Labeled inhibitors of prostate-specific membrane antigen (PSMA), their use as imaging agents, and pharmaceutical agents for the treatment of PSMA-expressing cancers

Abstract

To provide new compounds that can be used for the treatment of various disease states of prostate specific membrane antigen (PSMA) expressing cancers.SOLUTION: For example, provided is a complex comprising a compound of Formula CA009 as shown in the Figures, or pharmaceutically acceptable salts or solvates thereof, and a radionucleide selected from 203Pb and 212Pb.SELECTED DRAWING: Figure 1-10

Description

[Technical Field]

[0001] The present invention relates generally to the field of radiopharmaceuticals and their use as tracers, imaging agents in nuclear medicine and for the treatment of various disease states of PSMA-expressing cancers, particularly prostate cancer and its metastases. [Background technology]

[0002] Prostate cancer (PCa) is the leading cancer in the US and Europe. It is estimated that at least 1 to 2 million men in the Western Hemisphere suffer from prostate cancer, with the disease affecting one in six men between the ages of 55 and 85. There are more than 300,000 new cases of prostate cancer diagnosed each year in the USA. The mortality rate from the disease is second only to lung cancer. Currently, high-resolution anatomical imaging methods, such as computed tomography (CT), magnetic resonance (MR) imaging, and ultrasound, dominate clinical imaging of prostate cancer. An estimated $2 billion is currently spent annually worldwide on surgical, radiation, drug, and minimally invasive procedures. However, there is currently no effective treatment for recurrent, metastatic, androgen-independent prostate cancer.

[0003] Currently, various experimental low molecular weight PCa imaging agents are radiolabeled choline analogs [ 18 F] Fluorodihydrotestosterone ([ 18 F]FDHT), anti-1-amino-3-[ 18 F]fluorocyclobutyl-1-carboxylic acid (anti[ 18 F]F-FACBC, 11 C] acetate and 1-(2-deoxy-2-[ 18 F]fluoro-L-arabinofuranosyl)-5-methyluracil (-[ 18F]FMAU) are being pursued clinically (Scher, B. et al., Eur J Nucl Med Mol Imaging 2007, 34, 45-53; Rinnab, L. et al., BJU Int 2007, 100, 786, 793; Reske, SN. et al., J Nucl Med 2006, 47, 1249-1254; Zophel, K., Kotzerke, J. Eur J Nucl Med Mol Imaging 2004, 31, 756-759; Vees, H. et al., BJU Int 2007, 99, 1415-1420; Larson, SM. et al., J Nucl Med 2004, 45, 366-373; Schuster, DM. et al., J Nucl Med 2007, 48, 56-63; Tehrani, OS. et al., J Nucl Med 2007, 48, 1436-1441). Each acts by a different mechanism and provides certain benefits, e.g., 11 C]choline has low urinary excretion, and disadvantages such as the short physical half-life of the positron-emitting radionuclide.

[0004] It is well known that tumors can express unique proteins associated with their malignant phenotype or overexpress normal constitutive proteins in greater numbers than normal cells. The expression of different proteins on the surface of tumor cells provides an opportunity to diagnose and characterize the disease by exploring the phenotypic identity and biochemical composition and activity of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins offer an attractive route to imaging and treating tumors under non-invasive conditions. A promising new series of low molecular weight imaging agents targets prostate-specific membrane antigen (PSMA) (Mease RC et al., Clin Cancer Res. 2008, 14, 3036-3043; Foss, CA et al., Clin Cancer Res 2005, 11, 4022-4028; Pomper, MG et al., Mol Imaging 2002, 1, 96-101; Zhou, J. et al., Nat Rev Drug Discov 2005, 4, 015-1026; WO 2013 / 022797).

[0005] PSMA is a transmembrane 750-amino acid type II glycoprotein with abundant and restricted expression on the surface of PCa, particularly in androgen-independent advanced and metastatic disease (Schulke, N. et al., Proc. Natl. Acad. Sci. USA 2003, 100, 12590-12595). The latter is important because almost all PCa becomes androgen-independent over time. PSMA has the potential to be a promising target for therapy (Schulke, N. et al., Proc. Natl. Acad. Sci. USA 2003, 100, 12590-12595). The PSMA gene is located on the short arm of chromosome 11 and functions as both a folate hydrolase and a neuropeptidase. It has a neuropeptidase function equivalent to glutamate carboxypeptidase II (GCPII), has been called "brain PSMA", and can modulate glutamatergic transmission by cleaving N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate (Nan, F. et al., J Med Chem 2000, 43, 772-774). Up to 10 per cancer cell 6 There are several PSMA molecules, further suggesting it as an ideal target for imaging and therapy using radionuclide-based techniques (Tasch, J. et al., Crit Rev Immunol 2001, 21, 249-261).

[0006] A radioimmunoconjugate of the anti-PSMA monoclonal antibody (mAb) 7E11, known as the PROSTASCINT® scan, is currently used to diagnose prostate cancer metastasis and recurrence. However, this agent tends to produce images that are difficult to interpret (Lange, PH PROSTASCINT scan for staging prostate cancer. Urology 2001, 57, 402-406; Haseman, MK et al. Cancer Biother Radiopharm 2000, 15, 131-140; Rosenthal, SA et al. Tech Urol 2001, 7, 27-37). More recently, monoclonal antibodies that bind to the extracellular domain of PSMA have been developed, radiolabeled, and shown to accumulate in PSMA-positive prostate tumor models in animals. However, diagnosis and tumor detection using monoclonal antibodies is limited by the low penetration of monoclonal antibodies in solid tumors.

[0007] Selective targeting of cancer cells with radiopharmaceuticals, either for imaging or therapeutic purposes, is challenging. 111 In, 90 Y, 68 Ga, 177 Lu, 99m Tc, 123 I and 131 It is known that PSMA is useful for radioimaging or cancer radiotherapy, including I. Recently, some compounds containing glutamate-urea-glutamate (GUG) or glutamate-urea-lysine (GUL) recognition elements linked to radionuclide-ligand conjugates have been shown to exhibit high affinity for PSMA.

[0008] WO 2015 / 055318 describes new imaging agents with improved tumor targeting properties and pharmacokinetics. These compounds contain a motif that specifically binds to the cell membrane of cancerous cells, including the prostate-specific membrane antigen (PSMA) motif, which is the glutamate-urea-lysine motif described above. Preferred molecules described in WO 2015 / 055318 further contain a linker that binds to the carboxylic acid group of DOTA via an amide bond as a chelating agent. Some of these compounds have been shown to be promising agents for specific targeting of prostate tumors. The compounds include: 177 Lu (for therapeutic purposes) or 68 It is labeled with Ga (for diagnostic purposes) to allow visualization and targeting of prostate cancer for radiotherapy purposes.

[0009] However, for the detection, treatment and management of PSMA-expressing cancers, particularly prostate cancer, it is necessary to develop a suitable radionuclide that interacts with PSMA, e.g. 177 Lu or 68 There remains a need for alternative or improved Ga-bearing ligands.

[0010] Additionally, any of the compounds described in WO 2015 / 055318 64 Cu and 67 It should be noted that the formation of a stable complex with Cu has not been described. 64 Cu / 67 The Cu pair has favorable properties, 64 Cu is ideally suited for long-term PET imaging, as 67 It allows the determination of dosimetry for Cu-labeled radiotherapeutic agents. 67 Cu is cyclotron produced and suitable for GMP (Good Manufacturing Practice) production. Its half-life allows for optimization of repeated dosing, hospitalization for only a few days, and reduced waste management costs. 1 / 2 =12.7h, β + 17.4%, E max =0.656MeV, β - 39%, Emax =0.573MeV), 64 Cu is 68 Ga(t 1 / 2 =67.71 minutes, 88.9% β + ) are available in high amounts compared to (Wadas TJ, Wong EH, Weisman GR, Anderson CJ. Copper chelation chemistry and its role in copper radiopharmaceuticals. Curr Pharm Des. 2007;13:3-16). 68 In contrast to Ga (67.71 min), 64 The adequate half-life of Cu (12.7 h) favors imaging and subsequent increased tumor delineation at later time points (Lewis MR, Wang M, Axworthy DB, et al., In vivo evaluation of pretargeted 64 Cu for tumor imaging and therapy. J Nucl Med. 2003;44:1284-1292. 21. De Silva RA, Jain S, Lears KA et al., Copper-64 radiolabeling and biological evaluation of bifunctional chelators for radiopharmaceutical development. Nucl Med Biol. 2012;39:1099-1104). Another major advantage of this radioisotope is that it can be used for diagnostics as well as therapy. Therefore, there is a need for PSMA ligands labeled with copper radionuclides.

[0011] Furthermore, in bone metastatic prostate cancer, survival benefit was observed in bone seekers. 223 This was observed after alpha-radiation therapy using RaCl2, its beta-emitting analogue 89It should be noted that the results could not be demonstrated for SrCl2 (Rubini G, Nicoletti A, Rubini D, Asabella AN. Radiometabolic treatment of bone-metastasizing cancer: from 186 Re to 223 Ra. Cancer Biother Radiopharm. 2014; 29:1-11). Alpha-emitting 213 Bi-DOTATOC is a beta-emitting 90 Y / 177 The ability to overcome resistance to Lu-DOTATOC has already been demonstrated in patients with neuroendocrine tumors [Kratochwil C, Giesel FL, Bruchertseifer F, et al. 213 Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumors refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014 Nov; 41(11):2106-19. Subsequently, the benefits of alpha-emitter-based radionuclide therapy are increasing. Despite the interest in research objectives, 213 Bi(t 1 / 2 =0.8h), 212 Bi(t 1 / 2 =1.0h), 149 Tb(t 1 / 2 =4.1h) and 211 At(t 1 / 2 The short physical half-life (=7.2 h) of the full-length antibody makes possible clinical applications difficult. On the other hand, long half-life alpha-emitters, e.g., α-emitters, may be necessary to address the slow pharmacokinetics of full-length antibodies. 227 Th(t 1 / 2= 18.7d) accumulate in the environment and can cause problems with waste disposal if applied on a large scale, for example for the treatment of tumors of epidemiological importance. Intense radiation and a fairly short range are the main properties of alpha emitters. However, alpha emitters with adequate half-lives suitable for clinical routine, e.g. 212 There is only a small amount of Pb.

[0012] Thus, there remains a need for PSMA ligands that form suitable complexes with alpha-emitting radionuclides. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] WO 2013 / 022797 [Patent Document 2] WO 2015 / 055318 [Non-patent literature]

[0014] [Non-Patent Document 1] Scher, B. et al., Eur J Nucl Med Mol Imaging 2007, 34, 45~53 [Non-patent document 2] Rinnab, L et al., BJU Int 2007, 100, 786,793 [Non-patent document 3] Reske, SN et al., J Nucl Med 2006, 47, 1249~1254 [Non-patent document 4] Zophel, K., Kotzerke, J. Eur J Nucl Med Mol Imaging 2004, 31, 756~759 [Non-patent document 5] Vees, H. et al., BJU Int 2007, 99, 1415~1420 [Non-patent document 6] Larson, SMら, J Nucl Med 2004, 45, 366~373

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[0015] Therefore, the overall objective of the present invention is to develop improved ligands carrying suitable radionuclides that interact with PSMA and provide advantageous options for the detection, treatment and management of PSMA-expressing cancers, particularly prostate cancer. [Means for solving the problem]

[0016] The solution to the above object is achieved by providing the embodiments characterized in the claims. The inventors have found new compounds that are useful and advantageous radiopharmaceuticals and can be used in nuclear medicine as tracers, imaging agents, and for the treatment of various disease states of PSMA-expressing cancers, in particular prostate cancer. These compounds are described in more detail below.

[0017] In particular, the present invention provides a compound represented by formula (1) [ka] [In the formula, Y 3 is O or S; s, t, u, and w are each independently 0 or 1; i is an integer of 1 to 3; j is an integer of 3 to 5; Z 1 , Z 2 and Z 3are each independently selected from the group consisting of -COH, -SOH, -SOH, -OSOH, and -OPOH; R 1 is —CH or H, preferably H; X is selected from the group consisting of optionally substituted alkylaryl, aryl, alkylheteroaryl, and heteroaryl; Y 1 and Y 2 are each independently selected from the group consisting of optionally substituted aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl, and alkylheteroaryl, and A is selected from (Ia), (Ib), and (Ic). [ka] (In the formula, R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of H, —CH—COOH and —CH—C(═O)—NH, or R 2 and R 4 Ha-(CH2) n - bridge, n is an integer from 1 to 3, n is preferably 2, r, v and q are each independently 0 or 1, However, if u and w are 0, then q and v are 0. is a chelator residue having a structure selected from the group consisting of: (A) u and w are 1, or (B) u is 0, w is 1, and A is selected from (Ia) or (Ib); or (C) A is [ka] isn't it] or a pharmaceutically acceptable salt or solvate thereof.

