIC as a chelator remains challenging (North et al., Inorg. Chem. 2017, 56, 9725 (Non-Patent Literature 4); Philip J. Blower, Int. J. Nucl. Medi. Res. 2017, 39 (Non-Patent Literature 5)).

[0008] As a result, for SPECT imaging of prior art 99m Tc-labeled PSMA ligands are inferior to current PSMA ligands labeled with PET radionuclides in terms of radiolabeling, stability, pharmacokinetics, and diagnostic performance. Therefore, novel chelators with optimized pharmacological properties are being sought, while also being able to form stable complexes with other metals such as rhenium. 99m It is desirable to develop a Tc-labeled PSMA ligand. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Chang et al., Clin Cancer Res 1999, 5, 2674 [Non-Patent Document 2] Werner et al., EJNMMI Research 2020, 10, 45 [Non-Patent Document 3] Vallabhajosula et al., J Nucl Med 2014, 55, 1791 [Non-Patent Document 4] North et al., Inorg. Chem. 2017, 56, 9725 [Non-Patent Document 5] Philip J. Blower, Int. J. Nucl. Medi. Res. 2017, 39 [Overview of the project] [Problems that the invention aims to solve]

[0010] The object of the present invention is to overcome the shortcomings of the prior art. In particular, functionalized bisaminothiol derivatives that enable the formation of stable complexes with metals, especially rhenium and technetium, should be provided. Furthermore, complexes that function as ligands for prostate-specific membrane antigens (PSMAs) and can be used for the diagnosis and treatment of certain diseases involving PSMAs should be provided. [Means for solving the problem]

[0011] This problem is solved by the features of claims 1, 8, 10, 11, 13, and 14. A practical development of the present invention is derived from the features of the dependent claims.

[0012] According to the present invention, compounds of general formula I are provided. [ka] [In the formula, A is a chelator selected from the following group: [ka] k is independently 0, 1, or 2 in each occurrence; m is independently 1, 2, 3, 4, or 5 in each occurrence; n is independently 0, 1, 2, or 3 in each occurrence; p is independently 1, 2, or 3 in each occurrence; q is independently 1, 2, or 3 in each occurrence; u is either 0 or 1 independently in each occurrence; X and Y are substituted or unsubstituted amino acids; L is a bifunctional linker selected from the group consisting of the following: [ka] (wherein v, x, and y are independently 0, 1, 2, or 3, and z is 0, 1, 2, 3, 4, or 5); and R is H, methyl, or ethyl.

[0013] Compounds of general formula I are bisaminothiol derivatives because they contain group A. Hereinafter, group A is also referred to as the N2S2 chelator. Compounds of general formula I can form complexes with metals, particularly radioactive metals. The bisaminothiol moiety of compounds of general formula I enables the complexation of metals, especially radioactive metals, thereby yielding complexes. Due to the bisaminothiol moiety, compounds of general formula I are ligands for the complexation of metals, particularly radioactive metals.

[0014] Compounds of general formula I are functionalized bisaminothiol derivatives because they are functionalized by different amino acid sequences and urea-based pharmacophore groups acting as linkers.

[0015] The complex can be used as a ligand that binds to prostate-specific membrane antigen (PSMA). That is, it has been found that the complex can be used as a PSMA inhibitor. Therefore, the complex can be used in the diagnosis and treatment of diseases involving PSMA. In particular, the complex can be used in the diagnosis and treatment of specific diseases in which PSMA is upregulated. Therefore, the complex can be used as a pharmaceutical agent in the diagnosis and treatment of prostate cancer.

[0016] According to the present invention, group X is a single amino acid (p=1) or a sequence of amino acids (p=2 or 3). When p is 1, preferably the amino acid is selected from the group consisting of substituted or unsubstituted glutamic acid, substituted or unsubstituted aspartic acid, substituted or unsubstituted phenylalanine, substituted or unsubstituted histidine, and substituted or unsubstituted serine. Preferably the amino acid is substituted or unsubstituted phenylalanine or substituted or unsubstituted glutamic acid, and particularly preferably substituted or unsubstituted glutamic acid. When p is 2 or 3, preferably each of the amino acids forming the amino acid sequence is independently selected from the group consisting of substituted or unsubstituted glutamic acid, substituted or unsubstituted aspartic acid, substituted or unsubstituted phenylalanine, substituted or unsubstituted histidine, and substituted or unsubstituted serine. Preferably each of the amino acids in the amino acid sequence is substituted or unsubstituted phenylalanine or substituted or unsubstituted glutamic acid, and particularly preferably substituted or unsubstituted glutamic acid.

[0017] Group X may be bonded to group Y via a first peptide bond and to partial BM via a second peptide bond. Partial BM is a general formula [ka] This is the part where k, m, and n have meanings given in relation to general formula I. Therefore, compounds of general formula I are general formula BM-X p -Y q -L u -A It can also be represented by [this].

[0018] If group X has a sequence of two or three amino acids, these amino acids are each linked by peptide bonds. Group BM is a urea-based pharmacophore group. Groups X and Y form a linker between group BM on the one hand and partial LA on the other.

[0019] According to the present invention, group Y is one amino acid (p=1) or a sequence of amino acids (q=2 or 3). When q is 1, preferably the amino acid is selected from the group consisting of substituted or unsubstituted glutamic acid, substituted or unsubstituted aspartic acid, substituted or unsubstituted phenylalanine, substituted or unsubstituted histidine, and substituted or unsubstituted serine. Preferably the amino acid is substituted or unsubstituted phenylalanine or substituted or unsubstituted glutamic acid, and particularly preferably substituted or unsubstituted glutamic acid. When q is 2 or 3, preferably each of the amino acids forming the amino acid sequence is independently selected from the group consisting of substituted or unsubstituted glutamic acid, substituted or unsubstituted aspartic acid, substituted or unsubstituted phenylalanine, substituted or unsubstituted histidine, and substituted or unsubstituted serine. Preferably each of the amino acids in the amino acid sequence is substituted or unsubstituted phenylalanine or substituted or unsubstituted glutamic acid, and particularly preferably substituted or unsubstituted glutamic acid.

[0020] Group Y is connected to group X via a first peptide bond, and to part L via a second peptide bond. u It may be bound to. If group X has a sequence of two or three amino acids, these amino acids are linked to each other by peptide bonds.

[0021] Groups X and Y may be the same or different. In one embodiment of the present invention, the term "substituted amino acid" refers to an amino acid having a phenyl ring, wherein the phenyl ring has one or two substituents independently selected from the group consisting of halogens and hydroxyls. The term "halogen" refers to fluorine, chlorine, bromine, or iodine unless otherwise specified. Preferably, the halogen is iodine. In a preferred embodiment, the phenyl ring has two substituents, one of which is iodine and the other substituent is hydroxyl.

[0022] According to the present invention, L in the compound of formula I can be L1 or L2, where v, x, and y are independently 1, 2, or 3. In a more preferred embodiment of the present invention, the linker L can be L1 or L2, where v, x, and y are independently 1. In a more preferred embodiment of the present invention, the linker L is L1, where v is 1.

[0023] According to the present invention, A in the compound of formula I may be A1 or A2. In a more preferred embodiment of the present invention, A is A1.

[0024] In a more preferred embodiment of the present invention, a compound of general formula I can be provided, wherein k is 1, m is 3, n is 2, p is 1 or 2, q is 1 or 2, u is 1, preferably p and q are 1, X and Y are independently substituted or unsubstituted phenylalanine or glutamic acid; L is L1 with v=1, or L2 with x and y=1, and A is A1 or A2.

[0025] In the first embodiment of the present invention, X is unsubstituted phenylalanine and Y is substituted or unsubstituted phenylalanine. Preferably, X is unsubstituted phenylalanine and Y is substituted phenylalanine, more preferably X is unsubstituted phenylalanine and Y is phenylalanine substituted with iodine and OH in the phenyl ring. In the first embodiment, L is preferably L1 or L2, and particularly preferably L1. Preferably, L is L1 with v=1, or L2 with x and y=1. In the first embodiment, A is preferably selected from the group consisting of A1 to A4. A is preferably A1 or A2, and particularly preferably A1. In the first embodiment, k is preferably 1, m is preferably 3, n is preferably 2, p is preferably 1, q is preferably 1, and u is preferably 1.

[0026] In the second embodiment of the present invention, X and Y are independently phenylalanine or glutamic acid. Preferably, both X and Y are glutamic acid. In the second embodiment, L is preferably L1 or L2, and particularly preferably L1. Preferably, L is L1 with v=1, or L2 with x and y=1. In the first embodiment, A is preferably selected from the group consisting of A1 to A4. A is preferably A1 or A2, and particularly preferably A1. In the first embodiment, k is preferably 1, m is preferably 3, n is preferably 2, p is preferably 1, q is preferably 1, and u is preferably 1.

[0027] If part A is A4, it is preferable that k, m, n, p, q, v, x, y, and z, as well as X, Y, and L in A4, have the same meanings as in part BM.

[0028] According to the present invention, the following compounds 1, 2, 4, 5, and 6 are preferred.

[0029] [ka] Compound 1 is a compound of general formula I, where k is 1, m is 3, n is 2, p, q, and u are 1, X and Y are phenylalanine; L is L1 with v=1, and A is A1.

[0030] [ka] Compound 2 is a compound of general formula I, where k is 1, m is 3, n is 2, p, q, and u are 1, X and Y are phenylalanine; L is L1 with v=1, and A is A1.

