Prostate-specific membrane antigen (PSMA) ligand

Abstract

The present invention generally relates to radiolabeled, preferably fluorescently labeled radiopharmaceuticals, and their use as tracers, imaging agents in nuclear medicine, and for the treatment of various disease states of PSMA-expressing cancer, particularly prostate cancer, and its metastases, as well as their use in preoperative PET imaging and fluorescence-guided surgery of cancer, particularly prostate cancer, and its metastases.

Description

Technical Field

[0001] The present invention generally relates to radiolabeled, preferably fluorescently labeled 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, and their use in preoperative PET imaging and fluorescence-guided surgery for cancer, particularly prostate cancer and its metastases.

Background Art

[0002] Prostate cancer (PCa) is a major cancer in people in the US and Europe. It is estimated that at least 1 to 2 million men in the Western Hemisphere suffer from prostate cancer, and the disease is estimated to affect 1 in 6 men between the ages of 55 and 85. There are over 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, imaging methods using high-resolution anatomy, such as computed tomography (CT), magnetic resonance (MR) imaging, and ultrasound, are superior for the clinical imaging of prostate cancer. Currently, an estimated $2 billion is spent worldwide annually on surgical, radiation, drug, and minimally invasive treatments for prostate cancer. For the treatment of localized prostate cancer, radical prostatectomy with lymph node dissection is an established curative strategy. However, accurate localization and delineation of the tumor margin and metastases remain difficult. Currently, there is no effective treatment for recurrent, metastatic, androgen-independent prostate cancer.

[0003] Tumors are well known to be able to express unique proteins associated with their malignant phenotypes or to overexpress normal constitutive proteins in greater numbers than normal cells. The expression of different proteins on the surface of tumor cells provides opportunities to diagnose and characterize the disease by exploring the phenotypic identity as well as the biochemical composition and activity of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins offer an attractive route for imaging and treating tumors under non-invasive conditions. A promising new series of low molecular weight imaging agents target the prostate-specific membrane antigen (PSMA) (Mease R.C. et al., Clin Cancer Res. 2008, 14, 3036-3043; Foss, C.A. et al., Clin Cancer Res 2005, 11, 4022-4028; Pomper, M.G. et al., Mol Imaging 2002, 1, 96-101; Zhou, J. et al., Nat Rev Drug Discov 2005, 4, 015-1026; WO 2013 / 022797).

[0004] 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(- 18A variety of experimental low molecular weight PCa imaging agents containing [[F]FMAU] are currently 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, S.N. 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, S. M. et al., J Nucl Med 2004, 45, 366 - 373; Schuster, D.M. et al., J Nucl Med 2007, 48, 56 - 63; Tehrani, O.S. et al., J Nucl Med 2007, 48, 1436 - 1441). Each acts by a different mechanism and has certain advantages, such as 11 low urinary excretion for [[C]choline] and disadvantages, such as a short physical half - life of the positron - emitting radionuclide.

[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 U S A 2003, 100, 12590-12595). The latter is important because almost all PCa becomes androgen-independent over time. PSMA has the criteria of a promising target for therapy (Schulke, N. et al., Proc. Natl. Acad. Sci. U S A 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), also known as "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). There are up to 10 6 PSMA molecules per cancer cell, which further suggests 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] The radioimmunoconjugate of the anti-PSMA monoclonal antibody (mAb) 7E11, known as PROSTASCINT® scan, is currently used to diagnose prostate cancer metastases and recurrences. However, this agent tends to produce images that are difficult to interpret (Lange, P.H. PROSTASCINT scan for staging prostate cancer. Urology 2001, 57, 402-406; Haseman, M.K. et al., Cancer Biother Radiopharm 2000, 15, 131-140; Rosenthal, S.A. 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, diagnostic and tumor detection using monoclonal antibodies are limited by the low permeability of monoclonal antibodies in solid tumors.

[0007] The selective targeting of cancer cells using radiopharmaceuticals for either imaging or therapeutic purposes is difficult. 111 In 90 Y, 68 Ga, 177 Lu, 99m Tc, 123 I and 131 I, various radionuclides are known to be useful for radioimaging or cancer radiotherapy. In recent years, some compounds containing a glutamate-urea-glutamate (GUG) or glutamate-urea-lysine (GUL) recognition element linked to a radionuclide-ligand conjugate have been shown to exhibit high affinity for PSMA.

[0008] In WO 2015 / 055318, new imaging agents with improved tumor targeting properties and pharmacokinetics are described. These compounds contain a motif that specifically binds to the cell membrane of cancerous cells, and the motif contains prostate-specific membrane antigen (PSMA), which is the glutamate-urea-lysine motif described above. Preferred molecules described in WO 2015 / 055318 further include 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 the specific targeting of prostate tumors. The compounds are 177 labeled with Lu (for therapeutic purposes) or 68 Ga (for diagnostic purposes), enabling visualization and targeting of prostate cancer for radiotherapy purposes.

[0009] However, in the therapeutic use of radiolabeled PSMA inhibitors, organs with physiological PSMA expression have been found to be dose-limiting, thus minimizing the success of treatment. In particular, the high uptake of radiolabeled PSMA inhibitor substances by the adrenal and salivary glands is noteworthy, as this causes significant side effects in the case of therapeutic use. Attempts to improve the uptake of PSMA inhibitors by the kidneys led to the development of PSMA-617 [Benesova, M. et al. (2016) J Med Chem 59, 1761-75], which is a compound that has already been clinically used with 177Lu or 225Ac for the internal radiotherapy of prostate cancer. However, the reduction of uptake by the salivary and lacrimal glands has still not been achieved and is still described as decisive and dose-limiting in early clinical work. In a first-in-human study using 225Ac-PSMA-617, two patients with very advanced and terminal disease showed complete remission. In both patients, the PSA values decreased below the limit of detectability. A concomitant diagnostic record using 68Ga-PSMA-11 confirmed complete efficacy.

[0010] As already described above, the strong accumulation of PSMA ligands in non-target tissues, particularly the salivary and lacrimal glands, as described in numerous scientific publications, results in significant side effects. The salivary and lacrimal glands can be severely and partially irreversibly damaged, particularly during alpha therapy using 225Ac. The resulting symptoms of dry mouth, for example, represent a dose-limiting side effect. To address this issue, an improvement in the tissue specificity of PSMA ligands has been proposed, for example, in WO 2020 / 165420 A1.

Summary of the Invention

Problems to be Solved by the Invention

[0011] Accordingly, there remains a need for improved PSMA ligands that provide advantageous options for the detection, treatment, and management of PSMA-expressing cancers, particularly prostate cancer. The technical problem underlying the present invention can be regarded as providing PSMA ligands and methods to meet the aforementioned need. This technical problem is solved by the embodiments characterized below in the claims and in this specification.