[0018] Furthermore, the present invention provides (a) Radionuclides, and (b) a compound as described above or below, or a salt, solvate, metabolite or prodrug thereof The present invention relates to a complex comprising:

[0019] The present invention further relates to pharmaceutical compositions comprising a compound as described above or below or a complex as described above or below. Furthermore, the present invention relates to a compound as described above or below, or a complex as described above or below, or a pharmaceutical composition as described above or below, for use in treating, ameliorating, or preventing PSMA-expressing cancer and / or metastasis thereof, particularly prostate cancer and / or metastasis thereof. Furthermore, the present invention relates to a compound as described above or below, or a complex as described above or below, or a pharmaceutical composition as described above or below, for use in diagnostic medicine. Additionally, the present invention relates to a compound as described above or below, or a complex as described above or below, or a pharmaceutical composition as described above or below, for use in diagnosing cancer, particularly PSMA-expressing tumors and / or metastases thereof.

[0020] The term "PSMA-expressing cancer and / or metastases thereof", as used within the meaning of the present invention, relates to any cancer in which cancerous cells express prostate-specific membrane antigen (PSMA) and its respective metastases. Preferably, the cancers (or cancer cells) that can be treated according to the present invention are selected from prostate cancer, conventional renal cell carcinoma, transitional cell carcinoma of the bladder, testicular embryonal carcinoma, neuroendocrine carcinoma, colon cancer, brain tumor and breast cancer. In a particularly preferred embodiment of the present invention, the PSMA-expressing cancer is prostate cancer or breast cancer, in particular prostate cancer.

[0021] As described above, the compounds included in the compounds or complexes of the present invention have the following structure: [ka] It has.

[0022] It should be understood that the compound included in the compound or complex may be in the anionic or salt form of the compound of formula (1).

[0023] The present invention therefore also relates to salts, in particular pharmaceutically acceptable salts, of compounds or complexes of general formula (1).The present invention also relates to salts and solvates of these compounds, including their active metabolites, and, where appropriate, their tautomers, including prodrug formulations.

[0024] A "pharmaceutically acceptable salt" is a pharmaceutically acceptable organic or inorganic acid or base salt of a compound of the present invention. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts such as acetates, carbonates, chlorides, gluconates, glutamates, lactates, laurates, malates, or tartrates.

[0025] The term "prodrug" refers to a drug precursor, a compound that, upon administration to a patient, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent. Exemplary prodrugs of compounds according to formula (1) are esters and amides, preferably alkyl esters of fatty acid esters. Prodrug formulations herein include all substances formed, either enzymatically, metabolically, or in any other manner, by simple transformations, including hydrolysis, oxidation, or reduction. Suitable prodrugs include, for example, substances of formula (1) linked to a solubility-improving substance (e.g., tetraethylene glycol, sugars, formic acid, or glucuronic acid) via an enzymatically cleavable linker (e.g., carbamate, phosphate, N-glycoside, or disulfide group). Such prodrugs of compounds according to the present invention can be administered to a patient, and the prodrug can be converted to a substance of formula (1) to achieve the desired pharmacological effect.

[0026] Some compounds of formula (1) may be included in the form of stereoisomeric mixtures, including all possible mixtures thereof, such as racemic mixtures and / or mixtures of cis / trans isomers, or as single enantiomers, diastereomers and / or specific cis / trans isomers.

[0027] According to the invention, all chiral C atoms shall have the D and / or L configuration, and furthermore, combinations within one compound shall be possible, i.e. some of the chiral C atoms may have the D configuration and others the L configuration. Most preferably, the amino acid residues present in the compound have the L configuration.

[0028] The resulting compounds can optionally be separated into their enantiomers and / or diastereomers by known methods (e.g., Allinger, NL and Elliel, EL, in "Topics in Stereochemistry," Vol. 6, Wiley Interscience, 1971). One possible method for separating enantiomers is the use of chromatography.

[0029] Urea skeleton: Compound (1) contains a urea building block (1A). This urea building block (1A) of compound (1) [ka] In Z 1 , Z 2 and Z 3 are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H and -OPO3H2, more preferably Z 1 , Z 2 and Z 3 At least one of, and more preferably all of, them is -CO2H.

[0030] It should be understood that building block (1A) can exist in any stereoisomeric form, but preferably (1A) has the structure (1Aa): [ka] It has.

[0031] Therefore, preferably, the compounds of the present invention and the compounds contained in the complexes of the present invention have the structure [ka] It has.

[0032] The integers i and j are as described above.

[0033] Preferably, i is 2. The present invention therefore also relates to compounds of formula (1), preferably (1a), in which i is 2, and to compounds contained in the complexes of the present invention.

[0034] Preferably, j is 4. The present invention therefore also relates to compounds of formula (1), preferably (1a), in which j is 4, and to compounds contained in the complexes of the present invention.

[0035] R 1 is preferably H.

[0036] The urea building block (1Aa) therefore most preferably has the structure (1Aa_1) [ka] It has.

[0037] Residue X and building block (1B): When s is 1, the compound of formula (1) is a compound having the structural unit (1B) [ka] Includes.

[0038] As described above, in this building block, X preferably comprises a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl and benzothiazolyl. Preferably, X is a naphthyl group, an alkyl-naphthyl group, a phenyl group, a benzyl group, a biphenyl group, an alkyl-biphenyl group, an indolyl group, an alkyl-indolyl group, a benzothiazolyl group or an alkyl-benzothiazolyl group.

[0039] Within the meaning of the present invention, the terms naphthyl, phenyl, biphenyl, indolyl and benzothiazolyl include groups that are further substituted by one or more suitable substituents. When used in this context of the present invention, the term "substituted" preferably refers to a group that is substituted at any position with one or more substituents, preferably with 1, 2, 3, 4, 5 or 6 substituents, more preferably with 1, 2 or 3 substituents. When two or more substituents are present, each substituent may be the same or different from at least one other substituent. Preferably, the group is unsubstituted.

[0040] Within the meaning of the present invention, the term "alkyl" relates to unbranched and branched alkyl residues. The term also encompasses alkyl groups which are further substituted by one or more suitable substituents. The term "substituted alkyl", as used in this context of the present invention, preferably refers to an alkyl group substituted at any position with one or more substituents, preferably with 1, 2, 3, 4, 5 or 6 substituents, more preferably with 1, 2 or 3 substituents.

[0041] More preferably, residue X is [ka] wherein these groups may be suitably substituted. Preferably, these groups are unsubstituted. Most preferably, X, when present, is selected from the group consisting of: [ka] is.

[0042] Building block (1B), if present, therefore preferably has the following structure: [ka] It has.

[0043] Y 1 Groups and Building Blocks (1C): When t is 1, the compound of formula (1) is a compound having the structural unit (1C) [ka] Includes.

[0044] As stated, Y 1 is selected from the group consisting of aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl, and alkylheteroaryl.

[0045] The term "aryl" as used in the context of the present invention refers to optionally substituted aryl groups, i.e., in particular, optionally substituted 5- and 6-membered aromatic rings, as well as substituted or unsubstituted polycyclic aromatic groups (aryl groups), such as tricyclic or bicyclic aryl groups. Optionally substituted phenyl or naphthyl groups may be mentioned as examples. Polycyclic aromatic groups may also contain non-aromatic rings.

[0046] The term "heteroaryl" as used in the context of the present invention refers to optionally substituted heteroaryl groups containing one or more, for example 1 to 4, for example 1, 2, 3 or 4 heteroatoms in the ring system, i.e., in particular optionally substituted 5- and 6-membered aromatic rings, and substituted or unsubstituted polycyclic aromatic groups, for example tricyclic or bicyclic aryl groups. When more than one heteroatom is present in the ring system, the at least two heteroatoms present may be the same or different. Suitable heteroaryl groups are known to those skilled in the art. The following optionally substituted heteroaryl residues may be mentioned by way of non-limiting example: benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, methylenedioxyphenylyl, naphthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0047] The term "alkylaryl" or "alkylheteroaryl," as used within the meaning of the present invention, refers to a group in which an aryl group or heteroaryl is linked to the rest of the structural unit via an alkyl group. For example, in the case of X relative to a C skeleton, "alkylaryl" in this case refers to an -alkyl-aryl group, and "alkylheteroaryl" refers to an -alkyl-heteroalkyl group. In the case of Y, the aryl group or heteroaryl is linked to the carbonyl group via an alkyl group, i.e., "alkylaryl" in this case refers to an -alkyl-aryl group, and "alkylheteroaryl" refers to an -alkyl-heteroalkyl group. In the case of Y, the aryl group or heteroaryl is linked to the NH group via an alkyl group, i.e., "alkylaryl" in this case refers to an -alkyl-aryl group, and "alkylheteroaryl" refers to an -alkyl-heteroalkyl group.

[0048] The term "cycloalkyl" in the context of the present invention denotes optionally substituted cyclic alkyl residues, which may be monocyclic or polycyclic groups. Optionally substituted cyclohexyl can be mentioned as a preferred example of a cycloalkyl residue.

[0049] The term "heterocycloalkyl", as used in the context of the present invention, denotes optionally substituted cyclic alkyl residues having at least one heteroatom, such as O, N or S, in the ring, which may be monocyclic or polycyclic groups.

[0050] The term "substituted cycloalkyl residue" or "cycloheteroalkyl" as used in the context of the present invention denotes a cycloalkyl residue or a cycloheteroalkyl residue in which at least one H has been replaced with a suitable substituent.

[0051] Preferably, Y 1 is a cycloalkyl group or a heterocycloalkyl group, more preferably a cycloalkyl group, more preferably [ka] is.

[0052] The building block (1C), if present, therefore preferably has the following structure: [ka] It has.

[0053] The structure should be understood to include any possible stereoisomers, e.g., cis / trans isomers. Preferably, the group [ka] The structural unit (1C), if present, therefore preferably has the following structure: [ka] It has.

[0054] Y 3 base As stated above, Y 3 is preferably O or S.

[0055] Radionuclides (radionucleotides) Depending on whether the compounds of the invention are to be used as radioimaging agents or radiopharmaceuticals, different radionuclides are complexed with chelating agents.

[0056] Exemplary radionuclides include, for example: 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Radionuclides of Er, Fe (e.g. 52 Fe and 59 Fe) and Pb radionuclides (e.g. 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197Pb).

[0057] Preferably, the radionuclide is 111 In, 90 Y, 68 Ga, 177 Lu, 153 Gd, 155 Gd, 213 Bi, 225 Ac, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Radionuclides of Cu, Fe (e.g. 52 Fe and 59 Fe) and Pb radionuclides (e.g. 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb).

[0058] The radionuclide of Pb is more preferably 203 Pb and 212 It is Pb.

[0059] The radionuclide of Cu is more preferably 64 Cu and 67 It is Cu.

[0060] The complexes of the compounds according to the invention can contain one or more radionuclides, preferably one radionuclide. These radionuclides are preferably suitable for use as radioimaging agents or as therapeutic agents for the treatment of proliferating cells, such as PSMA-expressing cancer cells, particularly PSMA-expressing prostate cancer cells. According to the invention, they are referred to as "metal complexes" or "radiopharmaceuticals."