[0031] [ka] Compound 4 is a compound of general formula I, where k is 1, m is 3, n is 2, p, q, and u are 1, X is unsubstituted phenylalanine, Y is phenylalanine substituted with iodine and OH in the phenyl ring; L is L1 with v=1, and A is A1.

[0032] [ka] Compound 5 is a compound of general formula I, where k is 1, m is 3, n is 2, p, q, and u are 1, X and Y are glutamic acid; L is L1 with v=1, and A is A1.

[0033] [ka] Compound (6) is a compound of general formula I, where k is 1, m is 3, n is 2, p, q, and u are 1, X and Y are glutamic acid; L is L2, where x and y = 1, and A is A2.

[0034] Compounds of general formula I may exist in the form of tautomers or stereoisomers, depending on their structure. Therefore, compounds of general formula I include all enantiomers and all diastereomers. Accordingly, the present invention also encompasses tautomers, enantiomers, or diastereomers of compounds of general formula I, and mixtures thereof. Stereoisomerically homogeneous components can be isolated from such mixtures of enantiomers and / or diastereomers by known methods.

[0035] The present invention further provides complexes comprising a compound of general formula I as a ligand and a metal. Such complexes can be used as pharmaceuticals, particularly as pharmaceuticals for the diagnosis and treatment of prostate diseases. Metal complexation is preferably carried out via chelator moiety A. The complex is a coordination complex of the corresponding metal. The metal can exist as a metal ion or as a metal oxide. In metal oxides, the metal can exist as an ion. In one embodiment, the complex may consist of a compound of general formula I as a ligand and a metal ion. In another embodiment, the complex may consist of a compound of general formula I as a ligand and a metal oxide. The metal forms the central particle of the complex of the present invention.

[0036] In a preferred embodiment of the present invention, the metal is selected from the group consisting of rhenium ions, technetium ions, and copper ions. Preferably, the metal is a radioactive metal. Therefore, a preferred complex is a metal complex comprising a radionuclide and a compound of general formula I.

[0037] More preferably, the metal is 99m Tc, 99 Tc, 94m Tc, 186 Re, 188 Re, 64 Cu and 67 It is an isotope selected from the group consisting of Cu. More preferably, the metal is 99m Tc, 186 Re and 188 It is an isotope selected from the group consisting of Re. 99m It is Tc.

[0038] In one embodiment of the present invention, the complex is a compound of formula ReO-5: [ka] (wherein Re is a rhenium ion). Preferably, the rhenium ion is 186Re or 188 It is Re. The rhenium ion exists as part of ReO.

[0039] In one embodiment of the present invention, the complex is a compound of formula TcO-5: [ka] (wherein Tc is a technetium ion). Preferably, the technetium ion is 99m Tc, 99 Tc, 94m It is an isotope selected from the group consisting of Tc. The technetium ion exists as part of TcO. Particularly preferably, the technetium ion is an isotope. 99m Tc. In a preferred embodiment of the present invention, the complex is of formula [ 99m It is a compound of Tc]TcO-5: [ka]

[0040] 99m For the production and application of Tc-containing complexes, their respective ligands, i.e., each compound of general formula I, are commercially available 99 Mo / 99m Sodium pertechnetate in physiological saline, such as that provided by the Tc Generator [ 99m This can be achieved by reacting [Tc] with the applied and adapted method described in the literature (IAEA. Labelling of small biomolecules using novel Technetium-99m Cores; International Atomic Energy Agency: Vienna, 2007). Sodium pertechnetate [ 99m [Tc] exists within 99m In the complex of Tc(VII), 99m It exists as Tc(V)O 99mTo enable the necessary reduction to Tc(V), a reducing agent, preferably stannous chloride, is used under optimized conditions, for example, its preparation is carried out under acidic conditions, preferably using dilute hydrochloric acid, under saturation by a flow of an inert gas, such as helium, and thus excluding oxygen. The labeling step is carried out under weakly acidic conditions, for example, in a pH range of 5 to 6.5. The total volume of the reaction solution can be in the range of 0.2 to 12 mL, and sodium pertechnetate ( 99m The amount of Tc) can be in the range of 0.1 to 50 GBq. The amount of ligand used may vary depending on the volume of the generator eluate used (10 to 200 μg). The labeling step can be carried out at room temperature. In particular, the reaction parameters used may require elevated temperatures up to 100°C, preferably up to 80°C, in order to complete the reaction or to minimize the reaction time. Furthermore, heating for a specific period, e.g., heating at 80°C for 20 minutes, is advantageous because it leads to the decomposition of unreacted excess ligand and thus supports the imaging properties of the complex. If labeling is incomplete, the complex-containing solution can be purified by solid-phase extraction (SPE) or semi-preparative HPLC, for example, using RP-C18 or Sephadex (G-25, superfine) as the stationary phase. Auxiliary materials that contribute to complete conversion and minimize the reaction time, such as salts of gluconic acid or heptagluconic acid, preferably calcium heptagluconate, can be used. Other auxiliary substances such as D-mannose, galactose, or cyclodextrin can be used, with D-mannose being preferred. Similarly, stabilizers and antioxidants, such as dithiothreitol and ascorbic acid, can be used, respectively.

[0041] The complexes according to the present invention can bind to prostate-specific membrane antigen (PSMA). Therefore, they are ligands for prostate-specific membrane antigen (PSMA). Hereinafter, the complexes according to the present invention will also be referred to as ligands or PSMA ligands. If a complex contains a radioactive metal, it will also be referred to as a radioactive ligand or PSMA radioactive ligand.

[0042] The PSMA ligands according to the present invention include a urea-based pharmacophore group BM, various amino acid sequences in the linker-XY-, and various N2S2 chelators. A synthetic strategy that does not require mercury-containing intermediates has been employed, enabling the production of the PSMA ligands of the present invention free from potentially toxic mercury impurities. Mercury salts are commonly applied to cleave thiol protecting groups; see Peter GM Wuts, Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, 2014.

[0043] Compounds of general formula I can be synthesized by various methods using known synthetic routes, for example, by using the Merrifield synthesis (see Robert Bruce Merrifield, Solid phase peptide synthesis, Journal of the American Chemical Society, Volume 85, issue 14 pp. 2149-2154). One method provides compounds of general formula II. [ka] [In the formula, R 11 represents a solid carrier, preferably a 2-CTC resin, and R 12 and R 13 [where represents an orthogonal protecting group, and n has a meaning given in relation to general formula I]. In a preferred embodiment, R 12 is Fmoc, R 13 is Dde. In another preferred embodiment, R 12 is Dde, and R 13 It is Fmoc.

[0044] R 12 Dde is R 13If is Fmoc, the first synthetic route can be used. In the first synthetic route, the Fmoc deprotection of the compound of general formula II is performed in the first step, thereby producing the first reaction product of general formula III. [ka] In the second step, the first reaction product of general formula III and general formula IV are obtained. [ka] An amide coupling occurs between the compound and the general formula V, thereby performing an amide coupling. [ka] A second reaction product of general formula V and general formula VI is obtained. In the third step, the second reaction product of general formula V and general formula VI [ka] An amide coupling is performed between the compound and the compound, thereby forming general formula VII [ka] A third reaction product is obtained. In the fourth step, Dde cleavage of the compound of general formula VII is performed, thereby yielding general formula VIII [ka] A fourth reaction product is obtained.

[0045] In the fifth step, General Formula IX [ka] The fifth reaction product is synthesized. Part X p X is part of general formula I pThis corresponds to the condition that the reactive side chain can be protected by a protecting group. For example, -COOH can be protected as -COOtBu. To synthesize the reaction product of general formula IX, if p=1, an amide coupling is performed between the fourth reaction product of general formula VIII and the compound of general formula Fmoc-X-OH. If p=2, a first amide coupling is performed between the fourth reaction product of general formula VIII and the first compound of general formula Fmoc-X-OH, thereby obtaining an intermediate. After Fmoc deprotection of the intermediate, a second amide coupling is performed between the Fmoc-deprotected intermediate and the second compound of general formula Fmoc-X-OH. When p=3, a first amide coupling occurs between the fourth reaction product of general formula VIII and the first compound of general formula Fmoc-X-OH, thereby obtaining a first intermediate. After Fmoc deprotection of the first intermediate, a second amide coupling occurs between the Fmoc-deprotected first intermediate and the second compound of general formula Fmoc-X-OH, thereby obtaining a second intermediate. After Fmoc deprotection of the second intermediate, a third amide coupling occurs between the Fmoc-deprotected second intermediate and the third compound of general formula Fmoc-X-OH.

[0046] In the sixth step, General formula X [ka] The sixth reaction product is synthesized. Part Y q This is part Y of general formula I. qThis corresponds to the condition that the reactive side chain can be protected by a protecting group. For example, -COOH can be protected as -COOtBu. To synthesize the reaction product of general formula X, if q=1, the reaction product of general formula IX is deprotected by Fmoc, and then an amide coupling is performed between the Fmoc-deprotected reaction product of general formula IX and a compound of general formula Fmoc-Y-OH. If q=2, the reaction product of general formula IX is deprotected by Fmoc, and then a first amide coupling is performed between the Fmoc-deprotected reaction product of general formula IX and a first compound of general formula Fmoc-Y-OH, thereby obtaining an intermediate, and after Fmoc deprotection of the intermediate, a second amide coupling is performed between the Fmoc-deprotected intermediate and a second compound of general formula Fmoc-Y-OH. When q=3, the reaction product of general formula IX is deprotected by Fmoc, followed by a first amide coupling between the Fmoc-deprotected reaction product of general formula IX and a first compound of general formula Fmoc-Y-OH, thereby obtaining a first intermediate. After the Fmoc deprotection of the first intermediate, a second amide coupling is performed between the Fmoc-deprotected first intermediate and a second compound of general formula Fmoc-Y-OH, thereby obtaining a second intermediate. After the Fmoc deprotection of the second intermediate, a third amide coupling is performed between the Fmoc-deprotected second intermediate and a third compound of general formula Fmoc-Y-OH.