Means for Solving the Problems

[0012] The solution to the above object is achieved by providing embodiments characterized in the claims. The inventors have found novel compounds that are pigment-labeled, preferably fluorescent dye-labeled, complexed PSMA ligands. Accordingly, the compounds can be used not only, for example, in intraoperative or diagnostic labeling of PSMA-expressing cells, but also as tracers, imaging agents in nuclear medicine, and for the treatment of various disease states of PSMA-expressing cancers, particularly prostate cancer. Accordingly, the PSMA-binding ligands described herein can be used, for example, in preoperative PET imaging and fluorescence-guided surgery for cancer, particularly prostate cancer, and its metastases. These compounds are described in more detail below.

[0013] In particular, the present invention relates to a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising a PSMA-binding motif Q, a chelator residue A, a dye group Z, and at least one amino acid X 1 and at least one linker L BQ wherein preferably X 1 is an N-alkylated amino acid, more preferably an N-methylated amino acid, and in particular X 1 is -N(CH 3 )-CH 2 -C(=O)-, to a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof.

[0014] Furthermore, the present invention relates to a complex comprising (a) a radionuclide, and (b) a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof as described above and below to a complex.

[0015] Furthermore, the present invention relates to a pharmaceutical composition comprising a PSMA-binding ligand as described above or below, or a pharmaceutically acceptable salt or solvate thereof as described above or below, or a complex as described above or below.

[0016] Furthermore, the present invention relates to a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof 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 or preventing PSMA-expressing cancer, particularly prostate cancer, and / or its metastasis.

[0017] Furthermore, the present invention relates to a PSMA-binding ligand and / or complex as described above or below for use as a labeling agent for detecting cancerous tissue in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0018]

Figure 1

Figure 2

Figure 3

Figure 4a

Figure 4b

Figure 4c

Figure 5

Mode for Carrying Out the Invention

[0019] When used hereinafter, the terms "having", "comprise", or "include" or any grammatical variations thereof are used non-exclusively. Thus, these terms can refer to both situations where no additional features are present in the entity described in the context other than the features introduced by these terms, and situations where one or more additional features are present. As an example, the expressions "A has B", "A comprises B", and "A includes B" can refer to both situations where no other elements are present in A other than B (i.e., the situation where A consists solely and exclusively of B), and situations where one or more additional elements such as element C, elements C and D, or further elements are present in entity A in addition to B. Moreover, as understood by those skilled in the art, the expressions "comprising a" and "comprising an" preferably refer to "comprising one or more", i.e., are equivalent to "comprising at least one".

[0020] Furthermore, when used hereinafter, the terms "preferably", "more preferably", "most preferably", "especially", "more specifically", "specifically", "even more specifically" or similar terms are used with optional features without further limiting possibilities. Accordingly, the features introduced by these terms are optional features and are never intended to limit the scope of the claims. The present invention can be implemented by using alternative features, as will be recognized by those skilled in the art. Similarly, features introduced by "in one embodiment" or similar expressions are optional features without any limitation regarding further embodiments of the present invention, without any limitation regarding the scope of the present invention, and without any limitation regarding the possibility of combining features introduced in this way with other optional or non-optional features of the present invention.

[0021] As used herein, the term "standard conditions" refers to IUPAC Standard Ambient Temperature and Pressure (SATP) conditions, i.e., preferably a temperature of 25 °C and an absolute pressure of 100 kPa, and preferably, standard conditions include pH 7, when not otherwise specified. Further, when not otherwise indicated, the term "about" relates to the indicated value with the technical accuracy generally accepted in the relevant art, preferably ±20% of the indicated value, more preferably ±10%, most preferably ±5%. Further, the term "essentially" indicates that there is no deviation having an impact on the indicated result or use, i.e., the possible deviation does not cause a deviation of more than ±20%, more preferably ±10%, most preferably ±5% of the indicated result. Thus, "consisting essentially of" means excluding other components, including substances present as impurities, inevitable substances present as a result of the process used to provide the components, and components added for purposes other than achieving the technical effects of the present invention, while including the specified components. For example, a composition defined using the phrase "consisting essentially of" includes any known acceptable additives, excipients, diluents, carriers, etc. Preferably, a composition consisting essentially of a set of components contains less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1%, most preferably less than 0.1% by weight of unspecified components.

[0022] The use of a PSMA ligand and / or a complex-labeled compound, when referred to herein, includes at least administration of the labeled dose of the labeled compound. However, the use may further include additional steps before, simultaneous with, and / or after said administration, which are considered appropriate by those skilled in the art. The use preferably further includes at least one step as specified herein, in particular a step of the use and / or a step of the method as described herein. Preferably, the use includes intraoperative identification of cancerous tissue.

[0023] As described above, the PSMA binding ligand comprises a PSMA binding motif Q, a chelator residue A, a dye group Z, and at least one linker L BQ and.

[0024] Preferably, the PSMA binding ligand has the structure

[0025] [Chemical formula] (wherein Q is a PSMA binding motif, A is a chelator residue, Z is a dye group, B is a branching group, L BQ is a linker connecting Q to B, and the linker contains at least one amino acid X 1 and, L BZ is a linker, n bz is 0 or 1, L BA is a linker, n ba is 0 or 1) and has.

[0026] The PSMA binding motif Q The PSMA binding motif Q preferably has the structure

[0027] [Chemical formula] (wherein R 1 is H or -CH 3 , preferably H, and R 2 , R 3 and R 4 are independently of each other selected from the group consisting of -CO 2 H, -SO 2 H, -SO 3 H, -OSO 3 H, -PO 2 H, -PO 3 H and -OPO 3 H 2 ). has. More preferably, R 2 , R 3 and R 4 are CO 2 H. In particular, R 1 is H, and R 2 , R 3 and R 4 are CO 2 H. The wavy line indicates the connection site to the linker L BQ .

[0028] Chelating agent residue A A is a chelating agent residue derived from a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (=DOTA), N,N''-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N''-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), Trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), and 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA (MX-DTPA).

[0029] The term "chelating agent residue" and typically the term "chelating agent residue derived from a chelating agent selected from the group" as described above means that the chelating agent described above, and thus typically the chelating agent defined in the "group", is linked to the remainder of the PSMA binding ligand, preferably via a suitable functional group to the linker L BA as shown.

[0030] More preferably, the chelating agent defined in the "group" is linked to the NH group of the remainder of the PSMA molecule via the original carboxylic acid group of the chelating agent, for example, to the amine group L BA such that an amide bond is formed between the chelating agent and the remainder of the pSMA binding ligand, for example using L BA to form an amide bond.