[0061] A preferred imaging method is positron emission tomography (PET) or single photon emission computed tomography (SPECT). [Brief explanation of the drawings]

[0062] [Figure 1-1] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-2] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-3] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-4] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-5] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-6]Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-7] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-8] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-9] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-10] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-11]Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-12] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-13] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 1-14] Table 1A: A summary of preferred compounds. If a stereocenter in each depicted structure is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Table 1B: A summary of highly preferred compounds. [Figure 2]FIG. 1 shows reaction schemes for the synthesis of PSMA-chelator conjugates: (a) triphosgene, DIPEA, CHCl, 0° C.; (b) H-Lys(Alloc)-2CT-resin, CHCl; (c) Pd[P(CH)], morpholine, CHCl; (d) Fmoc-2-Nal-OH, HBTU, DIPEA, DMF; (e) 20% piperidine, DMF; (f) trans-4-(Fmoc-aminomethyl)-cyclohexanecarboxylic acid, HBTU, DIPEA, DMF; (g) 20% piperidine, DMF; (h) chelator, HBTU (if required), DIPEA, DMF; (i) 95% TFA, 2.5% HO, 2.5% TIPS. [Figure 3] Figure 1 shows the PSMA inhibitory potency and specific internalization values ​​of novel PSMA ligands labeled with the nuclides specified in the table. Competitive cell binding was performed using the PSMA-positive C4-2 cell line. The novel ligands exhibited good inhibitory potency with K in the low nanomolar range and internalization values ​​(specific lysate) that were partially higher than PSMA-617. [Figure 4A] A. PET scans and time-activity curves of C4-2 tumor-bearing mice showing the biodistribution of 64Cu-PSMA-617, 64Cu-CA003, and 64Cu-CA023. 64Cu-PSMA-617 shows high accumulation not only in the tumor and kidney but also in the liver. A. Visualization of the biodistribution of 64Cu-PSMA-617, 64Cu-CA003, and 64Cu-CA023 at different time points (0-20 min, 40-60 min, 2 h, 48 h). [Figure 4B] B. Time-activity curves of dynamic PET scans (0-60 min) of C4-2 tumor-bearing mice showing the biodistribution of 64Cu-PSMA-617 and 64Cu-CA003. Standard uptake values ​​(SUVs) for tumor and liver show higher uptake of 64Cu-PSMA-617 in the liver than in the tumor, contrary to 64Cu-CA003. [Figure 5]Figure 1 shows the maximum standardized uptake values ​​(mSUV) of 64Cu-PSMA-617, 64Cu-CA003, and 64Cu-CA023 in PET images of C4-2 tumor-bearing mice at different time points (0-48 h). 64Cu-CA003 showed high accumulation in the tumor and kidney, while 64Cu-CA023 showed high accumulation in the tumor and rapid clearance from the kidney. [Figure 6A] FIG. 1 shows that accumulation of 64Cu-CA003 in dissected organs of interest in C4-2 tumor-bearing mice confirms tumor specificity and fast clearance from the kidney. [Figure 6B] FIG. 1 shows that accumulation of 64Cu-CA023 in dissected organs of interest in C4-2 tumor-bearing mice confirms tumor specificity and fast clearance from the kidney. [Figure 6C] Figure 1 shows the organ distribution of 0.025 nmol 64Cu-CA003 at 10 min, 1 h, 4 h, 24 h, and 72 h post-injection. Values ​​are expressed as % ID / g of tissue ± standard deviation. n=3 for all tissues. [Figure 6D] In the blocking experiment (B), the radiotracer 64Cu-CA003 (0.030 nmol) was co-injected with 2 mg of PSMA-617 per kilogram of body weight. Values ​​are expressed as % ID / g of tissue ± standard deviation. n=3 for all tissues. [Figure 7] Figure 1 shows 64Cu-CA003 (200 MBq, 0.5 nmol) PET / CT maximum intensity projections of a patient at 2 h (A) and 20 h (B) post-injection. Red arrows point to selected right shoulder soft tissue infiltration from scapular origin, lung, bone, and lymph node metastases, which increased in contrast over time. Hepatobiliary clearance causes hot spots inside the intestine, and cross-sectional sections (C) are essential to avoid false-positive readings. [Figure 8]Planar scintigraphic imaging of different 203Pb-labeled compounds in BALB / c nu / nu C4-2 tumor-bearing mice (A) 1 h after tail vein injection and (B) the time course of distribution of 203Pb-CA012. Radiolabeled derivatives of CA009 and CA012 demonstrate high uptake of the tracer in tumor tissue. The uptake kinetics determined for 203Pb-CA012 reveals prolonged retention of the radiotracer in tumor tissue. The selectivity of uptake of 203Pb-CA012 is enhanced when compared to 203Pb-CA009. This is a result of rapid clearance from non-target organs. [Figure 9] Figure 1 shows the organ distribution of 203Pb-PSMA-CA012 in tumor-bearing mice, 0.025 nmol of 203Pb-PSMA-CA012. This quantification confirms the results of imaging experiments. The high ratio of tumor to kidney uptake is accompanied by the high excretion values ​​observed for the kidney. [Figure 10] 1 shows geometric mean images of 203Pb-CA012 planar scans over time (A) compared with a treatment scan using 177Lu-PSMA-617 (B), both acquired with a medium-energy collimator. [Figure 11] FIG. 1 shows safety dosimetry estimates for diagnostic 203Pb-CA012 (left column) and therapeutic 212Pb-CA012 (right column) based on a male adult phantom in OLINDA (ULI = upper large intestine, LLI = lower small intestine). [Figure 12] FIG. 1 shows dosimetry of 212Pb-CA012 ("TCMC"-PSMA-617) for salivary glands, randomly selected tumor lesions (sphere model), and potentially dose-limiting organs in comparison with 213Bi-PSMA-617 and 225Ac-PSMA-617. [Figure 13A](C) Maximum intensity projection of 68Ga-PSMA-CA028 PET scan of a patient with multiple lymph node prostate cancer metastases at 1 h and 3 h post-injection. Cross-sectional slices demonstrate lymph node metastases (indicated by red arrows) in the axilla and hilum (D), as well as delineable lymph node metastases on the correlative CT scan that served as the reference standard. [Figure 13B] Maximum intensity projections of PSMA-PET performed 1 h (A) and 3 h (B) after injection of 295 MBq / 20 nmol 68Ga-CA030. Arrows indicate the location of cross-sectional slices demonstrating bone metastases in multiple regions of the axial skeleton (C-E). In CT (F), the typical osteoblastic response did not allow tumor delineation by morphological information alone. [Figure 14] FIG. 1 shows the organ distribution of 68Ga-PSMA-CA028 expressed as % ID / g of tissue±SD (n=3) at 1 h, 2 h, and 4 h post-injection. [Figure 15] Figure 1 shows a comparison of whole-body small animal PET imaging of selected 68Ga-PSMA ligands at 2 h post-injection (A) and over the time course of 68Ga-CA028 (B) and 68Ga-CA030 (C) in BALB / c nu / nu mice bearing C4-2 tumor xenografts. [Figure 16] FIG. 1 shows the serum stability of 177Lu-CA028, 177Lu-CA029, 177Lu-CA030 in comparison to 177Lu-PSMA-617 over 72 h (mean ± SD, n=3) at 37° C. as determined by radioactive ITLC. [Figure 17] FIG. 1 shows the serum stability of 64Cu-CA003, 64Cu-CA005, and 64Cu-PSMA-617 over 72 h (mean ± SD, n=4) at 37° C. as determined by radioactive ITLC. [Figure 18] FIG. 1 shows the serum stability of 64Cu-CA003, 64Cu-CA005, and 64Cu-PSMA-617 over 72 h at 37° C. (mean±SD, n=4) as determined by activity measurements. [Figure 19]Figure 1 shows in vivo metabolism analysis of 64Cu-CA003 in BALB / c nude mice (tumor-free) at 10 min p.i. Radioactive HPLC chromatograms of extracts from kidney, blood, and liver show that the activity elutes at the retention time of the intact tracer, demonstrating the integrity of the copper complex within the main distribution window. [Figure 20] FIG. 1 shows radioactive HPLC chromatograms of extracts of 64Cu-CA003 in liver in comparison with 64Cu-chloride in liver in BALB / c nude mice (tumor-free) at 10 min pi. [Figure 21A] Whole-body small-animal PET scans of BALB / c nu / nu mice bearing C4-2 tumor xenografts as maximum intensity projections. PET imaging of 64Cu-PSMA-617 (10 MBq, 0.2 nmol), 64Cu-PSMA-CA003 (10 MBq, 0.2 nmol). [Figure 21B] Figure 1 shows 64Cu-PSMA-CA003 (5 MBq, 0.030 nmol) co-injected with an excess of unlabeled PSMA-617 (2 mg per kilogram of body weight) and 64Cu-chloride (10 MBq). The color bar indicates the correlation between SUV and the color scale of the PET image, with 0 = minimum and 4 = maximum. [Figure 22] Comparison of whole-body small-animal PET scans as maximum intensity projections of BALB / c nu / nu mice bearing C4-2 tumor xenografts. PET imaging of four new PSMA ligands radiolabeled with 68Ga (20 MBq, 0.2 nmol) 2 h post-injection (A), 68Ga-CA028 time course (B), and 68Ga-CA030 time course (C). The color bar indicates the link between SUV and the color scale of the PET images, with 0 = minimum and 4E0 = maximum. [Figure 23] FIG. 1 shows blood time-activity curves for 68Ga PSMA-CA027 (0.6 nmol, 5 MBq) and 68Ga PSMA-CA028 (0.6 nmol, 6 MBq) including biexponential curve fits. [Figure 24]Figure 1 shows in vivo metabolism analysis of 177Lu-CA028 in comparison with 177Lu-PSMA-617 (10 MBq, 0.2 nmol in approximately 100 μl of 0.9% saline) in BALB / c nude mice (tumor) at 1 h pi. Radioactive HPLC chromatograms of extracts from kidney, blood, liver, and tumor show that the activity elutes at the retention time of the intact tracer, demonstrating the integrity of the complex within the main distribution window. [Figure 25] FIG. 1 shows the organ distribution of 0.05 nmol 68Ga-CA028 expressed as % ID / g of tissue±SD (n=3) at 20 min, 1 h, 2 h, and 4 h post-injection. [Figure 26-1] FIG. 1 shows a radioactive HPLC chromatogram of a novel compound labeled with 64Cu. [Figure 26-2] FIG. 1 shows a radioactive HPLC chromatogram of a novel compound labeled with 64Cu. [Figure 27] Figure 1 shows time-activity curves for a novel PSMA ligand labeled with 68Ga. (A) Time-activity curve for kidney and (B) time-activity curve for tumor up to 1 h post-injection. Data are mean standardized uptake values ​​(SUV average). [Figure 28] (A) PET image of 9 MBq (0.30 nmol) of 64Cu-CA003 in a female Swiss mouse 10 minutes after injection. Maximum intensity projection (MIP) illustrates circulating blood and renal uptake. (B) PET image of a female Swiss mouse at 10 minutes pi of 10 MBq of 64Cu 10 minutes after injection. Maximum intensity projection (MIP) illustrates strong uptake in the liver and kidney. DETAILED DESCRIPTION OF THE INVENTION

[0063] Embodiment (A) According to a preferred embodiment of the present invention, u and w are 1. According to this embodiment, the compounds of the present invention therefore have the following structure: [ka] It has.

[0064] In this case, Y 3 is most preferably S. Thus, the compounds of the present invention more preferably have the following structure: [ka] It has.

[0065] As stated above, Y 2 is selected from the group consisting of aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl, and alkylheteroaryl. More preferably, Y 2 is an aryl group, and more preferably, Y 2 comprises an optionally substituted phenyl ring, and even more preferably, Y 2 teeth [ka] [In the formula, R 6 , R 7 , R 8 and R 9 are each independently H or alkyl, alkenyl, alkynyl, alkyloxy, alkanoyloxy, aryl, heteroaryl, halogen, hydroxyl, mercapto, nitrile, amine, or in each case optionally substituted alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, alkanoyloxy, cycloalkyl, benzyloxy or aryl, most preferably R 6 , R 7 , R 8 and R 9 are each independently alkyl or H, more preferably R 6 , R 7 , R 8 and R 9 is H] is.

[0066] Thus, the compounds of the present invention preferably have the following structure: [ka] It has.

[0067] Surprisingly, it has been found that with these compounds, the interaction with PSMA can be optimized. With the compounds according to the invention, improved tumor versus non-target tissue accumulation and tissue levels can be achieved, and improved distribution patterns in non-target tissues can be obtained.

[0068] Furthermore, the chelating agents applied according to the present invention allow the stable conjugation of radionuclides that cannot be used to target PSMA-expressing tumors with practically known tracers.

[0069] As described above, generally the chelating agent is selected from the group consisting of (Ia), (Ib) and (Ic).

[0070] For embodiment A, the integer r described above and below is preferably 0. More preferably, A is [ka] The chelating agent is selected from the group consisting of:

[0071] The present invention therefore also relates to compounds as described above and below, as well as complexes comprising said compounds, wherein the compounds have the following structure: [ka] and more preferably has the following structure: [ka] and In the formula, A is [ka] JPEG2026027253000027.jpg35144.

[0072] Preferred compounds according to this embodiment are CA007, CA008 * , CA009 * , CA029 * and CA030 * (see Table 1A), wherein compounds CA007, CA008 * and CA009 * is even more preferred. If a stereocenter in each depicted structure in Table 1A is not specified, it should be understood that this means that all individual stereoisomers are encompassed in isolated form as well as in the form of mixtures of individual stereoisomers. Thus, compound CA008 * , CA009 * , CA029 * and CA030 * can exist as a single stereoisomer or as a mixture of stereoisomers. More preferably, according to this embodiment, the compound has a structure selected from the group consisting of CA007, CA008, CA009, CA029, and CA030 (see Table 1B), with compounds CA007, CA008, and CA009 being particularly preferred.

[0073] Surprisingly, these compounds exhibited high binding affinity for PSMA and were shown to be effectively internalized.

[0074] Embodiment (B) According to another preferred embodiment of the invention, u is 0 and w is 1. According to this embodiment, the compounds of the invention therefore have the following structure: [ka] It has.

[0075] According to this embodiment, A is of structure (Ia) or structure (Ib) [ka] It has.

[0076] As stated above, Y 2 is selected from the group consisting of aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl, and alkylheteroaryl. More preferably, Y 2 is an aryl group or a heteroaryl group, and more preferably, Y 2 comprises an optionally substituted phenyl ring, and even more preferably, Y 2 teeth, [ka] [In the formula, R 6 , R 7 , R 8 and R 9 are each independently H or alkyl, most preferably H.

[0077] The present invention therefore also relates to compounds as described above and below, as well as complexes comprising said compounds, wherein the compounds have the following structure: [ka] wherein A has structure (Ia) or structure (Ib). More preferably, in this case, Y 3 is O.