[0047] If u=1, in the seventh step, the reaction product of general formula X is deprotected by Fmoc, followed by amide coupling between the resulting reaction product and the compound of general formula Fmoc-L-OH, thereby producing general formula XI [ka] The reaction product is obtained. Part L corresponds to part L of general formula I, provided that the reactive side chain can be protected by a protecting group.

[0048] In the eighth step, if u=1, the reaction product of general formula XI is deprotected by Fmoc, or if u=0, the reaction product of general formula X is deprotected by Fmoc, followed by amide coupling between the resulting reaction product and the compound of general formula A-OH, thereby producing general formula XII [ka] The reaction product is obtained. Part A corresponds to part A of general formula I, provided that the reactive side chain can be protected by a protecting group. For example, -COOH can be protected as -COOtBu, and the PMB protecting group may be on the thiol group of A. In the next step, the reaction product of general formula XII is cleaved from the 2-CTC resin and deprotected by removing all protecting groups, thereby obtaining the compound of general formula I. In formulas II to XII, the subscripts k, m, n, p, q, u, v, x, y, and z have the meanings given in the context of general formula I.

[0049] R 12 Fmoc is R 13 If is Dde, a second synthetic route can be used. In the second synthetic route, the first step involves the Fmoc deprotection of the compound of general formula II, thereby producing general formula XIII [ka] The first reaction product of general formula XIV is obtained. In the second step, [ka] The second reaction product is synthesized. Part X p X is part of general formula I pThis corresponds to the condition that the reactive side chain can be protected by a protecting group. For example, -COOH can be protected as -COOtBu. To synthesize the reaction product of general formula XIV, if p=1, an amide coupling is performed between the first reaction product of general formula XIII and the compound of general formula Fmoc-X-OH. If p=2, a first amide coupling is performed between the first reaction product of general formula XIII and the first compound of general formula Fmoc-X-OH, thereby obtaining an intermediate. After Fmoc deprotection of the intermediate, a second amide coupling is performed between the Fmoc-deprotected intermediate and the second compound of general formula Fmoc-X-OH. When p=3, a first amide coupling occurs between the first reaction product of general formula XIII and the first compound of general formula Fmoc-X-OH, thereby obtaining a first intermediate. After Fmoc deprotection of the first intermediate, a second amide coupling occurs between the Fmoc-deprotected first intermediate and the second compound of general formula Fmoc-X-OH, thereby obtaining a second intermediate. After Fmoc deprotection of the second intermediate, a third amide coupling occurs between the Fmoc-deprotected second intermediate and the third compound of general formula Fmoc-X-OH.

[0050] In the third step, General formula XV [ka] A third reaction product is synthesized. Part Y q This is part Y of general formula I. qThis corresponds to the condition that the reactive side chain can be protected by a protecting group. For example, -COOH can be protected as -COOtBu. To synthesize the reaction product of general formula XV, when q=1, the reaction product of general formula XIV is deprotected by Fmoc, and then an amide coupling is performed between the Fmoc-deprotected reaction product of general formula XIV and a compound of general formula Fmoc-Y-OH. When q=2, the reaction product of general formula XIV is deprotected by Fmoc, and then a first amide coupling is performed between the Fmoc-deprotected reaction product of general formula XIV and a first compound of general formula Fmoc-Y-OH, thereby obtaining an intermediate. After Fmoc deprotection of the intermediate, a second amide coupling is performed between the Fmoc-deprotected intermediate and a second compound of general formula Fmoc-Y-OH. When q=3, the reaction product of general formula XIV is deprotected by Fmoc, followed by a first amide coupling between the Fmoc-deprotected reaction product of general formula XIV and a first compound of general formula Fmoc-Y-OH, thereby obtaining a first intermediate. After the Fmoc deprotection of the first intermediate, a second amide coupling is performed between the Fmoc-deprotected first intermediate and a second compound of general formula Fmoc-Y-OH, thereby obtaining a second intermediate. After the Fmoc deprotection of the second intermediate, a third amide coupling is performed between the Fmoc-deprotected second intermediate and a third compound of general formula Fmoc-Y-OH.

[0051] If u=1, in the fourth step, the reaction product of general formula XV is deprotected by Fmoc, followed by amide coupling between the resulting reaction product and the compound of general formula Fmoc-L-OH, thereby producing general formula XVI. [ka] The reaction product is obtained. Part L corresponds to part L of general formula I, provided that the reactive side chain can be protected by a protecting group.

[0052] In the fifth step, if u=1, the reaction product of general formula XVI is deprotected by Fmoc, or if u=0, the reaction product of general formula XV is deprotected by Fmoc, followed by amide coupling between the resulting reaction product and the compound of general formula A-OH, thereby producing general formula XVII [ka] The reaction product is obtained. Part A corresponds to part A of general formula I, provided that the reactive side chain can be protected by a protecting group. For example, -COOH can be protected as -COOtBu, and the PMB protecting group may be on the thiol group of A.

[0053] In the sixth step, Dde cleavage is performed on the compound of general formula XVII, thereby producing general formula XVIII [ka] The reaction product of general formula XVIII and general formula IV is obtained. In the seventh step, the reaction product of general formula XVIII and general formula IV [ka] An amide coupling is performed between the compound and the compound, thereby producing the general formula XIX [ka] The reaction product of general formula XIX and general formula VI is obtained. In the eighth step, the reaction product of general formula XIX and general formula VI [ka] An amide coupling occurs between the compound and the compound, thereby producing the general formula XII [ka] The reaction product of general formula XII is obtained. In the next step, the reaction product of general formula XII is cleaved from the 2-CTC resin and deprotected by removing all protecting groups, thereby obtaining the compound of general formula I. In formulas XII to XIX, the subscripts k, m, n, p, q, u, v, x, y, and z have the meanings given in the context of general formula I.

[0054] The synthesis of compounds of general formula I is described in more detail in the Examples section.

[0055] N2S2 chelators incorporated into compounds of general formula I can be used to label these PSMA ligands with various metals by complex formation. These complexes are useful for the diagnosis and treatment of PSMA-related diseases, such as prostate cancer. The complexes are also useful for the diagnosis and treatment of specific diseases in which PSMA is upregulated. Prostate cancer is one example of a disease in which PSMA is upregulated.

[0056] Surprisingly, in the LNCaP xenograft model, compound 5 in particular was found to exhibit faster pharmacokinetic properties and more favorable organ distribution (high tumor uptake, low to moderate uptake in non-target organs such as the kidney) than those known from prior art. High tumor-to-muscle and tumor-to-kidney ratios were achieved as early as one hour after injection, enabling early imaging. Further increases in tumor-to-muscle and tumor-to-kidney ratios over time were observed. These findings suggest better visualization of tumors compared to compounds known from prior art.

[0057] To demonstrate the effects of parts X and Y of the compound of the present invention, the inventors have used the general formula BM-L u A comparative compound of -A (wherein BM, L, A, and u have meanings related to general formula I) was synthesized. General formula BM-L u Compound A is a compound of general formula I, where p is 0 and q is 0. Comparative compound BM-L u - An example of A is comparative compound 3.

[0058] [ka] The comparison between compound 5 and compound 3 revealed that the advantageous properties of the compound of general formula I may arise from the presence of amino acids X and Y in the compound of general formula I. Although not bound by this explanation, the inventors believe that the faster pharmacokinetic properties and more favorable organ distribution (high tumor uptake, low to moderate uptake in non-target organs such as the kidneys) of compound 5 compared to comparative compound 3 can be explained by the presence of partials X and Y in the compound of general formula I.

[0059] A prostate cancer imaging agent approved by the U.S. Food and Drug Administration (FDA), well-researched, and widely used. 68 Compared to Ga-PSMA-11 (which is a PET tracer), 99m The complexes of Tc and compounds of general formula I were surprisingly found to have similar properties in the in vivo and in vitro experiments described herein. The compounds of the present invention showed similar affinity to PSMA, higher internalization in LNCaP tumor cells, and comparable tumor uptake values ​​in LNCaP xenograft models when compared 1 hour after injection of each compound. Since technetium and rhenium correspond to a theranostic pair, the inventors believed that, 186 A complex of Re and a compound of general formula I, and 188 Similar properties are expected for complexes of Re with compounds of general formula I.

[0060] Therefore, the complex according to the present invention can be used as a pharmaceutical, particularly as a pharmaceutical for diseases involving PSMA. Furthermore, pharmaceutically acceptable salts of the complex according to the present invention can be used as a pharmaceutical, particularly as a pharmaceutical for diseases involving PSMA. In one embodiment, the complex according to the present invention can be used as a pharmaceutical in the diagnosis and treatment of diseases involving PSMA. Furthermore, pharmaceutically acceptable salts of the complex according to the present invention can be used as a pharmaceutical in the diagnosis and treatment of diseases involving PSMA. Diseases involving PSMA are, for example, diseases in which PSMA is upregulated. An example of a disease in which PSMA is upregulated is prostate cancer.