[0031] Preferably, A is a group consisting of

[0032]

Chemical formula

[0033] Most preferably, A has the structure

[0034]

Chemical formula

[0035] At least one linker L BQ : As described above, the PSMA ligand preferably comprises at least one linker L 1 comprising at least one amino acid X BQ as described above.

[0036] The term "amino acid" is to be understood to include all naturally occurring amino acids and non-naturally occurring amino acids, such as all stereoisomers of these amino acids, such as enantiomers and diastereomers. Most preferably, the amino acid is an alpha amino acid. With regard to chirality, L-amino acids are preferred.

[0037] Preferably, X 1 is - a neutral amino acid, or - an N-alkylated amino acid, preferably an N-methylated amino acid is.

[0038] More preferably, X 1 is an N-alkylated amino acid, more preferably an N-methylated amino acid, such as a neutral N-alkylated amino acid, more preferably a neutral N-methylated amino acid.

[0039] The term "neutral amino acid", when used within the scope of the meaning of the present invention, includes any amino acid having no net charge at pH 7. The term includes all naturally occurring amino acids and non-naturally occurring amino acids, such as all stereoisomers of these amino acids, such as enantiomers and diastereomers, such as glycine, alanine, valine, isoleucine, phenylalanine, beta-alanine, and non-natural amino acids containing a neutral linker between the N-terminus and the C-terminus, such as at least one -(CH2-CH2-O)- group between the N-terminus and the C-terminus, and N-alkylated, such as N-methylated amino acids, that is, amino acids containing an alkyl or methyl group attached to the amino group of the amino acid instead of a proton - H.

[0040] Preferably, the amino acid X 1is an N-alkylated amino acid. This term refers to an amino acid containing an alkyl such as methyl bonded to the amino group of the amino acid in place of proton-H. N-alkyl amino acids are also referred to hereinafter as N-alkylated or alkylated amino acids. N-methyl amino acids are also referred to hereinafter as N-methylated or methylated amino acids.

[0041] Preferred N-alkylated amino acids include, but are not limited to, N-alkyl-glycine, N-alkyl-alanine, N-alkyl-valine, N-alkyl-isoleucine, N-alkyl-leucine, N-alkyl-methionine, N-alkyl-phenylalanine, N-alkyl-tyrosine or N-alkyl-tryptophan. Preferably, X1 is a neutral N-alkylated amino acid.

[0042] More preferably, amino acid X 1 is an N-methylated amino acid, preferably a neutral N-methylated amino acid.

[0043] It should be understood that this term also includes all naturally occurring amino acids and non-naturally occurring amino acids, for example all stereoisomers of these amino acids, such as enantiomers and diastereomers of N-methyl derivatives. Most preferably, the amino acid is an N-methyl alpha amino acid. With respect to chirality, L-amino acids are preferred.

[0044] The term methylated amino acid or N-methyl amino acid includes, but is not limited to, N-methylarginine, N-methylhistidine, N-methyllysine, N-methylaspartic acid, N-methylglutamic acid, N-methylserine, N-methylthreonine, N-methylasparagine, N-methylglutamine, N-methylcysteine, selenocysteine, N-methylglycine, N-methylproline, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methyllucine, N-methylmethionine, N-methylphenylalanine, N-methyltyrosine, N-methyltryptophan.

[0045] More preferably, the at least one N-methyl amino acid is a neutral amino acid, such as N-methylglycine, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methylleucine, N-methylmethionine, N-methylphenylalanine, N-methyltyrosine or N-methyltryptophan.

[0046] More preferably, the at least one N-methyl amino acid is selected from the group consisting of N-methylglycine, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methylleucine, N-methylphenylalanine.

[0047] More preferably, the methylated amino acid is N-methylalanine or N-methylglycine (sarcosine), more preferably N-methylglycine, and therefore at least one amino acid preferably has the structure -N(CH 3 )-CH 2 -C(=O)- or -N(CH 3 )-CH(CH 3 )-C(=O)-, more preferably -N(CH 3 )-CH 2 Has -C(=O)-.

[0048] Preferably, the linker L BQ is a configuration block (X 1 ) n1 (wherein n1 is in the range of 2 to 25). When the linker comprises two or more amino acids, the amino acids may be the same or different from each other. Preferably, the amino acid sequence AA comprises a block (X 1 ) n1 (Wherein, all amino acids X 1 are the same). Thus, the linker can be, for example, -N(CH 3 )-CH 2 -C(=O)- and -N(CH 3 )-CH(CH 3 )-C(=O)- group or -N(CH 3 )-CH 2-C(=O)- or -N(CH 3 )-CH(CH 3 )-C(=O)- group only or -N(CH 3 )-CH 2 -C(=O)- group only may be included.

[0049] Preferably, the linker contains at least 3, preferably 3 to 25, methylated amino acids which may be the same or different.

[0050] According to a preferred embodiment, at least two N-methylated amino acids are bonded to each other.

[0051] Preferably, the linker is a building block -(X1)n1 (wherein X 1 is preferably an N-alkylated, preferably methylated amino acid, more preferably a neutral methylated amino acid, and more preferably X 1 is -N(CH 3 )-CH 2 -C(=O)-, and n1 is an integer from 1 to 25, more preferably from 3 to 20, more preferably from 5 to 15, such as 5, 6, 7, 8, 9, 10, 11, 12, 23, 24, 15, more preferably 5 or 10, particularly 10).

[0052] Preferably, the PSMA binding ligand, particularly the linker L BQ is X 1 or (X 1 ) n1 In addition, further contains at least one amino acid building block AS a and / or at least one amino acid building block AS b .

[0053] Amino acid building block AS a Amino acid building block AS a is preferably of the structure

[0054]

Chemical formula

[0055] The term "aryl", as used in the context of this invention, means optionally substituted 5- and 6-membered aromatic rings, as well as substituted or unsubstituted polycyclic aromatic groups (aryl groups), for example, tricyclic or bicyclic aryl groups. Optionally substituted phenyl or naphthyl groups may be mentioned as examples. The polycyclic aromatic group may also contain non-aromatic rings.

[0056] The term "alkylaryl", as used in the context of this invention, refers to an aryl group (alkyl-aryl-) in which at least one proton has been replaced by an alkyl group.

[0057] The term "arylalkyl", as used in the context of this invention, refers to an aryl group (aryl-alkyl-) linked via an alkyl group.

[0058] As used in the context of this invention, the term "heteroaryl" means a optionally substituted 5- or 6-membered aromatic ring containing one or more, for example 1 to 4, for example 1, 2, 3, or 4 heteroatoms in the ring system, and a substituted or unsubstituted polycyclic aromatic group, such as a tricyclic or bicyclic aryl group. When two or more heteroatoms are present in the ring system, at least two of the heteroatoms present may be the same or different. Suitable heteroaryl groups are known to those skilled in the art. The following heteroaryl residues may be described as non-limiting examples: benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, methylenedioxyphenyl, naphthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0059] As used in the context of this invention, the term "alkylheteroaryl" refers to a heteroaryl group (alkyl-heteroaryl-) in which at least one proton has been replaced by an alkyl group.