[0078] Preferred A groups in this context include the following: [ka] JPEG2026027253000033.jpg36146

[0079] More preferably, A is [ka] and most preferably A is selected from the group consisting of: [ka] is.

[0080] Preferred compounds according to this embodiment are CA001, CA002 * , CA003 * , CA005 * , CA006 * , CA007, CA008 * , CA009 * , CA023 * , CA025 * , CA026 * , CA027, CA028 * and CA029 * (The structures of these compounds are illustrated in Table 1A).

[0081] More preferably, the compound is CA007, CA008 * and CA009 * (The structures of these compounds are depicted in Table 1A.) If a stereocenter in each depicted structure in Table 1A is not specified, it should be understood that this means that all individual stereoisomers are encompassed in isolated form as well as in the form of mixtures of individual stereoisomers. Thus, compound CA002 * , CA003 * , CA005 * , CA006 * , CA008 * , CA009 * , CA023 * , CA025 * , CA026 * , CA027, CA028 * and CA029 *can exist as a single stereoisomer or as a mixture of stereoisomers. More preferably, according to this embodiment, the compound has a structure selected from the group consisting of CA001, CA002, CA003, CA005, CA006, CA007, CA008, CA009, CA023, CA025, CA026, CA027, CA028, and CA029 (the structures of these compounds are depicted in Table 1B), with compounds CA007, CA008, and CA009 being particularly preferred.

[0082] Surprisingly, these compounds exhibited high binding affinity for PSMA and were shown to be effectively internalized.

[0083] Embodiment (C) According to another preferred embodiment of the present invention, A is [ka] isn't it.

[0084] Preferably, according to this embodiment, A is [ka] is selected from the group consisting of:

[0085] Surprisingly, it has been found that the compounds of the present invention containing these chelating units form stable complexes with lead and / or copper radionuclides and have advantageous tumor targeting properties.The new compounds offer the possibility of fine-tuning the pharmacokinetic profile according to the respective radionuclides applied.Furthermore, the compounds allow stable labeling with specific radionuclides.

[0086] Copper binding compound: If the compound is to be used as a copper-binding PSMA ligand as described above, A is preferably [ka] is selected from the group consisting of:

[0087] It has surprisingly been found that stable and effective complexes with copper radionuclides can be formed with these compounds. The present invention therefore also relates to compounds as described above or below or complexes as described above or below, wherein A is [ka] and the radionuclide is copper, more preferably 64 Cu and / or 67 It is a radioactive nuclide of Cu.

[0088] For example, the following copper-binding compounds are CA001, CA002 * , CA003 * , CA005 * , CA006 * , CA022 * , CA023 * , CA024 * , CA025 * and CA026 * (The structures of these compounds are illustrated in Table 1A.) More preferred examples are CA001, CA002, CA003, CA005, CA006, CA022, CA023, CA024, CA025, and CA026 (see Table 1B). If a stereocenter in each depicted structure in Table 1A is not specified, it should be understood that this means that all respective stereoisomers are encompassed in isolated form as well as in the form of mixtures of the respective stereoisomers. Thus, compound CA002 * , CA003 * , CA005 * , CA006 * , CA022 * , CA023 * , CA024 * , CA025 * and CA026 * can exist as a single stereoisomer or as a mixture of stereoisomers.

[0089] More preferably, when the compound is to be used with copper as the radionuclide, the compound is CA003 * , CA006 * , CA022 * and CA023 * (the chemical structures of each are illustrated in Table 1A), preferably selected from the group consisting of CA003, CA006, CA022 and CA023 (see Table 1B).

[0090] More preferably, the compound is CA003 * (See Table 1A), and most preferably CA003 (See Table 1B).

[0091] Surprisingly, it has been found that with these compounds, two unmet needs in PSMA targeting can be realized: a) highly specific enrichment in tumors can be achieved together with favorable biodistribution characteristics, in particular significantly improved renal clearance, and b) the possibility to use isotopes of copper and lead, two metals for which preferred radioisotopes exist.

[0092] Lead-binding compounds: If the compound is to be used with, for example, lead as the radionuclide as described above, A is preferably [ka] is selected from the group consisting of:

[0093] Surprisingly, it has been found that with such compounds, preferred complexes with lead can be formed, which exhibit advantageous PSMA targeting properties.

[0094] The present invention therefore also relates to a compound as described above or below or a complex as described above or below, wherein A is [ka] and the radionuclide is lead, more preferably 203 Pb or 212 It is a radioactive nuclide of Pb.

[0095] By way of example, the following lead-binding compounds are available: CA007, CA008, CA009, CA010, CA011, and CA012 (the structures of these compounds are illustrated in Table 1A), preferably CA007, CA008 * , CA009 * , CA010 * , CA011 * and CA012 * It should be mentioned as such.

[0096] More preferably, the compound is CA009 * or CA012 * , most preferably CA009 or CA012. Thus, the present invention relates to a compound or complex as described above, wherein the compound has the structure CA009 * or CA012 (Table A1), more preferably CA009 or CA012 (see Table 1B), and the radionuclide is preferably lead, more preferably 203 Pb or 212 It is a radioactive nuclide of Pb.

[0097] Surprisingly, these compounds were found to exhibit high stability in human serum for 48 h. Furthermore, the compounds demonstrated high affinity for inhibiting PSMA.

[0098] moreover, 203 Pb-labeled compounds showed high rates of specific internalization in PSMA-positive cell lines.

[0099] Pharmaceutical Composition As described above, the present invention also relates to a pharmaceutical composition comprising a compound as described above or below or a complex as described above or below. It should be understood that a pharmaceutical composition comprises a therapeutically effective amount of the compound and / or complex, respectively. The composition may further comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0100] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient, without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0101] A "patient" includes an animal, such as a human, monkey, cow, horse, cat, or dog. The animal may be a mammal, such as a non-primate and a primate (e.g., monkey and human). In one embodiment, the patient is a human.

[0102] In general, the compounds of formula (1) or pharmaceutical compositions thereof can be administered orally or via parenteral routes, usually via injection or infusion.

[0103] "Parenteral route of administration" means a mode of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intrathecal, and intrasternal injection and infusion.

[0104] The dosage of the compounds according to the present invention (referring to the amount of carrier molecules) is determined by a physician based on patient-specific parameters, such as age, weight, sex, and disease severity. The dosage depends on the mode of application: generally, compounds used for molecular imaging purposes are administered in tracer amounts, i.e., by using a total dose of 1 to 100 nmol per patient, with a preferred dose being 5 to 20 nmol per patient. For therapeutic applications (internal radiotherapy), higher doses are required to achieve the radiation absorbed dose (Gray) required to induce a therapeutic effect. For therapeutic applications, the dosage is preferably in the range of 0.1 nmol / kg to 10 nmol / kg body weight, preferably 0.2 to 5 nmol / kg body weight, and most preferably 0.5 to 2 nmol / kg body weight. Depending on the type of administration, the pharmaceutical is suitably formulated, for example, in the form of a solution or suspension prepared according to conventional pharmaceutical methods, a simple tablet or sugar-coated tablet, a hard or soft gelatin capsule, a suppository, a vaginal suppository, or an injectable preparation.

[0105] The compounds according to the invention can be formulated, where appropriate, together with further active substances and with excipients and carriers common in pharmaceutical compositions, such as, depending on the preparation to be produced, talcum, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fat bodies of animal or vegetable origin, paraffin derivatives, glycols (especially polyethylene glycol), various plasticizers, dispersing or emulsifying agents, pharmaceutically compatible gases (e.g., air, oxygen, carbon dioxide, etc.), preservatives.

[0106] To produce liquid preparations, additives such as sodium chloride solution, ethanol, sorbitol, glycerin, olive oil, almond oil, propylene glycol or ethylene glycol may be used.

[0107] When solutions for infusion or injection are used, they are preferably aqueous solutions or suspensions, which can be prepared before use, for example, from freeze-dried preparations containing the active substance as it is or together with carriers such as mannitol, lactose, glucose, albumin, etc. Ready-made solutions are sterilized and, if appropriate, mixed with excipients, such as preservatives, stabilizers, emulsifiers, solubilizers, buffers, and / or salts for adjusting osmotic pressure. Sterilization can be achieved by sterile filtration, if appropriate, using a filter with a small pore size through which the composition can be freeze-dried. A small amount of antibiotics can also be added to ensure sterility.

[0108] The phrases "effective amount" or "therapeutically effective amount," as used herein, refer to an amount of a compound, material, or composition, including a compound of the invention, or other active ingredient, that is effective to produce some desired therapeutic effect in at least a subpopulation of cells in a patient applicable to any medical treatment, at a reasonable benefit / risk ratio. A therapeutically effective amount with respect to a compound of the invention means an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of disease prevention. The term, when used in connection with a compound of the invention, can encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of disease, or enhances the therapeutic effectiveness of, or synergizes with, another therapeutic agent.

[0109] Furthermore, the present invention also relates to a compound as described above or below, or a complex as described above or below, or a pharmaceutical composition as described, for use in treating, ameliorating or preventing a cell proliferative disease or disorder, in particular prostate cancer and / or metastasis thereof.

[0110] Furthermore, the present invention also relates to a compound as described above or below, or a complex as described above or below, or a pharmaceutical composition, for use in diagnostic medicine.

[0111] Furthermore, the present invention also relates to a compound as described above or below, or a complex as described above or below, or a pharmaceutical composition, for use in the diagnosis of cancer, in particular prostate cancer and / or metastasis thereof.

[0112] As used herein, the terms "treating" or "treatment" are intended to encompass diagnosis, prophylaxis, prevention, therapy and cure.

[0113] The terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of disease in a patient resulting from the administration of a prophylactic or therapeutic agent.

[0114] Preferably, the compounds as described above or below, or the complexes as described above or below, or pharmaceutical compositions are used for in vivo imaging and radiotherapy. Suitable pharmaceutical compositions can contain a radioactive imaging agent or a radiotherapeutic agent having a radionuclide either as an element, i.e., radioactive iodine, or as a radioactive metal chelate complex of the compound of formula (Ia) and / or (Ib) in an amount sufficient for imaging, together with a pharmaceutically acceptable radiological vehicle. The radiological vehicle should be suitable for injection or inhalation, such as human serum albumin; aqueous buffer solutions, such as tris(hydromethyl)-aminomethane (and its salts), phosphate buffer, citrate buffer, bicarbonate buffer, etc.; sterile water, saline; and balanced ionic solutions containing chloride and / or dicarbonate salts, or normal blood plasma cations, such as calcium, potassium, sodium, and magnesium.

[0115] The concentration of the imaging or therapeutic agent in the radiological vehicle should be sufficient to provide satisfactory imaging. For example, when using aqueous solutions, the dosage ranges from 0.1 to 300 millicuries. This wide range is due to the fact that alpha-emitting isotopes exert very strong cytotoxic effects, and therefore low doses, e.g., 0.135 mCi per treatment cycle for actinium-labeled PSMA-617, are required. 225This is caused by the fact that it is applied in Ac. beta-emitting radioisotopes, e.g. 177 In the case of Lu, doses of up to 216 mCi are typically applied in one treatment cycle. These doses can be determined by one skilled in the art. The actual dose administered to a patient for imaging or therapeutic purposes, however, will be determined by the treating physician. The imaging or therapeutic agent should be administered so that it remains in the patient for approximately 1 hour to 10 days, although both longer and shorter time periods are acceptable. Therefore, convenient ampoules containing 1 to 10 mL of aqueous solution can be prepared.

[0116] Imaging can be performed in a conventional manner, for example, by injecting a sufficient amount of the imaging composition to provide adequate imaging and subsequent scanning using a suitable imaging or scanning machine, such as a tomography or gamma camera. In certain embodiments, a method for imaging a region in a patient includes (i) administering to the patient a diagnostically effective amount of a compound complexed with a radionuclide, exposing the region of the patient to a scanning device, and (ii) obtaining an image of the region of the patient. In certain embodiments, the region to be imaged is the head or thorax. In other embodiments, the compounds and complexes of formula (1a) and / or (1b) target PSMA protein.

[0117] Thus, in some embodiments, a method of imaging tissue, e.g., spleen tissue, kidney tissue, or PSMA-expressing tumor tissue, is provided that includes contacting the tissue with a complex synthesized by contacting a radionuclide and a compound of Formula (1a) and / or Formula (1b).

[0118] The amount of a compound of the invention, or a formulation containing a complex of the compound, or a salt, solvate, stereoisomer, or tautomer thereof, administered to a patient will depend on several physiological factors known by the physician, including the nature of the imaging to be performed, the tissue to be targeted for imaging or treatment, and the weight and medical history of the patient to be imaged or treated with the radiopharmaceutical.