[0061] Accordingly, the present invention provides for the use of the complex according to the present invention as a pharmaceutical. Furthermore, it provides for the use of the complex according to the present invention as a pharmaceutical in the diagnosis and treatment of diseases involving PSMA. The pharmaceutical may be a radiopharmaceutical. Preferably, the pharmaceutical is a radiopharmaceutical for nuclear medicine imaging. For example, the pharmaceutical is a radiopharmaceutical for nuclear medicine imaging by single-photon emission computed tomography (SPECT) or positron emission tomography (PET). Also preferably, the pharmaceutical is a radiopharmaceutical for radioligand therapy. In a preferred embodiment, 99m Tc, 186 Re, 188 Re and 67 The complex of the present invention, comprising a metal selected from the group consisting of Cu, is used as a radiopharmaceutical for nuclear medicine imaging by single-photon emission computed tomography (SPECT). In another preferred embodiment, 94m Tc or 64 The Cu-containing complex of the present invention is used as a radiopharmaceutical for nuclear medicine imaging by positron emission tomography (PET). In yet another preferred embodiment, 186 Re, 188 Re, 64 Cu and67 The complex of the present invention containing a metal selected from the group consisting of Cu is used as a radiopharmaceutical for radio-ligand therapy. Instead of the pharmaceutical containing the compound of general formula I according to the present invention, pharmaceutically acceptable salts of said compound can be used. Due to its long half-life of 211,000 years, 99 The complex of the present invention containing Tc can be used for elucidating the structure of the shape of the complex of the present invention.

[0062] According to the present invention, there is further provided a method for producing a complex containing a compound of general formula I as a ligand and a metal. The method includes the step of contacting the compound of general formula I with a metal. In a preferred embodiment, the compound of general formula I is contacted with a metal at a reaction temperature in the range of 20 to 100 °C. Preferably, the compound of general formula I according to the present invention is contacted with a metal at room temperature. Preferably, the compound of general formula I is contacted with a metal at ambient pressure. The molar ratio of the compound of general formula I to the non-radioactive metal ions in solution can be 1:1. Preferably, the method according to the present invention is carried out using a protic solvent, such as water. The pH value can be selected according to the metal used.

[0063] Hereinafter, the present invention will be described in more detail with reference to examples, but it is not intended to limit the present invention with respect to the drawings.

Brief Description of the Drawings

[0064] Here Figure 1 shows the functional imaging of subcutaneous LNCaP tumor xenografts in mice using [99mTc]TcO-5 [= [99mTc]TcO-ABX474], compared with a reference compound. 99m [99mTc]TcO-5 [= 99m [99mTc]TcO-ABX474] Figure 2 shows a diagram showing the tumor-to-background kinetics of [99mTc]TcO-5 [= [99mTc]TcO-ABX474] in LNCaP tumor-bearing mice, compared with a reference compound. 99m [99mTc]TcO-5 [= 99m [99mTc]TcO-ABX474] Figure 3 shows in LNCaP tumor-bearing mice 99mThe figure shows tumor uptake of Tc-labeled radioactive ligand. Figure 4 shows the results in LNCaP tumor-carrying mice. 99m Tc]TcO-5 [= [ 99m The figure shows the tumor-to-background dynamics of [Tc]TcO-ABX474] compared to a reference compound. Figure 5 shows the [ 99m The figure shows the tumor-to-background ratio of Tc-labeled radioactive ligands. [Examples]

[0065] example General synthesis methods for compounds 1, 2, 4, 5, and 6

[0066] Compounds 1, 2, 4, 5, and 6 were synthesized by solid-phase peptide synthesis (SPPS) in 2-chlorotrityl resin.

[0067] The synthesized molecules were analyzed using reverse-phase high-performance liquid chromatography (RP-HPLC; Ascentis Express C18, 150x4.6mm; Supelco, Germany) with a linear AB gradient (from 5% B to 100% B in 10 minutes) at a flow rate of 1.5 mL / min (analysis). Purification was performed using reverse-phase high-performance liquid chromatography (RP-HPLC; Gemini-NX C18, 250x50mm; Phenomenex, Germany) with a linear AB gradient at a flow rate of 100 mL / min. Solvent A consisted of 0.1% aqueous TFA, and solvent B was 0.1% TFA in ACN.

[0068] The HPLC system (Dionex Ultimate 3000; Thermo-Fisher, Germany) was equipped with a UV detector. UV absorbance was measured at 200, 210, and 230 nm. Mass spectrometry was performed using an LC-MS system (Dionex 3000, Thermo-Fisher, Germany).

[0069] Examples 1-4 Synthesis of intermediates

[0070] The following intermediates were prepared to prepare compounds 1-6.

[0071] Example 1 Synthesis of intermediate 101: Glu-CO-Im((di-tert-butyl(1H-imidazole-1-carbonyl)-L-glutamate))

[0072] H-Glu(OtBu)-OtBu (29.59 g, 1 equivalent 100 mmol) was dissolved in 400 ml of DCM. Triethylamine (25.3 g, 2.5 equivalents, 250 mmol) was slowly added. Carbonyl diimidazole (17.84 g, 1.1 equivalents, 110 mmol) was added in small amounts. The reaction was stirred for 4 hours. The solution was washed with water, NaHCO3, and brine. The organic phase was dried over Na2SO4 and evaporated under reduced pressure to obtain the target compound 101 as an oil.

[0073] Example 2 Synthesis of intermediate 103: N'-[2-(4-methoxybenzylsulfanyl)-ethyl]-N'-{2-[4-methoxybenzylsulfanyl)-ethylamino]-ethyl}propane-l,3-diamine [ka]

[0074] The synthesis of intermediate 103 was carried out in the same manner as in WO2012 / 022812A1. Step 1: 2-(4-methoxy-benzylsulfanyl)-ethylamine (compound 104)

[0075] Sodium (4.5 g, 196 mmol) was added to vigorously stirred methanol (150 ml, dry). Once the sodium was completely dissolved, 2-aminoethanethiol hydrochloride (10.8 g, 95.0 mmol) was added. Then, p-methoxybenzyl chloride (14.9 g, 95.5 mmol) was added via a dropping funnel. The mixture was heated under reflux at 70°C for 30 minutes. The mixture was then cooled to room temperature. The solid was removed by filtration, and the filter cake was washed with methanol (three times with 25 ml). The organic extracts were combined, and volatile substances were removed under reduced pressure. This residue was redissolved in DCM (75 ml), extracted with water (75 ml x 3), dried (MgSiO4), filtered, and the solvent was removed to obtain compound 104 as a colorless oil. Yield 18.5 g (99%).

[0076] Step 2: N-[(4-methoxy-benzylsulfanyl)-ethyl]-2-chloroacetamide (compound 105)

[0077] Chloroacetyl chloride (4.24 ml, 53.2 mmol) in 50 ml of dry DCM was added dropwise to an ice-bath cooled (0°C) solution of 2-(4-methoxy-benzylsulfanyl)-ethylamine 104 (9.4 g, 47.5 mmol) and triethylamine (8.0 ml) in 200 ml of dry DCM, while stirring for 90 minutes. After addition, the cooling bath was removed and stirring was continued for 60 minutes. The solution was extracted with water (2 × 250 ml), dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure to obtain compound 105 as a colored solid. Yield: 12.93 g (99%).

[0078] Step 3: Methyl 3-[(4-methoxy-benzylsulfanyl)-ethylamino]-propanoate (Compound 106)

[0079] Methyl acrylate (4.46 ml, 49.2 mmol) in methanol (10 ml) was added to a stirred solution of 2-(4-methoxy-benzylsulfanyl)-ethylamine 104 (8.85 g, 48.3 mmol) in methanol (50 ml). The colorless solution was stirred at room temperature for 6 hours. Volatile substances were removed by rotary evaporation to obtain compound 106 as a colorless viscous oil. Yield: 1.35 g (97%).

[0080] Step 4: 3-[2-(4-methoxybenzylsulfanyl)-ethylamino]-propanamide (compound 107)

[0081] Methyl 3-[(4-methoxy-benzylsphanyl)-ethylamino]propanoate 106 (10.65 g, 37.6 mmol), methanol (120 ml), and ammonia solution (200 ml) were stirred at room temperature for 24 hours. Volatile substances were removed under reduced pressure to obtain compound 107 as a nearly white solid. Yield 9.98 g (99%).

[0082] Step 5: 3-([2-(4-methoxy-benzylsulfanyl)-ethyl]-{[2-(4-methoxy-benzylsulfanyl)-ethylcarbamoyl]-methyl}-amino)-propionamide (compound 108)

[0083] 3-[2-(4-methoxybenzylsulfanyl)-ethylamino]propenamide 106 (10.33 g, 38.5 mmol), N-[(4-methoxy-benzylsulfanyl)-ethyl]-2-chloroacetamide 105 (10.54 g, 38.5 mmol), triethylamine (6.5 ml), and acetonitrile (80 ml) were heated overnight at 70°C. The mixture was then cooled to room temperature. The solvent was removed under reduced pressure to obtain a brown residue, which was purified with silica eluted with DCM / methanol 20:1 to obtain compound 108 as a colorless oil (yield 8.3 g, 43%).