[0060] As used in the context of this invention, the term "heteroarylalkyl" refers to a heteroaryl group (heteroaryl-alkyl-) linked via an alkyl group.

[0061] As used in the context of this invention, the term "cycloalkyl" means an optionally substituted cyclic alkyl residue, where they may be monocyclic or polycyclic groups. Optionally substituted cyclohexyl may be described as a preferred example of a cycloalkyl residue.

[0062] The term "heterocycloalkyl", as used in the context of this invention, refers to an optionally substituted cyclic alkyl residue having at least one heteroatom, such as O, N or S, in the ring, where they may be monocyclic or polycyclic groups.

[0063] The term "substituted cycloalkyl residue" or "cycloheteroalkyl", as used in the context of this invention, means a cycloalkyl residue or cycloheteroalkyl residue in which at least one H has been replaced by a suitable substituent.

[0064] Preferably, Q1 comprises a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl, more preferably, Q 1 is from the group consisting of:

[0065]

Chemical formula

[0066]

Chemical formula

[0067] Amino acid building block AS b Amino acid building block AS b is preferably of structure (b)

[0068]

Chemical formula

[0069] The term "aryl", as used in the context of the present invention, refers to optionally substituted 5- and 6-membered aromatic rings, and substituted or unsubstituted polycyclic aromatic groups (aryl groups), such as tricyclic or bicyclic aryl groups (-Ar-). Optionally substituted phenyl or naphthyl groups may be mentioned as examples. The polycyclic aromatic group may also contain a non-aromatic ring or an aryl group in the context of the present invention.

[0070] The term "alkylaryl", as used in the context of the present invention, refers to an aryl group (-alkyl-aryl-) in which at least one proton has been replaced by an alkyl group and which is linked via the alkyl group to a -CH2- group and via the aryl group to a carbonyl group.

[0071] The term "arylalkyl", as used in the context of the present invention, refers to an aryl group (-aryl-alkyl-) which is linked via the alkyl group to a carbonyl group and via the aryl group to a -CH2- group.

[0072] The term "heteroaryl" (-heteroaryl-), when used in the context of this invention, means a 5- or 6-membered aromatic ring, optionally substituted, containing one or more, for example 1 to 4, for example 1, 2, 3, or 4 heteroatoms in the ring system, and a substituted or unsubstituted polycyclic aromatic group, such as a tricyclic or bicyclic aryl group. When two or more heteroatoms are present in the ring system, at least two of the heteroatoms present may be the same or different. Suitable heteroaryl groups are known to those skilled in the art. The following heteroaryl residues may be described as non-limiting examples: benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, methylenedioxyphenyl, naphthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0073] The term "alkylheteroaryl", when used in the context of this invention, refers to an aryl group (-alkyl-heteroaryl-) in which at least one proton is replaced by an alkyl group and which is linked via the alkyl group to a -CH2- group and via the heteroaryl group to a carbonyl group.

[0074] The term "heteroarylalkyl", when used in the context of this invention, refers to a heteroaryl group (-aryl-alkyl-) linked via an alkyl group to a carbonyl group and via the heteroaryl group to a -CH2- group.

[0075] The term "cycloalkyl" (-cycloalkyl-) means, in the context of the present invention, an optionally substituted cyclic alkyl residue, where they may be monocyclic or polycyclic groups. Optionally substituted cyclohexyl may be described as a preferred example of a cycloalkyl residue.

[0076] The term "heterocycloalkyl", when used in this context of the present invention, refers to an optionally substituted cyclic alkyl residue having at least one heteroatom, such as O, N or S, in the ring, where they may be monocyclic or polycyclic groups.

[0077] The term "substituted cycloalkyl residue" or "cycloheteroalkyl", when used in this context of the present invention, means a cycloalkyl residue or cycloheteroalkyl residue in which at least one H has been replaced by a suitable substituent.

[0078] Preferably, Q 2 is an aryl group or a cycloalkyl group, more preferably

[0079]

Chemical formula

[0080]

Chemical formula

[0081] Any stereoisomer of Q 2 is possible and should be understood to be included. Q 2 when

[0082]

Chemical formula

[0083] Preferably, the PSMA binding ligands described above and below, preferably linker L BQ comprises at least one amino acid building block AS a and at least one amino acid building block AS b wherein AS a has the structure

[0084]

Chemical formula

[0085]

Chemical formula

[0086]

Chemical formula

[0087]

Chemical formula

[0088] Preferably, the PSMA binding motif Q is the group -(AS b) q is more preferably part-(AS b ) q -AS a is linked to. Thus, the PSMA binding ligand preferably comprises the building block --(AS b ) q -AS a -Q .

[0089] More preferably, the building block -L BQ -Q has a particular structure

[0090] [Chemical formula] (wherein R 1 is H or -CH 3 , preferably H, and R 2 , R 3 and R 4 are, independently of one another, selected from the group consisting of -CO 2 H, -SO 2 H, -SO 3 H, -OSO 3 H, -PO 2 H, -PO 3 H and -OPO 3 H 2 and is selected from the group consisting of Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl q is an integer from 0 to 3 X 1 is as described above, and preferably, X 1 is a methylated amino acid, more preferably a neutral N-methyl amino acid, and more preferably, X 1 is -N(CH 3 )-CH2 -C(=O)-, where n1 is an integer from 1 to 25, more preferably from 3 to 20, still more preferably from 5 to 15, such as 5, 6, 7, 8, 9, 10, 11, 12, 23, 24, 15, more preferably 5 or 10, particularly 10) having the structural block -(X 1 ) n1 -(AS b ) q -AS a --Q, preferably consisting of the same.

[0091] Branching group B As described above, the present invention preferably has the structure

[0092]

Chemical formula

[0093]

Chemical formula

[0094] Therefore, preferably, the PSMA binding ligand is one of the following structures (Ia) or (Ib), preferably structure (Ia)

[0095] [Chemical formula] (wherein R 5 is an alkyl group, preferably a -(CH 2 ) 1~10 group, more preferably a -(CH 2 ) 2~4 group, and Y B is a functional group that links R 5 to the group -(L BZ )n bz -Z or -(L BA )n ba -A, and Y B is preferably a group -NH-, -O-, -S-, -NH-NH-, -NH-NH-C(=O)-, -C(=O)-NH-NH- or C(=O)-, more preferably NH- or -C(=O)-) has. Most preferably, R 5 is (CH 2 ) 4 and Y B is -NH-.