[0119] Thus, in another aspect, the present invention provides a method of treating a patient suffering from a cell proliferative disease or disorder by administering to the patient a therapeutically effective amount of a complex as described above for treating the patient. In particular, the cell proliferative disease or disorder to be treated or imaged using the compounds, pharmaceutical compositions or radiopharmaceuticals according to the present invention is cancer, e.g., prostate cancer and / or prostate cancer metastases, for example in the lung, liver, kidney, bone, brain, spinal cord, bladder, etc.

[0120] The synthesis of compounds of the present invention is described in detail in the Examples section.

[0121] To summarize the findings of the present invention, the following embodiments are particularly preferred: 1. Equation (1) [ka] [In the formula, Y 3 is O or S, s, t, u and w are each independently 0 or 1; i is an integer from 1 to 3, j is an integer from 3 to 5, Z 1 , Z 2 and Z 3 are independently selected from the group consisting of COH, -SOH, -SOH, -OSOH, and -OPOH; R 1 is —CH3 or H, preferably H, X is selected from the group consisting of optionally substituted alkylaryl (-alkyl-aryl), aryl, alkylheteroaryl (-alkyl-heteroaryl), and heteroaryl; Y 1 and Y 2are each independently selected from the group consisting of optionally substituted aryl, alkylaryl (-alkyl-aryl), cycloalkyl, heterocycloalkyl, heteroaryl, and alkylheteroaryl (-alkyl-heteroaryl); A is (Ia), (Ib) and (Ic) [ka] JPEG2026027253000044.jpg65151 (in the formula, R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of H, —CH—COOH and —CH—C(═O)—NH, or R 2 and R 4 Ha-(CH2) n - bridge, n is an integer from 1 to 3, n is preferably 2, r, v and q are each independently 0 or 1, However, if u and w are 0, then q and v are 0. is a chelator residue having a structure selected from the group consisting of: (A) u and w are 1, or (B) u is 0, w is 1, and A is selected from (Ia) or (Ib); or (C) A is [ka] isn't it] or a pharmaceutically acceptable salt or solvate thereof. 2. X preferably comprises a residue selected from the group consisting of optionally substituted naphthyl, phenyl, biphenyl, indolyl and benzothiazolyl, more preferably X is [ka] The compound of embodiment 1, selected from the group consisting of: 3. X is [ka] 2. The compound of embodiment 1, wherein 4. Z 1 , Z 2 and Z 3 The compound of any one of embodiments 1 to 3, wherein is —CO 2 H. 5. R 1 The compound of any one of embodiments 1 to 4, wherein is H. 6. Y 1 but [ka] 6. The compound of any one of embodiments 1 to 5, wherein 7. i is 2 and j is 4, preferably structure (1a) [ka] 7. The compound of any one of embodiments 1 to 6, having the following structure: 8. The compound of any one of embodiments 1 to 7, wherein u and w are 1. 9. Y 3 is S. 10. Y 2 but [ka] and R 6 , R 7 , R 8 and R 9 are, independently of each other, H or alkyl, preferably H. 11. A compound according to any one of embodiments 8 to 10, wherein r is preferably 0. 12. A, [ka] 12. The compound of any one of embodiments 8 to 11, wherein the compound is a chelating agent selected from the group consisting of: JPEG2026027253000052.jpg35141. 13. CA007, CA008 * , CA009 * , CA029 * and CA030 * (see Table 1A), preferably a structure selected from the group consisting of CA007, CA008, CA009, CA029, and CA030 (see Table 1B). 14. CA007, CA008 * and CA009 * (see Table 1A), preferably a structure selected from the group consisting of CA007, CA008 and CA009 (see Table 1B). 15. The compound of any one of embodiments 1 to 7, wherein u is 0, w is 1, and A is selected from (Ia) or (Ib). 16. Y 2 The compound of embodiment 15, wherein is an optionally substituted aryl or heteroaryl group. 17. Y 2 but [ka] and R 6 , R 7 , R 8 and R 9 are, independently of each other, H or alkyl, preferably H. 18. A, [ka] 18. The compound of any one of embodiments 15 to 17, selected from the group consisting of: 19. A, [ka] 19. The compound of any one of embodiments 15 to 18, selected from the group consisting of: 20. A [ka] 20. The compound of any one of embodiments 15 to 19, wherein 21. CA001, CA002 * , CA003 * , CA007, CA008 * , CA009 * , CA022 * , CA023 * , CA025 * , CA026 * , CA027, CA028 * and CA029 * (see Table 1A), preferably a structure selected from the group consisting of CA001, CA002, CA003, CA007, CA008, CA009, CA022, CA023, CA025, CA026, CA027, CA028 and CA029 (see Table 1B). 22. CA007, CA008 * and CA009 * The compound of any one of embodiments 15 to 21, having a structure selected from the group consisting of: 23. A, [ka] The compound of any one of embodiments 1 to 7, which is not 24. A, [ka] 24. The compound of embodiment 23, selected from the group consisting of: JPEG2026027253000059.jpg36153. 25. (a) Radionuclides, and (b) A compound according to any one of embodiments 1 to 24, or a salt thereof. A complex containing 26. A radionuclide is 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Sm, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Radionuclides of Er, Fe (e.g. 52 Fe and 59 Fe), and radionuclides of Pb (e.g. 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 26. The complex of embodiment 25, wherein the complex is selected from the group consisting of: 27. A radioactive nuclide is a lead radionuclide and A is [ka] 26. The complex of embodiment 25, wherein 28. The complex of embodiment 27, wherein (b) is a compound having a structure selected from the group consisting of CA007, CA008, CA009, CA010, and CA011, or a salt thereof. 29. A radioactive nuclide is a copper nuclide and A is [ka] 26. The complex of embodiment 25, wherein 30. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 24 or a complex according to any one of claims 25 to 29. 31. A compound according to any one of embodiments 1 to 24 or a complex according to any one of embodiments 25 to 29 or a pharmaceutical composition according to embodiment 30 for use in treating, ameliorating or preventing PSMA-expressing cancer and / or metastasis thereof, in particular prostate cancer and / or metastasis thereof. 32. A compound according to any one of embodiments 1 to 24 or a complex according to any one of embodiments 25 to 29 or a pharmaceutical composition according to embodiment 30 for use in a diagnostic agent. 33. A compound according to any one of embodiments 1 to 24 or a complex according to any one of embodiments 25 to 29 or a pharmaceutical composition according to embodiment 30 for use in the diagnosis of cancer, such as PSMA-expressing cancer and / or metastases thereof, in particular prostate cancer and / or metastases thereof.

[0122] All references cited throughout this specification are incorporated by reference herein in their entirety as well as with respect to the disclosure content specifically stated therein.

[0123] The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention in any way. [Example]

[0124] Materials and Methods Solvents and chemicals were purchased from Merck (Darmstadt, Germany) and Sigma-Aldrich (Munich, Germany) 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 performed. PET imaging of prostate cancer patients was consented to by the University Hospital Heidelberg in accordance with applicable German law and accepted by the Declaration of Helsinki (approval S321 / 2012).

[0125] Synthesis of the chelating agent moiety The chelator moiety was synthesized in high yield and characterized by LC-MS. The synthesis of the chelator 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid, a bifunctional macrocyclic cyclam analogue, was reported by Studer and Kaden (Studer M and Kadan, TA). One-step synthesis of mono-N-substituted azamacrocycles with a carboxylic group in the side-chain and their complexes with Cu. 2+ and Ni 2+ Helvetica. 1986; 69:2081-2086), while 4-carboxymethyl-11-(1,3-dicarboxypropyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-pentanedioic acid, a bridged chelator, was described by Boswell et al. (Boswell CA, Regino CA, Baidoo KE, et al., Synthesis of a cross-bridged cyclam derivative for peptide conjugation and 64 Cu radiolabeling. Bioconjug Chem. 2008;19:1476~1484).

[0126] I. General Procedure: Synthesis of Novel PSMA Ligands Eder et al. (Eder M, Schafer M, Bauder-Wust U, et al. 68The PSMA-binding motif was prepared by solid-phase synthesis on 2-chlorotrityl resin (2CT-resin) as previously described by Benesova et al. (Benesova M, Schafer M, Bauder-Wust U, et al., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. J Nucl Med. 2015;56:914-920) (see Figure 2). For this purpose, an equimolar amount of Fmoc-Lys(Alloc)-OH was immobilized on 2-chlorotrityl resin. Subsequently, triphosgene was used to generate the isocyanate of the glutamyl moiety (2). ε-Allyloxycarbonyl-protected lysine immobilized on 2-chlorotrityl resin was added and reacted for 16 h with careful stirring to give compound 3. The resin was filtered off, and the allyloxycarbonyl protecting group was cleaved to give compound 4. To give compounds CA001 and CA027, the respective chelating agents were coupled to this intermediate. Subsequently, the PSMA coupled to the chelating agent was cleaved from the resin. Alternatively, coupling of Fmoc-2-naphthylalanine proceeded to give compound 5. To give compounds CA002, CA005, CA008, and CA011, the respective chelating agents were coupled to this intermediate. Subsequently, the PSMA coupled to the chelating agent was cleaved from the resin.Alternatively, trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid was coupled to give (6), which was then coupled to the respective chelating agents to give compounds CA003, CA006, CA009, CA012, CA022, CA023, CA024, CA025, CA026, CA028, CA029, and CA030. Subsequently, the PSMA coupled to the chelating agent was cleaved from the resin. The structures were confirmed by HPLC and MS-LC. The materials were isolated by preparative HPLC using a water-acetonitrile gradient containing trifluoroacetic acid. For this purpose, the compounds were purified using a gradient of 20–50% acetonitrile in water over 15 min. The purified compounds were analyzed by analytical HPLC using acetonitrile in water (0–100%) containing trifluoroacetic acid over 5 min, a Monolith RP HPLC column (100 × 3 mm), and LC / MS. Product fractions were pooled and lyophilized.

[0127] II. Ligands for Imaging and Therapy Using Copper Isotopes Details about (CA001) The product was obtained by incubating the resin (compound 4) with 1.5 equivalents of CTPA-NHS-ester (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid) and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see section I). HPLC retention time: 1.68 min; ESI-MS (m / z): [M+H] + (Calculation C 30 H 50 N7O8): 636.37 (636.36)

[0128] [ka]

[0129] CA002 Details The product was obtained by incubating the resin (compound 5) with 1.5 equivalents of CTPA-NHS-ester (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid) and 10 equivalents of diisopropylamine (DIPEA) in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see section I). HPLC retention time: 2.39 min; ESI-MS (m / z): [M+H] + (Calculation C 43 H 61 N8O9): 833.42 (833.45)

[0130] CA003 Details The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of CTPA-NHS-ester (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid) and 10 equivalents of DIPEA in 500 μl of dimethylformamide (DMF). The compound was purified and the final product was analyzed by HPLC as described above (see section I). HPLC retention time: 2.50 min; ESI-MS (m / z): [M+H] + (Calculation C 51 H 74 N9O 10 ): 972.52 (972.55)

[0131] CA005 Details The product was prepared by dissolving the resin (compound 5) in 1.5 equivalents of a bridged TE2A chelator, 0.98 × n キレート剤 The compound was obtained by incubating with HBTU and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.38 min; ESI-MS (m / z): [M+H] + (Calculation C 44 H 64 N8O 13 ): 913.45 (913.47)

[0132] [ka]

[0133] CA006 Details The product was prepared by combining the resin (compound 6) with 1.5 equivalents of bridged TE2A chelating agent, 0.98 × n キレート剤 The compound was obtained by incubating with HBTU and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.55 min; ESI-MS (m / z): [M+H] + (Calculation C 52 H 78 N9O 14 ): 1052.62 (1052.56)

[0134] CA022 Details The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of the crosslinked CTPA chelator and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.72 min; ESI-MS (m / z): [M+H] + (Calculation C 53 H 76 N9O 10 ): 998.56 (998.57)

[0135] [ka]

[0136] More about CA023 The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of 8-carboxymethyl-CTPA chelating agent and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.54 min; ESI-MS (m / z): [M+H] + (Calculation C 53 H 76 N9O 12 ): 1030.55 (1030.56)

[0137] [ka]

[0138] CA024 Details The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of 8-carboxymethyl-bridged CTPA chelator and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.60 min; ESI-MS (m / z): [M+H] + (Calculation C 55 H 78 N9O 12 ): 1056.56 (1056.57)

[0139] [ka]

[0140] CA025 Details The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of 8,11-bis(carboxymethyl)-CTPA chelating agent [CPTA = 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoic acid] and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified, and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.60 min; ESI-MS (m / z): [M+H] + (Calculation C 55 H 78 N9O 14 ): 1088.55 (1088.56)

[0141] [ka]

[0142] More about CA026 The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of 8,11-bis(carboxymethyl)-CTPA chelating agent and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.53 min; ESI-MS (m / z): [M+H] + (Calculation C 57 H 80 N9O 16 ): 1146.56 (1146.57)

[0143] [ka]

[0144] III. Lead isotope ( 203 Pb / 212 PSMA ligands for alpha therapy with Pb CA007 Details The product was obtained by incubating the resin (compound 5) with 1.5 equivalents of p-SCN-Bn-TCMC chelating agent [TCMC = 1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane] and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified, and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.41 min; ESI-MS (m / z): [M+H] + (Calculation C 49 H 70 N 13 O 12 S): 1064.49 (1064.50)