[0084] Step 6: N'-[2-(4-methoxy-benzylsulfanyl)-ethyl]-N'-{2-[4-methoxy-benzylsulfanyl)-ethylamino]-ethyl}-propane-1,3-diamine (compound 109)

[0085] 1.0 M borane in THF (102 ml, 102 mmol) was added to 3-([2-(4-methoxybenzylsulfanyl)-ethyl]-{[2-(4-methoxybenzylsulfanyl)-ethylcarbamoyl]-methyl}-amino)-propionamide 108 (3.8 g, 7.5 mmol) via syringe under an argon atmosphere. The resulting colorless solution was heated under reflux at 70°C overnight. After cooling to room temperature, water (40 ml) was added dropwise. The solvent was removed under reduced pressure to obtain a waxy solid, which was diluted with HCl (0.5 N, 400 ml). The mixture was heated under reflux at 100°C for 3 hours. After cooling to room temperature, sodium hydroxide was added until a pH of 10-11 was obtained. The mixture was extracted with DCM (4 × 200 ml), the organic fractions were combined, dried (MgSO4), and filtered. The solvent was evaporated to obtain a waxy solid, which was purified with silica eluted in a DCM / methanol / NH4OH ratio of 9:1:0.1 to obtain compound 109 as a colorless oil. Yield: 1.29 mg (36%).

[0086] Example 3 Synthesis of intermediate 4: N-Boc-N'-(5-carboethoxypentyl-N,N'-bis-(2-(4-methoxybenzylthio)-2-methylpropyl)-ethylenediamine (compound 110) [ka]

[0087] The synthesis of intermediate 110 was carried out in the same manner as in US5776428A.

[0088] Step 1: 2,2'-Dithiobis(2-methylpropanal) (Compound 111)

[0089] 28.8 g, 0.4 mol of 2-methylpropanal in 30 ml of carbon tetrachloride was mixed with 27 g, 0.2 mol of sulfur monochloride. The reaction mixture was stirred at 50°C for 16 hours. After cooling to room temperature, volatile substances were evaporated under vacuum, and the residue was purified by distillation under vacuum (bp at 0.5 Torr: 98-102°C) to obtain 22.7 g (55%) of 2,2'-dithiobis(2-methylpropanal) 111.

[0090] Step 2: 3,3,10,10-tetramethyl-6,7-dihydro-1,2,5,8-dithiadiazecin (compound 112)

[0091] 5 g of 2,2'-dithiobis(2-methylpropanal) 111 was added to a stirred solution in 20 mL of chloroform, to which 1.8 g of ethylenediamine was added. The reaction mixture was stirred at room temperature for 2 hours. After removing the solvent, the residue was ground with water until crystals began to form. The white crystals were collected by filtration and washed with ethanol to obtain 4.8 g (86%) of 3,3,10,10-tetramethyl-6,7-dihydro-1,2,5,8-dithiadiazecin 112.

[0092] Step 3: N,N'-bis(2-mercapto-2-methylpropyl)ethylenediamine (Compound 113)

[0093] 4.1 g (18 mmol) of 3,3,10,10-tetramethyl-6,7-dihydro-1,2,5,8-dithiadiazecin 112 was dissolved in 70 ml of dry THF, and 1.35 g of LiAlH4 (0.36 mmol) was added with stirring (under an argon atmosphere). The reaction mixture was refluxed for 4 hours, followed by hydrolysis by carefully adding saturated NaK tartrate solution (20 ml), and then diethyl ether (100 ml). The sludge was separated by decant or filtration (Celite) and thoroughly washed with ether. The solvent was removed under vacuum to obtain 0.8 g (20%) of compound 113.

[0094] Step 4: N,N'-bis-(2-(4-methoxybenzylthio)-2-methylpropyl)-ethylenediamine (compound 114)

[0095] A solution of N,N'-bis(2-mercapto-2-methylpropyl)ethylenediamine 113 (1.1 g, 4.65 mmol) in methanol (50 mL) was cooled in an ice / water bath and then saturated with gaseous ammonia for 30 minutes. 4-methoxybenzyl chloride (1.9 g, 12.3 mmol) was added. The reaction mixture was warmed to room temperature overnight with stirring under argon. The methanol was evaporated under reduced pressure, and the residue was partitioned between diethyl ether (50 mL) and 0.5 M KOH (40 mL). The aqueous layer was further extracted with diethyl ether (2 × 25 mL). The combined organic layers were washed with NaCl solution and concentrated under vacuum to obtain a clear, colorless oil. The oil was dissolved in diethyl ether (200 mL) and then acidified with 4.0 M HCl in dioxane. The white precipitate was collected by filtration and washed with diethyl ether. The HCl salt was partitioned between 1 M KOH (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 30 mL), the combined organic layers were washed with NaCl, dried over Na₂SO₄, and concentrated to obtain pure compound 114 (free base) as a pale yellow oil (0.99 g, yield 45%).

[0096] Step 5: N-(5-carboethoxypentyl-N,N'-bis-(2-(4-methoxybenzylthio)-2-methylpropyl)-ethylenediamine (compound 115)

[0097] N,N'-bis-(2-(4-methoxybenzylthio)-2-methylpropyl)-ethylenediamine 114 (921 mg, 1.93 mmol) was added to acetonitrile (15 mL), followed by K2CO3 (270 mg), and then ethyl 5-bromovalerate (807 mg). The reaction mixture was stirred overnight under reflux and then concentrated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and 0.5 M KOH (50 mL). The aqueous layer was extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to obtain a yellow oil. This was purified with silica eluted in a DCM / methanol ratio of 20:1 to obtain the desired compound 115 as a yellowish oil. Yield: 635 mg (54%)

[0098] Step 6: N-Boc-N'-(5-carboethoxypentyl-N,N'-bis-(2-(4-methoxybenzylthio)-2-methylpropyl)-ethylenediamine (compound 116)

[0099] N-(5-carboethoxypentyl)-N,N'-bis-(2-(4-methoxybenzylthio)-2-methylpropyl)ethylenediamine 115 (635 mg, 1.05 mmol) was added to THF (40 mL), to which water (30 mL) and 1 M KOH (2.5 mL, 2.5 mmol) were added. The homogeneous solution was refluxed overnight. The solution was then cooled to room temperature, and the THF was removed under vacuum. The residue was diluted with 50 mL of water, and the pH was adjusted to 2-3 by adding 1 M HCl. The solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum to obtain 575 mg of crude intermediate.

[0100] The crude intermediate was dissolved in ACN (50 mL) and Boc2O (326 mg), followed by triethylamine (0.280 mL). The homogeneous solution was stirred overnight under argon at room temperature. The solution was then concentrated under vacuum and subsequently partitioned between ethyl acetate (25 mL) and 1 M KH2PO4 (25 mL). The organic layer was washed with 5% citric acid (2 × 25 mL) and brine (25 mL), dried over Na2SO4, and concentrated to obtain a yellow oil (890 mg). Purification by silica column chromatography eluting with DCM / methanol = 20:1 yielded compound 116 as a yellowish oil. Yield 455 mg (64%).

[0101] Example 4 Synthesis of compound 5 [ABX 474]

[0102] Compound 5 of the present invention [ka] The synthesis is shown in scheme EX-1.

[0103] [ka] In scheme EX-1, letter a) indicates the use of 20% piperidine in DMF; letter b) indicates the use of Fmoc-Glu(OtBu)-OH, HATU, HOAt, DIPEA, and DMF; letter c) indicates the use of intermediate 110, PyBOP, DIPEA, and DMF; letter d) indicates the use of N2H2.H2O in DMF; letter e) indicates the use of Sub-NHS, DIPEA, and DMF; letter f) indicates the use of TSTU, DIPEA, and DMF; letter g) indicates the use of Fmoc-Lys-OtBu, DIPEA, and DMF; letter h) indicates the use of Glu-CO-Im, NMM, and DMF; letter i) indicates the use of TFA:TIS:H2O:EDT(92.5:2.5:2.5:2.5), and letter j) indicates the use of 10% TFMSA.

[0104] For the synthesis of compound 501, Fmoc-D-Lys(Dde)-OH was loaded onto a 2-CTC resin (in scheme EX-1, the resin is represented by a circle), and Fmoc was deprotected with 20% piperidine in DMF. Next, for the synthesis of compounds 502 and 503, Fmoc-Glu(OtBu)-OH (2 equivalents) was activated with HATU (2 equivalents), HOAt (2 equivalents), and DIPEA (5,6 equivalents) in DMF and added to the resin. The reaction mixture was stirred at room temperature (rt) for 2 hours. Fmoc deprotection was performed using 20% ​​piperidine in DMF. For the synthesis of compound 504, intermediate 110 was conjugated to a peptide sequence using PyBOP (2 equivalents) and DIPEA (2 equivalents) in DMF for 2 hours at room temperature. Dde deprotection was performed using 2% hydrazine monohydrate in DMF. Subsequently, to synthesize compound 505, suberic acid mono-NHS ester (2 equivalents) and DIPEA (2 equivalents) were dissolved in DMF (1 mL) and reacted with the resin-bound peptide at room temperature for 2 hours. Then, to synthesize compound 506, the free carboxylic acid was treated with TSTU (2 equivalents) and DIPEA (2 equivalents) in DMF (10 mL / 1 g resin) for 1 hour at room temperature. After the formation of the NHS ester, the resin-bound peptide was treated with Fmoc-Lys-OtBu (2 equivalents) and DIPEA (2 equivalents) in DMF (2 mL) for 2 hours at room temperature. Fmoc was cleaved with 20% piperidine in DMF, and then the free amine was treated with Glu-CO-Im (intermediate 101, 3 equivalents) and NMM (3 equivalents) in DMF for 2 hours at room temperature. After the final coupling, the resin was washed with DMF (3 x 5 mL), DCM (3 x 5 mL), IPA (3 x 5 mL), and Et2O (3 x 5 mL). For the synthesis of compound 5, cleavage and final deprotection were performed from the resin by treatment with TFA / TIS / EDT / water (v / v / v / v; 92.5 / 2.5 / 2.5 / 2.5) at 0°C, followed by the dropwise addition of 10% TFMSA.