[0096] More preferably, the PSMA ligand is structure (IIa) or (IIb)

[0097] [Chemical formula] TIFF2025516756000021.tif52150(wherein R1 is H or -CH 3 , preferably H, R 2 , R 3 and R 4 are, independently of one another, -CO 2 H, -SO 2 H, -SO 3 H, -OSO 3 H, -PO 2 H, -PO 3 H and -OPO 3 H 2 selected from the group consisting of, Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, q is an integer from 0 to 3, X 1 is as described above, preferably a methylated amino acid, more preferably a neutral methylated amino acid, more preferably, X 1 is -N(CH 3 )-CH 2 -C(=O)-, n1 is an integer from 1 to 25, Z is a dye group, L BZ is a linker, n bz is 0 or 1, L BA is a linker, n ba is 0 or 1, R 5 is an alkyl group, preferably -(CH 2 ) 2~4 group, Y B is R 5 to the group -(L BA )n ba -A or the group -(L BZ )n bz -Z is a functional group for linking, Y B is preferably the group -NH- or -C(=O)-, more preferably the -NH- group) has.

[0098] Therefore, the PSMA ligand preferably has structure (IIIa) or (IIIb)

[0099]

Chemical formula

[0100]

Chemical formula

[0101] Linker L BQ and / or L Bz Any linker suitable for attaching Z and A to the branching group B, preferably to the amino group of structure (B1), can be used. Preferably, linker L BQ and / or L BZ contains at least one amino acid. This includes all naturally occurring amino acids and non-naturally occurring amino acids, such as all stereoisomers of these amino acids, such as enantiomers and diastereomers. Most preferably, the amino acid is an alpha amino acid. With respect to chirality, L-amino acids are preferred. Preferably, linker L BQ and / or L BZ contains at least one neutral amino acid or at least one methylated amino acid, preferably at least one neutral N-methyl amino acid, more preferably -N(CH 3 )-CH 2 -C(=O)-.

[0102] According to a first preferred embodiment, the PSMA ligand has structure (Ia), preferably (IIa), more preferably (IIIa), more preferably (IVa). In this case, L BZpreferably comprises an amino acid sequence, said sequence preferably comprising at least one neutral amino acid or at least one methylated amino acid, preferably at least one neutral N-methyl amino acid, more preferably -N(CH 3 )-CH 2 -C(=O)-.

[0103] Preferably, Z is attached to the N-terminus of L BZ or to the functional group of the side chain of the amino acid present in L BZ , provided that when L BZ is attached to the side chain of the amino acid present in L BZ , the N-terminus of the amino acid chain is preferably acylated with the group -C(=O)-R z , and R z is preferably a C10-C20 alkyl chain.

[0104] According to one preferred embodiment, Z is attached to the N-terminus of the amino acid chain. In this case, L BZ preferably comprises an amino acid sequence having the structure -(X 2bz ) n2bz -(X 1bz ) n1bz -, more preferably consists of it, Z is attached to the N-terminus of -(X 2bz ) n2bz -(X 1bz ) n1bz , X 1bz is preferably a methylated amino acid, more preferably X 1bz is -N(CH 3 )-CH 2 -C(=O)-, n1bz is 1-20, preferably 4-10, more preferably 5, X 2bz is preferably a neutral amino acid, more preferably beta-Ala, and n2bz is 1-20, preferably 1. In this case, the PSMA ligand preferably has the structure

[0105]

Chemical formula

[0106] According to an alternative embodiment, Z is attached to the side chain of an amino acid present in the amino acid chain. In this case, the amino acid sequence preferably has the structure -(X 3bz ) n3bz -(X 1bz ) nb1z -, where X 1bz is preferably a methylated amino acid, more preferably, X 1z is -N(CH 3 )-CH 2 -C(=O)-, n1bz is 1 to 20, preferably 4 to 10, more preferably 5, X 2bz is glutamic acid or lysine, preferably lysine, Z is attached to the side chain of X 2bz , and n2z is 1 to 20, preferably 1. In this case, the N-terminus is preferably acylated. Preferably, the N-terminus is acylated with the group -C(=O)-R z , where R z is preferably a C10-C20 alkyl chain. In this case, the PSMA ligand preferably has the structure (Va2), more preferably (VIa2)

[0107]

Chemical Structure

[0108] According to a second preferred embodiment, the PSMA ligand has the structure (Ib), preferably (IIb), more preferably (IIIb), even more preferably (IVb). In this case, L BA preferably contains an amino acid sequence, and the sequence preferably contains at least one methylated amino acid, preferably -N(CH 3 )-CH 2 -C(=O)-. Preferably, L BA contains an amino acid sequence, A is attached to the N-terminus of L BA or to the functional group of the side chain of an amino acid present in L BA , provided that L BAWhen it is attached to the side chain, the N-terminus is preferably the group -C(=O)-R z and is acylated with R z which is preferably a C10-C20 alkyl chain. More preferably, L BA is the amino acid sequence -(X 2a ) n2a -(X 1ba ) n1ba - and preferably consists of it, A is attached to the N-terminus of -(X 2ba ) n2ba -(X 1ba ) n1ba -, X 1ba is preferably a methylated amino acid, more preferably, X 1ba is -N(CH 3 )-CH 2 -C(=O)-, n1a is 1-20, preferably 4-10, more preferably 5, X 2ba is a neutral amino acid, preferably beta-Ala, and n2a is 1-20, preferably 1.

[0109] Dye group Z As used in the context of the present invention, the terms "dye group", "dye moiety", "label" and "dye" can be understood interchangeably in the broadest sense as any moiety having the above formula that provides a visible stain. Preferably, the dye moiety is a fluorescent dye moiety and / or a coloring moiety, and particularly preferably, the dye is a fluorescent dye.

[0110] A fluorescent dye, as used herein, can be understood in the broadest sense as any dye moiety that enables fluorescence detection. Preferably, such fluorescence detection is in the range of 350 to 1000 nm, i.e., in the visible and near-infrared (NIR) spectra, particularly in the range of 400 to 850 nm, i.e., in the visible spectrum. Preferably, the fluorescence signal emitted by the fluorescent dye moiety can be well distinguished from the autofluorescence of cancer and surrounding tissues. A number of fluorescent dye moieties are known in the art and will be readily apparent to those skilled in the art. Many fluorescent dyes having activated groups for reacting with protein side chains or other compounds, such as precursor compounds for the preparation of the compounds of the present invention, are commercially available. Preferably, the dye enables fluorescence detection by radiation having a wavelength in the range of 350 to 1000 nm, i.e., in the visible and near-infrared (NIR) spectra, preferably 400 to 850 nm, such as 600 nm to 850 nm, preferably 700 nm to 780 nm, and / or enables detection of fluorescence by eye and / or at wavelengths in the range of 780 nm to 850 nm.