[0145] [ka]

[0146] CA009 Details The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of p-SCN-Bn-TCMC chelating agent and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). ESI-MS (m / z): [M+H] + (Calculation C 57 H 83 N 14 O 13 S): 1203.59 (1203.60)

[0147] CA011 Details The product was prepared by dissolving the resin (compound 5) in 1.5 equivalents of 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid, the monocarboxylate derivative of the chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetamide (DO3AM), 0.98 × n キレート剤rThe compound was obtained by incubating with HBTU and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.07 min; ESI-MS (m / z): [M+H] + (Calculation C 41 H 62 N 11 O 12 ): 900.45 (900.46)

[0148] [ka]

[0149] CA012 Details The product was prepared by dissolving the resin (compound 6) in 1.5 equivalents of DO3AM chelating agent, 0.98 × n キレート剤 This was obtained by incubating with HBTU and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.21 min; [M+H] + (Calculation C 49 H 75 N 12 O 13 ): 1039.54 (1039.56)

[0150] IV. Chelator Spacer Moieties that Enhance the Pharmacokinetic Properties of PSMA-617 More about CA027 The product was obtained by incubating the resin (compound 4) with 1.5 equivalents of p-NHS-Bn-DOTA chelating agent and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 1.47 min; [M+H] + (Calculation C 34 H 52 N7O 14): 782.33 (782.36)

[0151] [ka]

[0152] More about CA028 The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of p-NHS-Bn-DOTA chelating agent and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.36 min; [M+H] + (Calculation C 55 H 76 N9O 16 ): 1119.53 (1118.54)

[0153] More about CA029 The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of p-SCN-Bn-DOTA chelating agent and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.49 min; [M+H] + (Calculation C 57 H 79 N 10 O 17 S): 1207.52 (1207.53)

[0154] [ka]

[0155] CA030 Details The product was obtained by incubating the resin (compound 6) with 1.5 equivalents of p-NCS-benzyl-DOTA-GA chelator and 10 equivalents of DIPEA in 500 μl of DMF. The compound was purified and the final product was analyzed by HPLC as described above (see Section I). HPLC retention time: 2.50 min; [M+H] + (Calculation C 60 H 84 N 11 O 18 S): 1278.56 (1278.57)

[0156] [ka]

[0157] V. Synthesis of radiolabeled complexes: V.1 64 Radiochemical synthesis of Cu-PSMA-derivatives The conjugate (1 mM in water, 5 μl, 5 nmol) was dissolved in 400 μl of sodium acetate buffer (0.4 M in water, pH 5.0) in 0.1 M HCl (200 MBq), 10 μl of ascorbic acid (20% in water) and 282 μl of [ 64 [Cu]CuCl was added to the mixture. The mixture was heated at 95°C for 5 min. Labeling was controlled by radio-HPLC (0-100% MeCN in 5 min, Monolith column) with a flow rate of 2 mL / min and a retention time of 2.3 min.

[0158] Labeling led to radiolabeling yields of >98% within 10 minutes (as illustrated by the radiochromatogram in Figure 26). 64 The specific activity of Cu-PSMA-CA003 was approximately 40 MBq / nmol. 67 The same protocol was used for labeling with Cu.

[0159] V.2 203 / 212 Radiochemical synthesis of Pb-PSMA-ligand 80 nmol of conjugate (1 mM in water, 80 μl, 80 nmol) was dissolved in 400 μl of sodium acetate buffer (0.4 M in water, pH 5.0) in 0.04 M HCl, 10 μl of ascorbic acid (20% in water) and 140 μl of 203 Pb-chloride solution was added, and the specific activity was approximately 102.6 TBq / g (Lantheus Medical Imaging, USA). The mixture was then heated at 95°C for 5 minutes. Labeling was controlled by radio-HPLC.

[0160] V.3 68 Radiochemical synthesis of Ga-PSMA-CA028 (CA027, CA029, CA030) 68 Ga 68 The conjugate (1 mM in DMSO, 20 μl, 20 nmol) was eluted from a Ge / Ga generator (iThemba LABS, South Africa) in 0.6 M HCl with 320 μl of sodium acetate buffer (0.4 M in water, pH 4-5), 10 μl of ascorbic acid (20% in water) and 400 MBq of 68 Ga was added to the mixture. The mixture was heated at 95°C for 5 min. Labeling was controlled by radio-HPLC (0-100% MeCN in 5 min, Monolith column) with a flow rate of 2 mL / min and a retention time of 2.4 min.

[0161] [Table 1]

[0162] V.4 177 Radiochemical synthesis of Lu-PSMA-CA028 (CA027, CA029, CA030) 177 For Lu labeling, approximately 20 MBq was mixed with 200 μl of 0.4 M sodium acetate buffer containing Chelex (pH = 5). 2 μl of a 1 mM solution of compound in 10% DMSO in water, 2 μl of a saturated solution of ascorbic acid, and 40 μl of a solution [ 177[Lu]LuCl3 was mixed and heated to 95° C. for 10 min. Labeling was checked by radio-HPLC (0-100% ACN in water within 5 min, Monolith column).

[0163] VI. Preclinical Evaluation In vitro and in vivo experiments were performed using the PSMA-positive C4-2 cell line, a subline of the LNCaP (lymph node carcinoma of the prostate) cell line (CRL-3314, American Type Culture Collection). C4-2 cells were cultured in RPMI 1640 (PAN Biotech) medium supplemented with 10% fetal bovine serum and stable glutamine (PAN Biotech). Cells were grown at 37°C and incubated in a humidified atmosphere equilibrated with 5% CO2.

[0164] VI.1 In vitro VI.1.1 Competitive binding assays and internalization rates MultiScreen HTS The -DV filter plates were incubated with 100 μl of PBS containing 1% BSA per well at room temperature for 30 minutes. After removal of the PBS / BSA solution, 1 × 10 5 0.75 nM of C4-2 cells were added to Opti-MEM in each well. 68 Ga-labeled PSMA-HBED-CC dimer ( 68 Ga-PSMA-10) (Schafer M, Bauder-Wust U, Leotta K et al., A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer. EJNMMI research. 2012;2:23-23) was used to determine the inhibitory potency of synthetic compounds. All unlabeled compounds were dissolved in Opti-MEM in a volume of 300 μl at the following concentrations: 0, 0.5, 1, 2.5, 5, 10, 25, 50, 100, 500, 1000, and 5000 nM. Subsequently, 3 μl of radiolabeled compound was added. 50 μl of this mixture was removed to obtain a 0.75 nM concentration of radiolabeled ligand. After 45 min of incubation at 37°C, cells were washed twice with PBS on a multiscreen vacuum manifold (Millipore, Billerica, MA), and cell-bound radioactivity was measured using a gamma counter (Packard Cobra II, GMI, Minnesota, USA). For reference, 68 Inhibitory potency was determined using Ga-labeled PSMA-HBED-CC dimer (i.e., PSMA-11). Ki was calculated using a nonlinear regression algorithm (Graph Pad Prism 5.01 software). Experiments were performed in quadruplicate.

[0165] For determination of specific internalization rates, 24-well plates were incubated with 0.1% poly-L-lysine in PBS for 20 min at room temperature and washed once with PBS. 5One ml of RPMI medium containing 1000 C4-2 cells was added to each well and incubated overnight. Experimental conditions for each compound were as follows: incubation at 37°C or 4°C in the presence or absence of receptor blocking via 2-(phosphonomethyl)pentanedioic acid (2-PMPA, Axxora) at a final concentration of 500 μM. Cells were then incubated with 250 μl of a 30 nM solution of labeled compound. Plates were incubated for 45 minutes either at 37°C in a water bath or at 4°C on ice. Subsequently, cells were washed three times with 1 ml of ice-cold PBS and incubated for 5 minutes with 0.5 ml of glycine (50 mM in HCl, pH 2.8). After an additional washing step with 1 ml of ice-cold PBS, cells were lysed with 0.5 ml of 0.3 M NaOH, collected, and radioactivity was measured in a gamma counter for 1 minute. Specific cellular uptake was measured using a 10 6 of cells (%IA / 10 6 The radioactivity bound to the IgG1 receptor was determined as a percentage of the initially added radioactivity (number of cells) by subtraction of the respective uptake under blocking conditions. All experiments were performed in triplicate.

[0166] The results are shown in Figure 3. i Determinations showed nanomolar binding affinities of the synthetic ligands to PSMA.

[0167] 203 Of the Pb-labeled compounds, compounds CA009 and CA012 demonstrated the highest affinity for inhibiting PSMA. 203 The Pb-labeled compounds CA009 and CA012 showed high rates of specific internalization in PSMA-positive cell lines. 203 Pb-CA009 and 203 Pb-CA012 is injected active / 10 6 The maximum internalization rates for C4-2 cells (n=3) were 28.36±2.23 and 7.33±1.26, respectively.

[0168] As shown in the table in Figure 3, for the Cu-labeled ligands, for example, CA003 revealed particularly high affinity for PSMA, followed by CA006, CA002, and CA026. 64 The Cu-labeled compounds showed specific binding to C4-2 cells. 64 34.63±2.77% of Cu-CA003; 64 18.63±4.46% of Cu-CA005 and 64 38.7±6.69% of Cu-CA022 was internalized (n=3). 10 6 C4-2 cells were used for these experiments.

[0169] Furthermore, for example, K for Ga-labeled ligands i The results of the determination revealed nanomolar binding affinities of the synthetic ligands for, for example, PSMA. Among all the new compounds, CA030 exhibited particularly advantageous properties, as shown in Figure 3.

[0170] VI.1.2 Serum stability VI.1.2.1 203 Serum stability of Pb-labeled compounds The stability of radiolabeled compounds was determined by incubation in 300 μl of human serum at 37°C for 1, 2, 3, 6, 24, 48, and 72 hours. Serum was precipitated by the addition of two volumes of acetonitrile. Subsequently, samples were vortexed and centrifuged (twice) at 13,000 rpm for 5 minutes, and the supernatants were analyzed by radio-HPLC (0-100% MeCN in 5 minutes, Monolith column).

[0171] All compounds showed high stability in human serum for at least 48 h. CA011 and CA012 showed particularly favorable stability, being stable for at least 72 h.

[0172] VI.1.2.2 68 Ga, 177 Lu and 64 Serum stability of Cu-labeled compounds After radiolabeling of the compounds, serum stability was determined by iTLC and HPLC analysis. 50 μl (20 MBq) of the labeled ligand was added to 200 μL of human serum (H4522, Sigma-Aldrich, Germany) and incubated at 37°C for different time points (0, 2 h, 24 h, 48 h, and 72 h). 0.5 × 5 cm strips of iTLC-SG-glass microfiber chromatography paper (Folsom, California, USA) were used. 0.5 μL of the radiolabeled compound in serum was applied to each strip 1 cm from the bottom (origin) and the solvent (sodium citrate buffer, 177 The front was raised 5 cm from the bottom in the case of the Lu ligand (0.5 M, pH = 5.0) and in the case of the Cu-labeled ligand (1% Na-EDTA, pH = 4). Finally, each strip was cut into eight pieces, and each piece was measured in a gamma counter. For HPLC analysis, an equal volume of ACN was added to the sample to precipitate serum proteins. Subsequently, the sample was centrifuged at 13,000 rpm for 10 min, and the pellet and supernatant were separated, and the relative activity was measured. Results are expressed as a percentage. Additionally, an aliquot of the supernatant was analyzed by radio-HPLC (0 to 100% ACN in 5 min, Monolith column) at a flow rate of 2 mL / min.

[0173] 68 Ga and 177 The results of the stability study of the Lu radiolabeled compound are shown in Figure 16. As shown by HPLC and radio-TLC, 68 The Ga-labeled compound showed no degradation after incubation in human serum for 2 h. 177 Lu-CA028 resulted in 40% release after 24 h of incubation. 177 Lu, whereas CA029, CA030 and the reference compound PSMA-617 did not demonstrate release activity at this time point (Figure 16).

[0174] 64The results of the stability studies of the Cu-labeled compounds are shown in Figures 17 and 18. Up to 2 h of incubation, ITLC showed that all compounds dissociated only to an extent of less than 2 ± 0.6%. After 24 h of incubation, 64 6±4% of Cu-CA003 and 64 Only 3±1% of Cu-CA006 was found to be dissociated. 64 Cu-PSMA-617 is free 64 The long-term stability test (72 h) showed 13±3% of the Cu activity. 64 Cu-CA006 (8±4%) 64 It was shown to have a stability comparable to that of Cu-CA003 (11±3%). 64 It was found that 18±6% of Cu-PSMA-617 was dissociated. After incubation for 2 h, activity measurements in the pellet (FIG. 18) showed 64 19.0±5.2% of Cu-CA003; 64 12±7.2% of Cu-CA006 and 64 We found that 40±7.5% of Cu-PSMA-617 precipitated with the protein fraction. The percentage of activity in the pellet increased over time. The highest amount of activity was 64 measured in pellets of Cu-PSMA-617, followed by 64 Cu-CA003 followed by Cu-CA003, which showed less activity. 64 Cu-CA006 was found to precipitate.