[0105] The crude peptide was precipitated from ice-cold diethyl ether and purified by RP-HPLC. After RP-HPLC purification, compound 4 [ABX 474] (TFA salt) was obtained as a white to off-white solid (isolation yield 38%). Calculated monoisotopic mass (C 51 H 89 N9O 18 S2): 1179.58; found: m / z = 1180.5 [M+H] + , 590.79 [M+2H] 2+ .

[0106] Example 5 Synthesis of compound 6 [ABX 490]

[0107] Compound 6 of the present invention

Chem.

[0108]

Chem.

[0109] For the synthesis of compound 601, Dde-D-Lys(Fmoc)-OH was loaded onto a 2-CTC resin (in scheme EX-2, the resin is represented by a circle), and Fmoc was deprotected with 20% piperidine in DMF. Subsequently, to synthesize compound 602, suberic acid mono-NHS ester (2 equivalents) and DIPEA (2 equivalents) were dissolved in DMF (1 mL) and reacted with the resin-bound peptide at room temperature for 2 hours. Then, to synthesize compound 603, the free carboxylic acid was treated with TSTU (2 equivalents) and DIPEA (2 equivalents) dissolved in DMF (2 mL) and reacted at room temperature for 1 hour. After the formation of the NHS ester, the resin-bound peptide was treated with Fmoc-Lys-OtBu (2 equivalents) and DIPEA (2 equivalents) in DMF (1 mL) for 2 hours at room temperature. To synthesize compound 604, Fmoc was cleaved with 20% piperidine in DMF, and the free amine was then treated with Glu-CO-Im101 (3 equivalents) and NMM (3 equivalents) in DMF at room temperature for 2 hours. Dde deprotection was performed using 2% hydrazine monohydrate in DMF. Subsequently, to synthesize compound 605, Fmoc-Glu(OtBu)-OH (2 equivalents) was activated with PyBOP (2 equivalents), HOBt (2 equivalents), and DIPEA (2 equivalents) in DMF and added to the resin. The reaction mixture was stirred at room temperature for 2 hours. To synthesize compound 606, Fmoc was deprotected with 20% piperidine in DMF. Succinic anhydride (2 equivalents) and DIPEA (2 equivalents) dissolved in DMF (2 mL) were added to the resin-bound peptide and stirred at room temperature for 2 hours. Next, the free carboxylic acid was activated with TSTU (2 equivalents) and DIPEA (2 equivalents) dissolved in DMF (2 mL), and the reaction was carried out at room temperature for 1 hour. After the formation of the NHS ester, the resin-bound peptide was treated with intermediate 103 (1 equivalent) and DIPEA (2 equivalents) in DMF (2 mL) for 2 hours to synthesize compound 607. After the reaction was complete, the resin was washed with DMF (3 × 5 mL), DCM (3 × 5 mL), IPA (3 × 5 mL), and Et2O (3 × 5 mL). For the synthesis of compound 6, cleavage and final deprotection from the resin were performed by treatment with TFA / TIS / EDT / water (v / v / v / v; 92.5 / 2.5 / 2.5 / 2.5) at 0°C, followed by dropwise addition of 10% TFMSA.

[0110] Crude peptides were precipitated from ice-cold diethyl ether and purified by preparative RP-HPLC. After RP-HPLC purification, compound 6[ABX 490 (TFA salt)] was obtained as a white to off-white solid (yield 12 percent). Calculated monoisotopic mass (C) 49 H 84 N 10 O 19 S2): 1180.54; Measured value: m / z = 1181.38 [M + H] + ,591.27[M+2H] 2+ .

[0111] Example 6 Synthesis of Compound 1 [ABX 408]

[0112] Compound 1 of the present invention [ka] Compound 4 was synthesized according to the procedure described in Example 4, except that Fmoc-L-Lys(Dde)-OH was used instead of Fmoc-D-Lys(Dde)-OH, and Fmoc-Phe-OH was used instead of Fmoc-Glu(OtBu)-OH. The crude peptide was purified by preparative RP-HPLC to obtain compound 4. Calculated monoisotopic mass (C) 59 H 93 N9O 14 S2): 1215.63; Measured value: m / z = 1214.73 [MH] + .

[0113] Example 7 Synthesis of compound 2 [ABX 451]

[0114] Compound 2 of the present invention [ka] The peptide was synthesized according to the procedure described in Example 4, except that Fmoc-Phe-OH was used instead of Fmoc-Glu(OtBu)-OH. The crude peptide was purified by preparative RP-HPLC. Calculated monoisotopic mass (C)59 H 93 N9O 14 S2): 1215.63; Measured value: m / z = 1216.70 [M + H] + .

[0115] Comparative Example 1 Synthesis of compound 3 [ABX 455]

[0116] Comparative compound 3 [ka] The peptide was synthesized according to the procedure described in Example 4, except for the omission of Fmoc-Glu(OtBu)-OH. The crude peptide was purified by preparative RP-HPLC. Calculated monoisotopic mass (C) 41 H 75 N7O 12 S2): 921.49; Measured value: m / z = 922.45 [M + H] + .

[0117] Example 8 Synthesis of compound 4 [ABX 456]

[0118] Compound 4 of the present invention [ka] The peptide was synthesized according to the procedure described in Example 4, except that Fmoc-D-Phe-OH and Fmoc-D-Tyr(3I)-OH were used instead of Fmoc-Glu(OtBu)-OH. The crude peptide was purified by preparative RP-HPLC. Calculated monoisotopic mass (C) 59 H 92 N9O 15 S2): 1357.52; Measured value: m / z = 1356.70 [MH] + .

[0119] Example 9 nat Synthesis of Re complexes

[0120] Compounds 1, 3, and 5 were used to obtain naturally abundant Re isotopes ( nat Complexes with Re) were synthesized. These synthesized complexes can be used as PSMA ligands.

[0121] 0.06 mmol of the corresponding compound 1, 3, or 5 was dissolved in 2 ml of methanol. Subsequently, 1 ml of 1N NaOAc solution and 0.06 mmol of oxotrichloro[(dimethyl sulfide)-triphenylphosphine oxide]-rhenium(V) were added. The reaction mixture was stirred overnight at room temperature. The crude product was precipitated with ice-cold diethyl ether and purified by preparative RP-HPLC. Table Ex-1 shows the results of LC-MS analysis of the synthesized rhenium complexes.

[0122] [Table 1]

[0123] Compounds 1, 3 and 5 nat Re complex is 186 Re and 188 It can be used as a standard for the radioactive synthesis of Re-labeled PSMA ligands. Similarly, compounds 2, 4 and 6 nat Re complex is 186 Re and 188 It can be used as a standard for the radioactive synthesis of Re-labeled PSMA ligands.

[0124] Example 10 99m Radiolabeling of compounds 1-6 with Tc

[0125] Using compounds 1-6, 99m Complexes containing Tc were synthesized. These synthesized complexes can be used as PSMA radioligands.

[0126] Combine the corresponding compound 1, 2, 3, 4, 5, or 6 (50 μg), mannitol (1 mg), and calcium heptagluconate (10 μg) in 1-1.5 mL of sodium pertechnetate / physiological saline solution (commercially available). 99 Mo / 99m From the Tc generator, the mixture was stirred at room temperature for 10 minutes in 0.2-4 GBq. After adding stannous chloride (1 μg in 100 μL of 0.01 N HCl; helium-saturated solution), the solution was held at room temperature for 20 minutes, and finally at 80°C for another 20 minutes. After cooling, the product was ready for further use. The product was, 99m These are complexes of Tc with corresponding compounds 1, 2, 3, 4, 5, or 6. These complexes were provided as solutions of their respective components.

[0127] Product quality control was performed by radioactive reverse-phase high-performance liquid chromatography (radio-RP-HPLC) using a Poroshell 120EC-C18 column (3.5 μm, 100 × 3 mm; Agilent Technologies Deutschland, Waldbronn, Germany) and a solvent system consisting of water (0.1% TFA) and ACN (0.1% TFA). The analysis was performed using two different gradient elution methods: a) 0-0.5 min 0%, 0.5-3 min 0-100%, 3-5 min 100%, 5-8 min 0% ACN (0.1% TFA); flow rate: 0.4 mL / min for 0-0.5 min, 0.7 mL / min for 0.5-8 min, and b) 0-1.5 min 0%, 1.5-10 min 0-100%, 10-12 min 100%, 12-15 min 0% ACN (0.1% TFA); flow rate: 0.7 mL / min, as well as a fixed-composition elution method using specific proportions of ACN (0.1% TFA) suitable for each radioligand. Furthermore, possible 99m Tc / 99 To determine Tc colloid formation, radioactive thin-layer chromatography (radio-TLC) was performed on a silica gel TLC sheet (POLYGRAM SIL G UV254, Macherey-Nagel, Düren, Germany) using methanol / ammonium acetate (2M) 1:1. Table 2 shows the radiochemical purity and retention time t of the obtained complex.R is shown.