[0111] Additionally or alternatively, the dye may be colored, i.e., it may cause a perception of color when irradiated by any light. Such coloring effects can be caused by absorbing light in one or more specific wavelength ranges in the visible range (i.e., in the range of approximately 350 nm to approximately 800 nm) and / or by emitting light in one or more specific wavelength ranges in the visible range. Preferably, the color is different from the neoplasm and surrounding tissues that are intended to be examined. Thus, the dye moiety is preferably not red or brown when fluorescence detection is not intended, but rather preferably blue or green. When the dye is intended for fluorescence detection, as long as the fluorescence can be detected above the autofluorescence background, the color difference typically plays a minor role. Preferably, the coloring dye moiety in the context of the present invention is a small molecule dye, i.e., a dye moiety having a molecular weight (MW) of 1000 Da or less, preferably 750 Da or less, particularly 500 Da or less.

[0112] Depending on the chemical properties of the fluorescent dye in the compound of the present invention and the presence of fluorophores and / or quenchers on the surface of the target cells, i.e., the cell membranes of respective cancer cells, when the compound according to the present invention binds to the cell membrane, it becomes possible to observe effects such as fluorescence energy transfer (FRET) and / or fluorescence quenching. Additionally or alternatively, due to the presence of the linkage of the fluorescent dye, it also becomes possible to carry out further fluorescence-based test methods, such as fluorescence recovery after photobleaching (FRAP), fluorescence loss in photobleaching (FLIP), etc. These methods can provide information regarding the mobility of the compound or its salt that is bound or associated with the cell membrane of cancer cells.

[0113] Preferably, neither the chemical groups present in the PSMA ligand nor the complexed radioactive metal quenches by more than 50% the intensity of the fluorescent signal obtainable from Dye Z at the maximum radiation in an aqueous environment at a substantially neutral pH (i.e., pH 6 to 8, particularly 6.5 to 7.5).

[0114] Preferably, Dye Z is suitable for emitting light in an aqueous environment at a substantially neutral pH, i.e., pH 6 to 8, particularly 6.5 to 7.5, particularly pH 7.0 to 7.5.

[0115] In a preferred embodiment, Dye Z is a fluorescent dye having a radiation maximum in the range of 350 nm to 1000 nm, preferably 400 nm to 850 nm.

[0116] Alexa Fluor 3, Alexa Fluor 5, Alexa Fluor 350, Alexa Fluor 405, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 500, Alexa Fluor 514, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 555, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 610, Alexa Fluor 633, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor 700, and Alexa Fluor 750, Cy2, Cy3, Cy3B, Cy3.5, Cy5, Sulfo Cy5, Cy5.5 and Cy7, DyLight 350, DyLight 405, DyLight 488, DyLight 550, DyLight 594, DyLight 633, DyLight 650, DyLight 680, DyLight 750 and DyLight 800, FluoProbes 390, FluoProbes 488, FluoProbes 532, FluoProbes 547H, FluoProbes 594, FluoProbes 647H, FluoProbes 682, FluoProbes 752 and FluoProbes 782, AMCA, DEAC (7-diethylaminocoumarin-3-carboxylic acid), 7-hydroxy-4-methylcoumarin-3, 7-hydroxycoumarin-3-carboxylic acid (Pubchem SID 135727263), MCA (7-methoxycoumarin-4-acetic acid) (Pubchem CID 342221), 7-methoxycoumarin-3, AMF (4'-(aminomethyl)fluorescein), 5-DTAF (5-(4,6-dichlorotriazinyl)aminofluorescein), 6-DTAF (6-(4,6-dichlorotriazinyl)aminofluorescein), 6-FAM (6-carboxyfluorescein), 5(6)-FAM cadaverine (fluorescein-5(6)-carboxamidocadaverine), 5-FAM cadaverine (fluorescein-5-carboxamidocadaverine), 5(6)-FAM ethylenediamine (fluorescein-5(6)-carboxamidoethylenediamine), 5-FAM ethylenediamine (fluorescein-5(6)-carboxamidoethylenediamine), 5-FITC (FITC isomer I; fluorescein-5-isothiocyanate), 5-FITC cadaverine; fluorescein-5-maleimide; 5-IAF (5-iodoacetamidofluorescein), 6-JOE (6-carboxy-4',5'-dichloro-2',7'-Dimethoxyfluorescein), 5-CR110 (5-Carboxyrhodamine 110), 6-CR110 (6-Carboxyrhodamine 110), 5-CR6G (5-Carboxyrhodamine 6G); 6-CR6G (6-Carboxyrhodamine 6G), 5(6)-Carboxyrhodamine 6G Cadaverine; 5(6)-Carboxyrhodamine 6G Ethylenediamine, 5-ROX (5-Carboxy-X-rhodamine), 6-ROX (6-Carboxy-X-rhodamine); 5-TAMRA (5-Carboxytetramethylrhodamine), 6-TAMRA (6-Carboxytetramethylrhodamine), 5-TAMRA Cadaverine, 6-TAMRA Cadaverine, 5-TAMRA Ethylenediamine (5-Carboxytetramethylrhodamine Ethylenediamine), 6-TAMRA Ethylenediamine (6-Carboxytetramethylrhodamine Ethylenediamine), 5-TMR C6 Maleimide, 6-TMR C6 Maleimide, TR C2 Maleimide, TR Cadaverine, 5-TRITC (Tetramethylrhodamine-5-(and -6)-isothiocyanate), 6-TRITC, R Isomer (Tetramethylrhodamine-6-isothiocyanate), Dansyl Cadaverine (5-Dimethylaminonaphthalene-1-(N-(5-aminopentyl))sulfonamide), EDANS C2 Maleimide (5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid C2 Maleimide), EDANS Acid (5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid); Fluorescamine (4-Phenylspiro-[furan-2(3H),1-phthalane]-3,3'-dione), NBD (4-Chloro-7-nitro-benzo-2-oxa-1,3-diazole), Pyromethene, Texas Red (1H,5H,11H,15H-Xantheno[2,3,4-ij:5,6,7-i'j']diquinolidin-18-ium, 9-[2(or 4)-(chlorosulfonyl)-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-, inner salt), Cy5, Cy5 Succinimidyl Ester (3H-Indolium, 2-[5-[1-[6-[(2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]-1,3-dihydro-3,3-dimethyl-5-sulfo-2H-indole-2-ylidene]-1,3-Pentadien-1-yl]-1-ethyl-3,3-dimethyl-5-sulfo-, inner salt), Cy5 acridine orange, 2,7-dichlorofluorescein, eosin, rose bengal, 1,2-dihydroxyanthraquinone, 1,4-dihydroxyanthraquinone, 1,8-dihydroxyanthraquinone, 1,3,8-trihydroxy-6-ethylanthraquinone, 1,2,5,8-tetrahydroxyanthraquinone, 1-aminonaphthalene, 2-aminonaphthalene, indocyanine green (ICG), IRDye800CW, Bodipy650-X, CF680R, 580CP-methoxy, 610CP, SiR-methyl, ATTO 390, ATTO 425, ATTO 465, ATTO 488, ATTO 495, ATTO 514, ATTO 520, ATTO 532, ATTO Rho6G, ATTO 550, ATTO 565, ATTO Rho3B, ATTO Rho11, ATTO Rho12, ATTO Thio12, ATTO Rho101, ATTO 590, ATTO Rho13, ATTO 594, ATTO 610, ATTO 620, ATTO Rho14, ATTO 633, ATTO 647, ATTO 647N, ATTO 655, ATTO Oxa12, ATTO 665, ATTO 680, ATTO 700, ATTO 725, ATTO647N, STAR 600, STAR635 P, STAR RED, 580CP-methoxy and derivatives thereof selected from the group consisting of.,