[0175] VI.2 In vivo experiments In vivo experiments were performed in accordance with the laws of the Federal Republic of Germany. For PET imaging and biodistribution studies, male nude mice (Balb / c nu / nu mice) (19-23 g) were obtained from Charles River at 4-5 weeks of age and kept under specific pathogen-free conditions for 1 week prior to the study. Mice were housed under a 12-h / 12-h light / dark cycle and had free access to water and food. Mice were anesthetized with 2% sevoflurane and cultured in 50% Matrigel in Opti-MEM I (1x) medium. 7C4-2 cells were inoculated subcutaneously on the right trunk. The tumor size was approximately 1 cm. 3 If so, organ distribution studies were performed.

[0176] VI.2.1 Lead-labeled compounds: VI.2.1 Scintigraphic imaging and biodistribution For small animal imaging, mice were anesthetized with 2% sevoflurane. 203 Pb-ligand was injected into the tail vein. Sequential planar scans were performed at 10 min, 1 h, 4 h, 24 h, and 72 h using a gamma imager SCT (Biospace Lab, Paris, France) with a parallel collimator (35 mm / 1.8 mm / 0.2 mm). Based on the imaging results, compound CA012 was selected for biodistribution studies. Experiments were performed in triplicate.

[0177] The results are shown in FIGS.

[0178] VI.2.2 64 Cu-labeled compounds: VI.2.2 a) 64 Cu-chloride and 64 Stability of Cu-CA003 in blood and in vivo fate In vivo 64 The stability of Cu-labeled CA003 was determined by ITLC and HPLC. Non-tumor-bearing male BALB / c nude mice (n=3) were administered the compound via the tail vein. 64 Cu-CA003 (3.6 MBq, 0.26 nmol, dissolved in a total volume of approximately 100 μl of 0.9% saline) was injected, and 800 μl of blood was collected 10 min after injection. Blood samples were centrifuged at 13,000 rpm for 10 min. The pellet and supernatant were subsequently separated, and relative activity was determined. ITLC was performed to assess the stability of the radiolabeled compound in blood as described above. Furthermore, after addition of an equal volume of ACN and removal of protein by centrifugation, an aliquot of the supernatant was analyzed by radio-HPLC (0-100% ACN in 5 min, Monolith column) at a flow rate of 2 mL / min.

[0179] In vivo metabolism was studied by radioactive HPLC analysis. Non-tumor-bearing female Swiss mice (n=3) were injected with 100 mg of ... 64 Cu-chloride (10 MBq in approximately 100 μL of 0.9% saline) or 64 Cu-CA003 (9 MBq, 0.30 nmol in approximately 100 μL of 0.9% saline) was injected. PET imaging was performed 10 min after injection, followed by collection of blood, liver, and kidney. Tissues were rinsed with pre-chilled saline, blotted dry, and treated with 2 mL of 0.1 M NH4OAc / EtOH (35:65). Tissues were homogenized using an Ultra-Turrax T8 (IKA Labortechnik, Germany). Samples were centrifuged at 13,000 rpm (4 °C) for 10 min. The pellet and supernatant were subsequently separated, and relative activity was measured. Results are expressed as a percentage. Additionally, an aliquot of the supernatant was prepared for HPLC measurement by protein precipitation with ACN as described above. Samples were analyzed by radio-HPLC (0 to 100% ACN in 5 min, Monolith column) at a flow rate of 2 mL / min. Fractions were collected every 10 seconds throughout the course of the chromatography, the relative activity of the samples was measured in a gamma-counter and the chromatogram was reconstructed.

[0180] ITLC results for blood stability are 64 Cu-CA003 is 3% 64 The results showed that Cu dissociated or received 97±2.3% intact tracer (see FIG. 19). Radioactive HPLC chromatograms also confirmed the integrity of the copper complex (see FIG. 20). 64 Cu-chloride or 64 Conducting in vivo fate of Cu-CA003 studies 64 Cu-chloride and 64 PET imaging of Cu-CA003 showed different pharmacokinetics (fig. S21). 64Maximum intensity projection PET imaging of Cu-chloride showed lower blood circulation (1.3), higher liver (2.7) and kidney uptake (3.4). 64 Cu-CA003 is 64 It demonstrated longer blood circulation (2.3), higher renal (5.7) uptake and lower liver accumulation (1.0) than Cu-chloride (Figure 28). 64 The integrity of Cu-CA003 was demonstrated by radioactive HPLC chromatograms of kidney, blood, and liver tissue extracts (FIG. 19). 64 The chromatogram for Cu-CA003 shows free copper, 64 It showed a different tracer retention time than Cu-chloride (Figure 20).

[0181] VI.2.2 b) Organ distribution experiments ( 64 Cu ligand) and small animal PET Based on the PET imaging results, CA003 and CA023 were selected for biodistribution analysis using C4-2 tumor-bearing mice. Experiments were performed in triplicate. 0.025 nmol 64 Cu-labeled compounds (1 MBq per mouse in approximately 100 μl of 0.9% saline) were administered via tail vein injection. At 10 min, 1 h, 4 h, 24 h, and 72 h, organs were dissected, weighed, and activity was measured using a γ-counter (Packard Cobra Auto-gamma). The percentage of injected dose per gram (% ID / g) was calculated (see Figures 6A and 6B).

[0182] Additionally, experiments (n=3) using simultaneous administration of PSMA-617 to block PSMA binding at 1 h are shown (Figures 6C and 6D).

[0183] Various 64For small animal PET imaging, Cu-labeled PSMA ligand was used at 10 MBq, 0.2 nmol in approximately 100 μl of 0.9% saline. The radiolabeled compound was injected into C4-2 tumor-bearing mice. Dynamic PET was recorded in a small animal PET scanner (Siemens Inveon D-PET, Malvern, PA USA). SUV values ​​were obtained from conventional (non-dynamic) PET images. The formula for SUV was:

[0184]

number

[0185] Volumes of interest (VOIs) were obtained by manual delineation of appropriate whole tissues (heart, kidney, bladder, tumor—with approximate volumes of 100–500 μl) or tissue liver and muscle sections. Procedure: Images were reconstructed based on OSEM 3D / SP MAP with 16 subsets and two repetitions, and image xy size: 256, image z size: 161. Data were not corrected with post-processing filters. The software used to analyze images and TACs was Inveon™ Acquisition Workplace (IAW) from Siemens IRW 4.1. Dynamic PET scans were performed 0–60 min after injection, and images were reconstructed in three 20-min time frames (0–20 min, 20–40 min, and 40–60 min) for visual display. For some compounds that showed long retention, later time points (2 h, 4 h, 20 h, 45 / 48 h) were included, as shown in Figures 2 / 3 and Tables S1+S2. After 1 h, static PET scans were generated. To compare the different radiotracers, the mean SUV was plotted over time.

[0186] PSMA Ligand 64The results obtained for the biodistribution of Cu-CA003 (n=3) are shown in Figures 6A-6D. Ten minutes after injection, a tumor uptake of 11.33 ± 4.11% ID / g is observed. After 4 h, the amount of tracer accumulation in the tumor (32.34 ± 10.6% ID / g) is much higher than in the kidney (13.33 ± 3.36% ID / g). Time-activity curves generated from dynamic PET imaging show tumor-to-muscle ratios of 10.5 and 3.0 for tumor-to-blood at 1 h post-injection, see Table VI.2.2b_1 below:

[0187] [Table 2]

[0188] These curves demonstrated rapid renal uptake. Organ distribution studies showed that the high renal uptake at 1 h (67.04 ± 20.89% ID / g) was largely eliminated within 24 h (7.48 ± 8.51% ID / g). In contrast, the high tumor uptake value (30.83 ± 12.61% ID / g at 1 h pi) remained nearly constant (19.99 ± 6.43% ID / g at 24 h pi). PET imaging confirmed strong accumulation of the radiotracer in the tumor (Figure 4). At 1 h postinjection, the amount of radioactivity in background organs, such as the kidney, decreased, while the tumor-to-background ratio increased. At 24 h postinjection, PET scans demonstrated very high tumor uptake, confirming enrichment in the tumor.

[0189] The specificity of binding to PSMA was demonstrated in blocking experiments: coinjection of unlabeled PSMA-617 [2 mg / kg] reduced the binding of IL-17 to IL-17 in C4-2 tumors (from 30.83 ± 12.61% ID / g to 2.35 ± 0.38% ID / g) and kidneys (from 67.04 ± 20.89% ID / g to 3.47 ± 0.48% ID / g) at 1 h postinjection. 64 This resulted in a strong decrease in the accumulation of Cu-CA003. 64 PET imaging of Cu-CA003 (FIGS. 6C / 6D) clearly confirmed the biodistribution results.

[0190] Time-activity curves generated from dynamic PET imaging showed tumor-to-muscle ratios of 10.5 and 3.0 for tumor and blood at 1 h postinjection (Table S1). These curves demonstrated rapid renal uptake. Organ distribution studies (Figure 6A) showed that the high kidney uptake at 1 h (67.04 ± 20.89% ID / g) was largely eliminated within 24 h (7.48 ± 8.51% ID / g). In contrast, the high tumor uptake value (30.83 ± 12.61% ID / g at 1 h pi) remained nearly constant (19.99 ± 6.43% ID / g at 24 h pi). PET imaging confirmed strong accumulation of the radiotracer in the tumor (Figure 4). At 1 h postinjection, the amount of radioactivity in background organs, such as the kidney, decreased, while the tumor-to-background ratio increased. 24 h postinjection, PET scans demonstrated very high tumor uptake, confirming enrichment in the tumor. High tumor accumulation was maintained at longer time points, ie, 45 h post-injection (FIG. 4).

[0191] IV.2.2 c) In vivo 64 Cu-PSMA-CA003 and 64 Cu-PSMA-617 and 64 Comparison with Cu-chloride To demonstrate the in vivo stability of the copper complex of PSMA-CA003, 64 Cu-PSMA-CA003 64 Along with Cu-PSMA-617 64 Compared to Cu-chloride (Figure 20). The compound was studied in C4-2 tumor xenografts in a small animal PET study. The results are shown in Figure 3. 64 The time-activity curve obtained from dynamic PET for Cu-CA003 showed a high tumor-to-liver ratio (4.0) at 1 h post-injection, while 64 For Cu-PSMA-617, the tumor-to-liver ratio was 0.37 (Figures 20 / 21 and Tables S1 / S2).

[0192] [Table 3]

[0193] The seeds that are taken up by the tumor are actually 64 Cu-CA003, free 64 To prove that Cu was not involved, a study was performed in C4-2 tumor-bearing mice. 64 Cu-chloride PET imaging (Fig. 20 / 21) was followed by homogenization, extraction and subsequent HPLC analysis of each tissue. 64 The pharmacokinetics observed for Cu-chloride were: 64 Different from Cu-CA003. 64 PET imaging of Cu-chloride reveals increasing tumor uptake up to 2 h after injection. 64 In contrast to Cu-CA003, 64 Cu-chloride showed very high liver accumulation (Figures 20 / 21). 64 For Cu-chloride, the tumor-to-liver ratio at 2 h was 0.38, while 64 The tumor-to-liver ratio of Cu-CA003 was 6.3.

[0194] 1 h after injection, 68 Time-activity curves and mean SUV body weight values ​​generated from dynamic PET imaging of Ga-CA028 demonstrated a tumor-to-kidney ratio of 0.78. At 2 h, this ratio increased to 3.0 (Figure 15 and Table S1.1), while the ligand 68 Ga-CA030 and 68 Ga-CA029 showed lower tumor-to-kidney ratios of 0.52 and 0.33, respectively (Figs. 3, 25, and 23).

[0195] [Table 4]

[0196] The time-activity curve revealed a fast clearance of the tracer, 68 Ga-CA028 showed high tumor accumulation and high kidney levels. 68 For Ga-CA027, a faster clearance by the kidney with tumor accumulation was found (FIG. 22). 68 Ga-CA030 is 68Even though it demonstrated higher kidney uptake values ​​than Ga-CA028, it also showed the highest tumor uptake of all compounds (Figure 15C). 68 We demonstrated very rapid renal clearance and low tumor accumulation of Ga-CA027. 68 Ga-CA028, 68 Ga-CA029 and 68 Ga-CA030 showed high tumor accumulation (Figure 27B). 68 Ga-CA029 showed the highest renal uptake, followed by 68 This was followed by Ga-CA030 (Figure 27A).

[0197] VII. First In-Human Study in Patients VII.1 64 PET using Cu-PSMA-CA003 The PET imaging of the prostate cancer patient shown in Figure 7 was consented to by the University Hospital Heidelberg in accordance with valid German law and accepted by the Declaration of Helsinki (authorization S321 / 2012).