[0128] [Table 2]

[0129] Example 11 Determining the logD value

[0130] For various media, the LogD values were determined by the shake-flask method (Andres, A.; Roses, M.; Rafols, C.; Bosch, E.; Espinosa, S.; Segarra, V.; Huerta, J. M. Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts. Eur. J. Pharm. Sci. 2015, 76, 181-191). In the preparation, octanol was saturated with each of the buffer solutions used, and vice versa. To 3 mL of octanol, together with 3 mL of buffer solution, 200 - 300 μL of 99m Tc-labeled radioligand (15 - 25 MBq, triple samples) was added and shaken vigorously for 30 minutes. After centrifuging at 9,000 rpm for 15 minutes, samples were taken from both separated phases and measured by a gamma counter. The LogD value was calculated as the ratio of the radioactivities determined in the octanol and aqueous phases. Table EX-3 shows the determined LogD values of the 99m Tc complexes in sodium phosphate, TRIS buffer, and PBS.

[0131] [Table 3]

[0132] Example 12 Stability test:

[0133] 99m The stability of the complexes between Tc and compounds 1-6 was measured in various culture media.

[0134] Simply put, newly generated 99m Tc-labeled radioligand solution (10–20 MBq, 20–100 μL) was added to each culture medium (200–400 μL), rapidly vortexed, and gently shaken at the temperatures described below. At specific time points, samples were collected, diluted, and measured by radioactive RP-HPLC. Here, the investigation of plasma samples included protein precipitation using four times the volume of an ice-cold methanol / water (4 / 1, v / v) mixture, vigorous shaking (5 min), and centrifugation (14,000 rpm, 10 min) before examining the supernatant. Furthermore, after measuring the activity of the supernatant and residue with a gamma counter, the recovery of extracted activity was calculated.

[0135] [Table 4]

[0136] [Table 5]

[0137] [Table 6]

[0138] [Table 7]

[0139] Example 11 In vitro assay

[0140] Example 11 describes in vitro assays performed to characterize compounds 1, 2, 3, 4, 5, and 6. For this reason, compounds 1, 2, 3, 4, 5, or 6 described in Example 10 are different from those described in Example 10.99m Complexes of Tc and compounds 1, 2, 3, 4, 5 or 6 described in Example 9 were nat prepared with Re.

[0141] a) Cell culture

[0142] Competitive, saturation and internalization assays were performed using the high PSMA-expressing human prostate cancer cell line LNCaP (ATCC (登録商標) CRL-1740). Cells were grown as a monolayer at 37 °C in a humidified atmosphere containing 5% CO2 and 95% air in RPMI medium containing 10% FCS (Merck KGaA, Germany). Confluent cells were washed twice with phosphate-buffered saline (PBS), detached with trypsin / EDTA (0.05% / 0.02%), and then the cells were suspended in medium and counted (Casy TT, Omni Life Science, Germany).

[0143] b) PSMA-11 68 Ga sign

[0144] 68 The Ga generator was purchased from iThemba LABS (South Africa). PSMA-11 (2 - 4 μg = 2.11 - 4.21 nmol) was labeled with Ga (100 - 200 MBq) in a mixture of ammonium acetate (2M) and HCl at pH 4.5. The reaction mixture was incubated at 90 °C for 10 minutes. Quality control of the radiolabeled PSMA-11 was performed using high performance liquid chromatography (HPLC) with a C-18 reverse phase column (semi-preparative Zorbax 300SB-C18, 9.4x250mm 5μm; Agilent Technologies, USA). For 68 Ga]Ga-PSMA-11 with a molar activity of 30 - 60 GBq / μmol, the radiochemical yield was >97%. 68

[0145] c) Determination of competitive and direct coupling affinity (competition and saturation)

[0146] ​For competition, a monolayer of LNCaP cells was prepared at 1 × 10⁶ two days prior to the assay. 5 Cells were seeded in 24-well plates at a rate of cells / well. On the day of competition, after aspirating the medium, 100 μL of PBS and different concentrations of the test compound in PBS were added for competition (10 -12 ~10 -6 Add 100 μL of M) to the well, and simultaneously add 1 nM [ 68 Ga]Ga-PSMA-11 was pipetteed into 400 μL of culture medium.

[0147] To ensure saturation, a monolayer of LNCaP cells was prepared 2 days prior to the assay, using 5 × 10⁶ cells. 4 Cells were seeded in 48-well plates at a concentration of cells / well. On the day of saturation, after aspirating the medium, nonspecific binding samples containing 100 μM 2-PMPA were placed in 160 μL of medium per well (containing D-mannitol). 99m Tc-labeled radioactive ligand (1 mg / mL) was pipetted into the solution. After a 5-minute pre-incubation, 40 μL of the active substance was added. 68 Ga]Ga-PSMA-11 or 99m A Tc-labeled radioligand solution was added (total volume / well: 200 μL). The eight concentrations ranged from 0.3 to 40 nM.

[0148] After incubation at 37°C for 1 hour for both competitive and saturated samples, the supernatant was aspirated and the cells were washed twice with cold PBS. Cell lawn was lysed by shaking in 500 μL NaOH / SDS (0.1 M / 1%) for 3–5 minutes. After transferring the lysis solution to a test tube, the activity of the samples was measured using a gamma counter (2480 Automatic Gamma Counter Wizard 2, Perkin Elmer, USA).

[0149] Using a nonlinear curve fitting program (GraphPad Prism 9), we obtained the 50% inhibitory concentration (half maximal inhibitory concentrations) (IC50) and the dissociation constant (K). d ) was calculated. [ in LNCaP68 Ga]Ga-PSMA-11's K d Values ​​and in competitive assays [ 68 Using known concentrations of Ga]Ga-PSMA-11, the inhibition constant (K i ) was also determined using a curve fitting program. nat Re (re) of K i Value and [ 99m K of the Tc]TcO complex d The values ​​are shown in Table EX-8.

[0150] [Table 8]

[0151] d) Decision on internalization

[0152] For internalization, LNCaP and PC3 cells were sampled at 1 × 10⁶ times two days prior to the assay. 5 Cells were seeded in 24-well plates at a rate of one cell per well. On the day of internalization, after aspirating the culture medium, 100 μL of PBS and, for nonspecific binding samples, 100 μL of 2-PMPA (100 μM) were pipetteed into the wells, followed by 400 μL of culture medium containing the active substance. 99m The concentration of Tc-labeled radioligand was 25 nM. After incubation at 37°C and in adjacent well plates at 4°C for 1 hour, the supernatant was removed and the cells were washed with cold PBS. Surface binding activity was stripped with cold acid wash buffer (0.2 M glycine, pH 2.8) at 4°C for 5 minutes. The acid wash buffer was transferred from the plate wells to the measurement tubes, as shown in PBS buffer (bound to the surface) after one wash. After treatment with cell lysis buffer (0.1 M NaOH / 1% SDS), cytoplasmic activity was determined. Cell surface and cytoplasmic activity were measured separately with a gamma counter. Protein content from the cell lysate was determined by absorbance at 280 nm using a spectrophotometer (NanoDrop, Thermo Fisher Scientific, USA). The results are shown in Table EX-9.

[0153] [Table 9]

[0154] Compared to comparative compound 3, the addition of substituted or unsubstituted amino acids X and Y results in an increase in internalized %AD / 1mg of protein.

[0155] Example 12 SPECT / CT and PET / CT imaging

[0156] All animal experiments are conducted in accordance with the guidelines of the German Regulations for Animal Welfare and approved by the local Ethical Committee for Animal Experiments.

[0157] 8-12 week old male nude mice (Rj:NMRI-Foxn1) nu / nu A prostate cancer xenograft model was created by subcutaneous injection of human LNCaP cells into the right shoulder of animals (Janvier Labs, Le Geneste Saint-Isle, France). Imaging studies were performed when the tumors reached a diameter of 6 mm or more. General anesthesia was induced and maintained by inhalation of 30 / 10% (v / v) oxygen / 10% (v / v) desflurane in air. During anesthesia, the animals were continuously warmed at 37°C.

[0158] Single-photon emission computed tomography (SPECT) for small animals was performed using a nanoSPECT / CT scanner (Mediso Medical Imaging Systems) equipped with an APT63 aperture consisting of four M3 multi-pinhole collimators. Each animal was given 30 MBq of saline solution in 0.2 mL of Dulbecco's phosphate-buffered saline. 99mTc-labeled compounds were administered as a single intravenous injection via a tail vein catheter. Photon emission was recorded using frame times of 60 seconds (1-hour scan: 40–70 minutes), 90 seconds (4-hour scan: 3.5–4.5 hours), and 320 seconds (20-hour scan: 18.5–21.5 hours), and simultaneously binned within a 20% energy window of the 140.5 keV photopeak. For each SPECT scan, a corresponding CT image was recorded and used for anatomical reference and attenuation correction. SPECT images were rendered in the normal range with a voxel size of 0.4 mm using Tera-Tomo. (商標) The model was reconstructed using a three-dimensional (3D) algorithm, and corrections for scattering decay and decay were applied.

[0159] Positron emission tomography (PET) was performed on small animals using a nanoPET / CT scanner (Mediso Medical Imaging Systems). 10 MBq of radiolabeled reference compound was supplied to Dulbecco's phosphate-buffered saline. 68 Ga]Ga-PSMA-11 was administered as a single intravenous injection via a tail vein catheter. Emission of 511 keV annihilation photons was continuously recorded in 1:5 simultaneous mode for 60 minutes after injection of the radioactive tracer. Corresponding CT images were recorded for each PET scan and used for anatomical reference and attenuation correction. Three-dimensional list-mode data were binned using an energy window of 400–600 keV. PET images of 40–60 minute timeframes were Tera-Tomo at a voxel size of 0.4 mm. (商標) The model was reconstructed using a three-dimensional (3D) algorithm, and corrections for random events, scattering, decay, and collapse were applied.