[0117] Preferably, Z is selected from the group consisting of Atto590, Alexa594, STAR600, STAR 635P, STAR RED, Atto647N, Bodipy650-X, 580CP-methoxy, 610CP, SiR-methyl, sulfo Cy5, IRDye800CW and indocyanine green (ICG).

[0118] Thus, according to one preferred embodiment, Z has the following structure:

[0119]

Chemical formula

[0120] According to a more preferred embodiment, Z has the following structure:

[0121]

Chemical formula

[0122] According to a more preferred embodiment, Z has the following structure:

[0123]

Chemical formula

[0124] According to a more preferred embodiment, Z has the following structure:

[0125]

Chemical formula

[0126] According to a further preferred embodiment, Z has the following structure:

[0127]

Chemical formula

[0128] According to a further preferred embodiment, Z has the following structure:

[0129]

Chemical formula

[0130] According to a further preferred embodiment, Z has the following structure:

[0131]

Chemical formula

[0132] According to a further preferred embodiment, Z has the following structure:

[0133] [Chemical formula] (wherein, "R" represents a chemical bond to L 2 ) Having 580CP-methoxy (N. Butkevich, G.Y. Mitronova, S.C. Sidenstein, J.L. Klocke, D. Kamin, D.N.H. Meineke, E. D'Este, P.-T. Kraemer, J.G. Danzl, V.N. Belov, S.W. Hell, Angew. Chem. Int. Ed. 2016, 55, 3290).

[0134] According to a further preferred embodiment, Z has the following structure:

[0135] [Chemical formula] (wherein, "R" represents a chemical bond to L 2 ) Having 610CP (CAS 1877282-17-1, see N. Butkevich, G.Y. Mitronova, S.C. Sidenstein, J.L. Klocke, D. Kamin, D.N.H. Meineke, E. D'Este, P.-T. Kraemer, J.G. Danzl, V.N. Belov, S.W. Hell, Angew. Chem. Int. Ed. 2016, 55, 3290).

[0136] According to a further preferred embodiment, Z has the following structure:

[0137] [Chemical formula] (wherein, "R" represents a chemical bond to L 2 )(see Lukinavicius, G. et al., Nature Chem 5, 132-139 (2013)). is SiR-methyl having (see Lukinavicius, G. et al., Nature Chem 5, 132-139 (2013)).

[0138] According to a further preferred embodiment, Z has the following structure

[0139] [Chemical formula] (wherein, "*" indicates the connection site to L 2 )(see Lukinavicius, G. et al., Nature Chem 5, 132-139 (2013)). is IRDye800CW (CAS 1088919-86-1) having (see Lukinavicius, G. et al., Nature Chem 5, 132-139 (2013)).

[0140] According to a further preferred embodiment, Z has the following structure:

[0141] [Chemical formula] is ICG (3599-32-4) having (see Lukinavicius, G. et al., Nature Chem 5, 132-139 (2013)).

[0142] According to a further preferred embodiment, Z has the structure -C(=O)-C 1 (wherein C 1 is

[0143] [Chemical formula] and Y + is sulfo Cy5 (CAS 1144107-82-3 (potassium salt), CAS 1121756-16-8 (inner salt), CAS 2098639-31-5 (sodium salt)) having a suitable pharmaceutically acceptable salt, preferably Na+ or K+, more preferably Na+).

[0144] According to a further preferred embodiment, Z is of formula (C)

[0145] [Chemical formula] [wherein X 1z and X 4z are independently selected from the group consisting of -N=, -N(R 5z )=, and -C(R 6z )=, X 2z and X 3z are independently selected from the group consisting of O, S, Se, N(R 5z ) and C(R 6z R 7z ) and are preferably both C(CH 3 ) 2 , Y z is a linker that connects two parts of (C) and enables electron delocalization between said parts, and Y z optionally contains the group (L z -) c Z 0 , az and bz are independently selected from the group consisting of 1, 2, and 3, each R 1z and each R 2z are independently selected from the group consisting of (L z -) c Z z , (L z -) c Z 0 and H, and two adjacent R 1z and / or two adjacent R 2z may optionally form an aromatic ring substituted by one or more (L z -) c Z z or (L z -) c Z 0 , R 3z , R 4z , R 5z, R 6z , R 7z , R 9z is independently selected from the group consisting of (L z -), c Z z , (L z -), c Z 0 and H, each c is independently 0 or 1, each L z is independently T 1 , -OT 1 -, -ST 1 -, -C(O)T 1 -, -C(O)OT 1 -, -OC(O)T 1 -, -C(O)NHT 1 -, -NHC(O)T 1 , or C 1~10 alkylene group, and the C 1~10 alkylene group may be interrupted by and / or terminated by one or more of -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)O-, and T 1 , T 1 is phenyl, naphthyl, indenyl, indanyl, tetralinyl, decalinyl, adamantyl, C 3~7 cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 11-membered heterobicyclic, and T 1 may optionally be halogen, CN, C(O)R 8z , COOR 8z , OR 8z , C(O)N(R 8z R 8az ), S(O) 2 N(R 8z R 8az ), S(O)N(R 8z R 8az ), S(O) 2 R 8z , N(R 8z ), S(O) 2 N(R 8az R 8bz ), SR 8z , N(R 8z R8az )、 NO 2 ; OC(O)R 8z 、 N(R 8z )C(O)R 8az 、 N(R 8z )S(O) 2 R 8az 、 N(R 8z )S(O)R 8az 、 N(R 8z )C(O)N(R 8az R 8bz )、 N(R 8z )C(O)OR 8az 、 OC(O)N(R 8z R 8az )、 oxo(=O) (the ring is at least partially saturated), or C 1~6 alkyl (C 1~6 alkyl is optionally substituted by one or more of the same or different halogens), and is substituted by one or more substituents selected from the group consisting of: each Z z is independently H, halogen, CN, C(O)R 8z 、 C(O)OR 8z 、 C(O)O - OR 8z 、 C(O)N(R 8z R 8az )、 S(O) 2 OR 8 z、 S(O) 2 O - 、 S(O) 2 N(R 8z R 8az )、 S(O)N(R 8z R 8az )、 S(O) 2 R 8z 、 S(O)R 8z 、 N(R z )S(O) 2 N(R 8az R 8bz )、 SR 8z 、 N(R 8z R 8az )、 NO 2 ; P(O)(OR 8z ) 2 、 P(O)(OR 8z )O - 、 OC(O)R8z , N(R 8z )C(O)R 8az , N(R 8z )S(O) 2 R 8az , N(R 8z )S(O)R 8az , N(R 8z )C(O)N(R 8az R 8bz ), N(R 8z )C(O)OR 8az , or OC(O)N(R 8z R 8az ), and R 8z , R 8az , R 8bz are, independently, H, or selected from the group consisting of C 1~6 alkyl, and C 1~6 alkyl is optionally substituted by one or more of the same or different halogens, Z 0 is a chemical bond connecting the dye Z to the group -(L BZ )n bz -B, provided that one of R 1z , R 2z , R 3z , R 4z , R 5z , R 6z , R 7z , R 9z is (L z -), c Z 0 , or Y z contains (L-) c Z 0 having.