[0198] First in-human study with 200MBq 64 The first PET imaging was performed with Cu-PSMA-CA003. Figure 7 shows the patient with high levels of prostate-specific membrane antigen. It is clearly evident that the patient had metastatic PCa, particularly via multiple lymph node metastases, on the right shoulder, where the primary tumor was located.

[0199] Using the new copper ligands, significant improvements in pharmacokinetics and tumor targeting for copper isotopes were observed. 64Despite the high labeling yield of PSMA-617 using Cu (>99%), poor in vivo stability was observed along with high liver uptake (Cui C, Hanyu M, Hatori A, et al. Synthesis and evaluation of [(64)Cu]PSMA-617 targeted for prostate-specific membrane antigen in prostate cancer. Am J Nucl Med Mol Imaging. 2017;7:40-52).

[0200] New 64 Cu-labeled PSMA ligands are promising agents for targeting PSMA and visualizing PSMA-positive tumor lesions, as demonstrated by preclinical evaluation in small animal PET studies, organ distribution, and the first in-human applications.

[0201] 64 Imaging in patients with Cu-PSMA-CA003 ligand demonstrated its successful translation into clinical studies.

[0202] VII.2 203 Experiments using Pb-CA012 Two patients with castration-resistant metastatic prostate cancer underwent planar whole-body scanning (GE Hawkeye Millennium, 1" crystal, ME-collimator, 279 keV peak + / - 10%, 8 cm / min) at 258 and 310 MBq, respectively. 203The Pb-CA012 injection was performed at 0.4, 4, 18, 28, and 42 h. Images were loaded into the QDOSE dosimetry software suite (ABX-CRO, Dresden) and coregistered. Using organ-dependent percentages of the maximum threshold (15–65%) at the most appropriate time point, regions of interest (ROIs) were segmented for the kidney, liver, spleen, bladder, salivary glands (both left and right parotid and submandibular glands), several tumor lesions, and the whole body. An additional organ-based automated rigid coregistration step was performed to extend to all other time points. These ROIs were used to determine time-activity curves (TACs) for each organ, tumor, and whole body. ROI counts were calibrated to injected activity (MBq) using the first time point (before urination) of the uncorrected geometric mean image. Red bone marrow TAC was calculated from venous blood (6 samples / patient) using established model assumptions [Shen, S., Meredith, RF, Duan, J., Macey, DJ, Khazaeli, MB, Robert, F., LoBuglio, AF: Improved Prediction of Myelotoxicity Using a Patient-Specific Imaging Dose Estimate for Non-Marrow-Targeting 90Y-Antibody Therapy. J Nucl Med, 43: 1245-1253, 2002. Sgouros, G. Bone Marrow Dosimetry for Radioimmunotherapy: Theoretical Considerations. J Nucl Med, 34: 689-694, 1993].

[0203] Using the replacement nuclide feature of QDOSE, all time points are automatically corrected for the physical decay of the source isotope, leaving only its biological clearance, and then the physical decay of the replacement radionuclide is applied. 203 All TACs derived from Pb data were recalculated.

[0204] Biexponential curve fitting was applied to all organ TACs (except for a few tumors and glands, which had to be fitted monoexponentially). Cumulative activity was integrated from 0 to the first measurement time point, numerically from the first to last measurement time point using a trapezoidal approximation, and from the last measurement time point to infinity using a fit function, assuming linear growth. The remaining body was calculated by subtracting all source organs from the total body. Using the organ masses of a male adult phantom, residence times for kidney, liver, spleen, bladder contents, red bone marrow, and the remaining body were exported for dose calculation in OLINDA 1.1 [Stabin, MG, Sparks, RB, Crowe, E. OLINDA / EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med, 46(6):1023-1027, 2005].

[0205] Potential therapeutic nuclides 212 Pb is 212 Bi, 212 Po and 208 The daughter nuclide decays further to Tl. 212 The same residence time as for 212Pb was applied to the daughter nuclides, assuming that they remain at the site of transient equilibrium between Pb and its daughter. Individual OLINDA calculations were performed for all nuclides. According to the branching ratios, 212 For Po, 64.07% and 208A weighting factor of 35.93% was used for Tl to sum each decay step. Following recommendations from the Medical Internal Radiation Dose Committee and the U.S. Department of Energy [Sgouros G, Roeske JC, McDevitt MR, et al., MIRD Pamphlet No. 22 (Abstract): Radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J Nucl Med. 2010;51:311-28. Feinendegen LE, McClure JJ. Conference Report: Alpha-emitters for medical therapy—Workshop of the United States Department of Energy, Denver, Colorado, May 30-31, 1996. Radiat Res. 1997;148:195-201], physical absorbed doses were converted to equivalent doses using a weighting factor of 5 for alpha and 1 for beta and photon radiation. Therefore, the reflection of relative biological effectiveness in relation to deterministic radiation effects is considered a major factor in therapeutic settings. Tumor and salivary gland volumes were measured individually based on CT-segmentation, and their absorbed doses were estimated by using a power function that interpolates spherical model estimates [Stabin, MG, Konijnenberg, M. Re-evaluation of Absorbed Fractions for Photons and Electrons in Small Spheres. J Nucl Med, 41: 149-160, 2000].

[0206] Patient 203 Pb imaging data Using an injection activity of 258-310MBq, there is an 80% probability of existence. 203The 279 keV gamma rays emitted from Pb were found to be sufficient to obtain clear planar scans (Figure 10). These scans demonstrate that the lead isotope-labeled tracer is specifically enriched in the target tissue. Consequently, the method provides a successful approach for using lead isotopes for the intended application. (in tumor-bearing mice 203 The organ distribution of Pb-PSMA-CA012 is shown in the table in Figure 11).

[0207] VII.3 Dosimetry estimates 203 Pb-CA012 Dosimetry estimates Diagnostic 203 Dosimetric estimates for Pb-CA012 are shown in the left column of the table in Figure 11. All organ absorbed doses are dominated by photons (primary emission at 279 keV), with low-probability emissions contributing, in effect, <10% each in all organs. For example, for individual dosimetric estimates, a typical clinical examination using 250-300 MBq translates to a radiation burden of 6.0-7.5 mSv.

[0208] 212 Stable from Pb 208 During decay to Pb, two beta and one alpha particles are emitted per atom, whether by the polonium or thallium branch. 212 The safety dosimetry estimates for Pb-CA012, considering the complete subsequent decay chain, are presented in the right column of Figure 11. Therapeutic doses are given assuming RBE=5 for alpha and RBE=1 for beta and gamma radiation. 212 The equivalent dose for Pb-CA012 consists of 96.4% alpha, 2.2% beta and 1.4% gamma contributions. Notably: 203 Directly traced by Pb 212 The initial beta decay of Pb contributes less than 1% to the total equivalent dose, with 99% of the equivalent dose coming from subsequent daughter nuclides.

[0209] Among the OLINDA organs, the kidneys and red bone marrow may be dose-limiting, along with the salivary glands, assessed using a spheroid model. The therapeutic range of the radiopharmaceutical is defined by the ratio between the tumor dose and the dose-limiting organ. The most relevant dosimetry information is summarized and compared with other PSMA-targeted alpha therapies in Figure 12.

[0210] VII.4 Human PET Scanning 68 Ga-CA028 and 68 Ga-CA030 The method for CA028 radiation dosimetry was performed as previously described in Afshar-Oromieh et al., 2015 (Afshar-Oromieh A, Hetzheim H, Kratochwil C, et al. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET / CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. J Nucl Med. 2015;56:1697-1705).

[0211] Each was applied via i.v. 68 Ga-CA028 and 68 Using Ga-CA030 (339 MBq / 20 nmol per patient) 68 Ga-CA028 or 295MBq / 20nmol 68 Images were obtained at 1 and 3 h after injection. 68 Diagnostic testing for Ga-CA028 was performed (see Figure 14).

[0212] 339MBq / 20nmol per patient, respectively 68 Ga-CA028 or 295MBq / 20nmol 68Diagnostic PSMA-PET / CT scans were performed 1 and 3 hours after antecubital injection of Ga-CA030. The method for assessing biodistribution was performed as previously described by Afshar-Oromieh et al. (Afshar-Oromieh A, Hetzheim H, Kratochwil C, et al., The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET / CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. J Nucl Med. 2015;56:1697-1705). Clinical standard software Syngo (Siemens) was used to determine the distribution of activity in the source organs and to define the VOI in the PET images. This reference by Afshar-Oromieh et al. 68 It was also used as a reference standard for Ga-PSMA-617.

[0213] 68 Ga-CA028 and 68 To demonstrate the clinical applicability of Ga-CA030, PET / CT imaging was performed in the first patient, and the resulting images are illustrated in Figures 13A and 13B. 68 Ga-CA028 and 68 Imaging with Ga-CA030 confirmed the results obtained in vitro and in animal models. PET scans and SUV were acquired with standard scanner settings and calibrated for pure positron emitters (Wadas TJ, Pandya DN, Solingapuram Sai KK, Mintz A. Molecular targeted alpha-particle therapy for oncologic applications. AJR Am J Roentgenol. 2014;203:253-260). SUV values ​​obtained 1 h vs. 3 h post-injection are shown in the table below. As reflected by these values, high and stable accumulation in the tumor is achieved.

[0214] Table 5

Claims

1. Formula (1) 【Chemistry 1】 [In the formula, Y 3 is O or S, s, t, u and w are each independently 0 or 1; i is an integer from 1 to 3, j is an integer from 3 to 5, Z 1 , Z 2 and Z 3 are independent of each other, -CO 2 H, -SO 2 H, -SO 3 H, -OSO 3 H and -OPO 3 H 2 is selected from the group consisting of R 1 Ha-CH 3 or H, preferably H, X is selected from the group consisting of optionally substituted alkylaryl (-alkyl-aryl), aryl, alkylheteroaryl (-alkyl-heteroaryl), and heteroaryl; Y 1 and Y 2 are each independently selected from the group consisting of optionally substituted aryl, alkylaryl (-alkyl-aryl-), cycloalkyl, heterocycloalkyl, heteroaryl, and alkylheteroaryl (-alkyl-heteroaryl); A is (Ia), (Ib) and (Ic) 【Chemistry 2】 【change】 (In the formula, R 2 , R 3 , R 4 and R 5 are independently H, -CH 2 -COOH and -CH 2 -C(=O)-NH 2 or R 2 and R 4 Ha-(CH 2 ) n - forms a bridge, n is an integer from 1 to 3, n is preferably 2, and r, v and q are each independently 0 or 1, However, if u and w are 0, then q and v are 0. is a chelator residue having a structure selected from the group consisting of: (A) u and w are 1, or (B) u is 0, w is 1, and A is selected from (Ia) or (Ib); or (C) A is 【Transformation 3】 isn't it] or a pharmaceutically acceptable salt or solvate thereof.

2. X comprises a residue selected from the group consisting of optionally substituted phenyl, biphenyl, indolyl and benzothiazolyl, more preferably X is 【Chemistry 4】 Preferably, X is selected from the group consisting of 【Transformation 5】 2. The compound of claim 1, wherein:

3. Z 1 , Z 2 and Z 3 Ga-CO 2 H and R 1 3. The compound of claim 1 or 2, wherein is H.

4. Y 1 but 【Transformation 6】 4. The compound according to any one of claims 1 to 3, wherein

5. i is 2 and j is 4, preferably structure (1a) 【Transformation 7】 5. The compound of claim 1, wherein

6. u and w are 1, and Y 3 is S and Y 2 but 【Transformation 8】 and R 6 , R 7 , R 8 and R 9 are each independently H or alkyl, preferably H.

7. A, 【Chemistry 9】 7. The compound of claim 6, which is a chelating agent selected from the group consisting of:

8. 6. The compound of any one of claims 1 to 5, wherein u is 0, w is 1, and A is selected from (Ia) or (Ib).

9. Y 2 but 【Chemistry 10】 and R 6 , R 7 , R 8 and R 9 are each independently H or alkyl, preferably H.

10. A, 【Chemistry 11】 10. The compound of claim 8 or 9, selected from the group consisting of:

11. (a) Radionuclides, and (b) A compound or a salt thereof according to any one of claims 1 to 10. A complex containing

12. The radioactive nuclide 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Sm, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 12. The complex of claim 11, selected from the group consisting of radionuclides of Er, Fe and Pb.

13. The radionuclide is a lead (Pb) radioactive nuclide, and A is 【Chemistry 12】 12. The complex of claim 11, wherein

14. The radionuclide is a copper radioactive nuclide, and A is 【Chemistry 13】 12. The complex of claim 11, wherein

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a complex according to any one of claims 11 to 14.

16. A compound according to any one of claims 1 to 10, or a complex according to any one of claims 11 to 14, or a pharmaceutical composition according to claim 15, for use in treating, ameliorating or preventing PSMA-expressing cancer and / or metastasis thereof, in particular prostate cancer and / or metastasis thereof, or for use in diagnostic medicine.

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