[0160] All images were post-processed and analyzed using ROVER (ABX), and displayed as maximum intensity projections with the indicated scaling. Three-dimensional VOIs were created by applying fixed thresholds to visualize tumors (30%), muscles (0%), and kidneys (39%). Standardized uptake values ​​(SUV = [detected active MBq / 1 mL of tissue] / [injected active MBq / 1 g of body weight], mL / g) were determined and reported as the maximum SUV (maximum VOI value). Time-activity curves were created and further analyzed using Prism (GraphPad Software, San Diego, CA, USA).

[0161] In LNCaP tumor-carrying mice [ 99m The tumor uptake of Tc-labeled radioligands is shown in Figure 3 (SUV = standardized uptake value; error bars represent SEM of measured values). In contrast to internalization in cell culture (Example 11), no significant increase in tumor uptake was observed for X and / or Y represented by phenylalanine or substituted phenylalanine. Surprisingly, a significant or substantial increase in tumor uptake was found for X and Y represented by glutamate (highest uptake for A=A1, second highest uptake for A=A2).

[0162] Figure 5 shows the results in LNCaP tumor-carrying mice after 1 hour and 4 hours. 99m This shows the tumor-to-muscle ratio and tumor-to-liver ratio of Tc-labeled radioligand (SUV = standardized uptake). In particular, X and Y ([ 99m Tc]TcO-5 [= [ 99m Tc]TcO-ABX474] and [ 99m Tc]TcO-6 [= [ 99m Regarding Tc[TcO-ABX490]), a significant or substantial increase in tumor-to-muscle ratio and tumor-to-liver ratio was observed. This is particularly [ 99m Tc]TcO-5 [= [ 99m This demonstrates that [Tc]TcO-ABX474] provides the most preferred tumor visualization for the [99mTc]-labeled radioligand of the present invention.

[0163] Figure 1 shows [ 99m Tc]TcO-5 [= [ 99m Functional imaging of subcutaneous LNCaP tumor xenografts in mice using [Tc]TcO-ABX474] is shown in comparison to the reference compound (maximum intensity projection; (SUV) normalized uptake value).

[0164] Figure 2 shows the results in LNCaP tumor-carrying mice. 99m Tc]TcO-5 [= [ 99m The tumor-to-background dynamics of Tc[TcO-ABX474] are shown in comparison to the reference compound ((SUV) standardized uptake value, (RT) radiotracer).

[0165] [ 99m Tc]TcO-5 [= [ 99m Tc]TcO-ABX474] is, [ 99m Compared to Tc]TcO-PSMA-I&S, it offers higher contrast, and [ 68 Compared to Ga]Ga-PSMA-11, it showed higher image resolution, as well as similar uptake in tumors and lower uptake in kidneys compared to the reference compound (see Figure 1). As a result, [ 99m Tc]TcO-5 [= [ 99m Tc]TcO-ABX474] is a reference compound [ 99m Tc]TcO-PSMA-I&S and [ 68 Compared to Ga]Ga-PSMA-11, it showed higher tumor-to-muscle ratios and tumor-to-kidney ratios within the first four hours after injection (see Figure 2). These results indicate that [ 99m Tc]TcO-5 [= [ 99m The study shows that [Tc]TcO-ABX474] provides improved tumor visualization compared to the reference compound. Concurrent administration of 1.5 mg of 2-PMPA blocked the uptake of radioactive tracers in tumors, confirming PSMA-specific binding (see Figure 2).

[0166] In Figure 4, 99m Tc]TcO-5 [= [ 99mTc]TcO-ABX474] is a reference compound that is present within the first hour after injection. 99m Tc]TcO-PSMA-I&S and [ 68 It was also shown to exhibit a higher tumor-to-liver ratio compared to Ga]Ga-PSMA-11.

[0167] List of Abbreviations Acetate ACN Acetonitrile AD applied dose Boc tert-butoxycarbonyl Boc2O di-t-butyldicarbonate Bp boiling point CT (Computed Tomography) 2-CTC 2-chlorotrityl chloride DCM Dichloromethane Dde N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) DIPEA N,N-diisopropylethylamine DMF Dimethylformamide DPBS Dulbecco's Phosphate-Buffered Saline EDT 1,2-Ethanedithiol EDTA (Ethylenediaminetetraacetic acid) Et2O Diethyl ether FCS fetal bovine serum Fmoc Fluorenylmethoxycarbonyl HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) HOAt 1-hydroxy-7-azabenzotriazole HYNIC (Hydradinonicotinic Acid) IPA 2-propanol LNCaP Prostate lymph node cancer (human prostate cancer cell line) logD distribution coefficient NaOAc sodium acetate NMM 4-methylmorpholine NHS N-hydroxysuccinimide PBS (phosphate-buffered saline) PC3 Human Prostate Cancer Cell Line PET Positron Emission Tomography 2-PMPA 2-(phosphonomethyl)pentanedioic acid PSMA prostate-specific membrane antigen PyBOP (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RLT radioligand therapy rt room temperature RP-HPLC (Reverse-Phase High-Performance Liquid Chromatography) RPMI is a growth medium for cell culture. RT Radioactive Tracer SDS Sodium Dodecyl Sulfate SEM mean standard error SPECT Single-Photon Emission Computed Tomography SPPS Solid-Phase Peptide Synthesis Suberic acid SUV standardized values tBu tert-butyl TFA (Trifluoroacetic Acid) TFMSA (Trifluoromethanesulfonic acid) THF (Tetrahydrofuran) TIS Triisopropylsilane TRIS (Tris-Hydroxymethyl)aminomethane TSTU O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate VOI (Volume of Interest) While this application relates to the invention described in the claims, it may also encompass the following other embodiments. 1. Compounds of General Formula I [ka] [In the formula, A is a chelator selected from the following group: [ka] k is independently 0, 1, or 2 in each occurrence; m is independently 1, 2, 3, 4, or 5 in each occurrence; n is independently 0, 1, 2, or 3 in each occurrence; p is independently 1, 2, or 3 in each occurrence; q is independently 1, 2, or 3 in each occurrence; u is either 0 or 1 independently in each occurrence; X and Y are substituted or unsubstituted amino acids; L is a bifunctional linker selected from the group consisting of the following:

change

change

Claims

1. Compounds of general formula I 【Chemistry 1】 [In the formula, A is a chelator selected from the following group: 【Chemistry 2】 k is independently 0, 1, or 2 in each occurrence; m is independently 1, 2, 3, 4, or 5 in each occurrence; n is independently 0, 1, 2, or 3 in each occurrence; p is independently 1, 2, or 3 in each occurrence; q is independently 1, 2, or 3 in each occurrence; u is either 0 or 1 independently in each occurrence; X and Y are substituted or unsubstituted amino acids; L is a bifunctional linker selected from the group consisting of the following: 【Transformation 3】 (wherein v, x, and y are independently 0, 1, 2, or 3, and z is 0, 1, 2, 3, 4, or 5); and R is H, methyl, or ethyl.

2. The compound of general formula I according to claim 1, wherein the amino acid is substituted or unsubstituted glutamic acid, substituted or unsubstituted aspartic acid, substituted or unsubstituted phenylalanine, substituted or unsubstituted histidine, or substituted or unsubstituted serine.

3. The compound of general formula I according to claim 1 or 2, wherein the amino acid is substituted or unsubstituted phenylalanine, or substituted or unsubstituted glutamic acid.

4. A compound of general formula I according to claim 1 or 2, wherein L is L1 or L2.

5. A compound of general formula I according to claim 1 or 2, wherein A is A1 or A2.

6. A compound of general formula I according to claim 1 or 2, wherein k is 1, m is 3, n is 2, p is 1 or 2, q is 1 or 2, u is 1, X and Y are independently substituted or unsubstituted phenylalanine or glutamic acid; L is L1 where v is 1, or L2 where x and y are 1, and A is A1 or A2.

7. The following are compounds of general formula I: 【Chemistry 4】 【change】 A compound of general formula I according to claim 1, selected from the group consisting of the following.

8. A complex of a compound according to claim 1 as a ligand and a metal, wherein the metal is selected from the group consisting of rhenium and technetium.

9. The aforementioned metal, ９９ｍ Tc, ９９ Tc, ９４ｍ Tc, １８６ Re and １８８ The complex according to claim 8, wherein the isotope is selected from the group consisting of Re.

10. The complex according to claim 8 or 9 for use as a pharmaceutical.

11. The complex according to claim 8 or 9, for use as a pharmaceutical agent for the diagnosis and treatment of diseases involving PSMA.

12. The complex according to claim 10, characterized in that the pharmaceutical is for use as a radiopharmaceutical for nuclear medicine imaging or radioligand therapy.

13. A pharmaceutical product comprising the complex described in claim 8 or 9 or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical product according to claim 13, which is a pharmaceutical product for the diagnosis and treatment of diseases involving PSMA.

15. A method for producing the complex according to claim 8 or 9, comprising contacting the compound according to claim 1 with the metal.

16. The method according to claim 15, wherein the compound is brought into contact with the metal at ambient pressure at a reaction temperature in the range of 20 to 100°C.

17. A complex of a compound according to claim 7 as a ligand and a metal, wherein the metal is selected from the group consisting of rhenium and technetium.

18. where the metal is ９９ｍ Tc, ９９ Tc, ９４ｍ Tc, １８６ Re and １８８ an isotope selected from the group consisting of Re, the complex according to claim 17.

19. The complex according to claim 11, characterized in that the pharmaceutical is for use as a radiopharmaceutical for nuclear medicine imaging or radioligand therapy.

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