[0146] ​The term "optionally substituted" means unsubstituted or substituted. Generally, but not limited to the following, "one or more substituents" means 1, 2 or 3, preferably 1 or 2 substituents, more preferably 1 substituent. Generally, these substituents may be the same or different. "Alkyl" means a straight-chain or branched hydrocarbon chain. Each hydrogen of the alkyl carbon may be replaced by a substituent as further specified herein. When used in the context of this application, the terms "alkyl", "alkyl residue", "alkyl group" and "alkyl moiety" can be understood as a straight-chain or branched saturated hydrocarbon chain. "Straight-chain" can also be referred to as "unbranched" or "linear". Preferably, the alkyl is straight-chain. When used in the context of this application, the term "alkylene" means a straight-chain or branched saturated hydrocarbon chain in which two parts of the molecule are linked by an alkylene residue. "Straight-chain" can also be referred to as "unbranched" or "linear". Each hydrogen of the alkylene carbon may or may not be replaced by a substituent as further specified herein (i.e., it may be substituted or unsubstituted).

[0147] "C 1~4 alkyl" means an alkyl chain having 1 to 4 carbon atoms, for example, when present at the end of a molecule, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or when two parts of a molecule are linked by an alkyl group, for example, -CH 2 -, -CH 2 -CH 2 -,-CH(CH 3 )-,-CH 2 -CH 2 -CH 2 -,-CH(C 2 H 5 )-,-C(CH 3 ) 2 -. Each hydrogen of the C 1~4 alkyl carbon may be replaced by a substituent as further specified herein. "C 1~6"Alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. For example, when present at the end of a molecule, it is C 1~4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or when two parts of a molecule are linked by an alkyl group, for example -CH 2 -, -CH 2 -CH 2 -,-CH(CH 3 )-,-CH 2 -CH 2 -CH 2 -,-CH(C 2 H 5 )-,-C(CH 3 ) 2 -. Each hydrogen of the C 1~6 alkyl carbon may be replaced by a substituent as further specified herein. "C 1~8 alkylene residue" refers to an alkylene chain having 1 to 8 carbon atoms. When two parts of a molecule are linked by an alkylene group, for example -CH 2 -,-CH 2 -CH 2 -,-CH(CH 3 )-,-CH 2 -CH 2 -CH 2 -,-CH(C 2 H 5 )-,-C(CH 3 ) 2 -,-CH 2 -C(CH 3 ) 2 -,-C(CH 2 -CH 3 ) 2 -,-CH(CH 2 -CH 3 )-,-CH 2 -CH(CH 3 )(CH 2 -CH 3 )-,-CH(CH 3 )(CH 2 -CH 3 )-,-(CH 2 ) 4 -,-(CH2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 - etc. mean. "C 4~8 alkylene" and "C 6 alkylene" terms are defined accordingly. "C 3~7 alkylene" and "C 5 (C 4 ) alkylene" terms are defined accordingly. "C 1~10 alkylene group" means a divalent straight-chain or branched hydrocarbon chain having 1 to 10 carbon atoms. Each hydrogen of the alkyl carbon may be replaced by a substituent as further specified herein. Examples are methylene (-CH 2 -), -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -C(CH 3 ) 2 -. Each hydrogen of the C 1~10 alkylene group carbon may be replaced by a substituent as further specified herein. Thus, "C 1~10 alkylene residue" means an alkylene chain having 1 to 10 carbon atoms when two parts of a molecule are linked by an alkylene group. Preferably, but not necessarily, the C 1~10 alkylene residue in the context of residue f of spacer y is a straight-chain, i.e., unbranched, C 1~10 alkylene residue, and optionally one or more hydrogens are substituted and / or optionally one or more -CH 2 - moieties may be replaced by -O- or -NH-. The expression "one or more -CH 2 - moieties may optionally be replaced by ~" means the indicated number of CH2 The base may be replaced by an atom or group specified herein. Further, one or more hydrogens may be replaced by a substituent as specified herein. "Optionally interrupted and / or terminated" C 1~10 An alkylene group means that the alkylene chain is interrupted (interrupted) between two carbon atoms by an atom or chemical group as specified herein, or the alkylene group is terminated (terminated) by said atom or group following the carbon at at least one end of the alkylene chain, or the alkylene chain is interrupted and terminated, or the alkylene chain is neither interrupted nor terminated. By way of example, but not limited thereto, C optionally interrupted and / or terminated by one or more X 3 The alkylene group may have the sequences C-C-C, C-C-C-X, X-C-C-C, X-C-C-C-X, C-X-C-C, C-C-X-C, C-X-C-X-C, X-C-C-X-C, X-C-X-C-X-C, X-C-X-C-C-X, X-C-X-C-X-C-X.

[0148] The term "carbocyclic" refers to a partially or fully saturated or aromatic carbocyclic monocyclic, bicyclic or tricyclic fused or unfused ring system. This includes phenyl and C 3~7 Cycloalkyl rings. Preferred carbocycles having 5, 6 or 7 carbon atoms are cyclopentene, cyclohexene, phenyl, cycloheptane, especially cyclohexane. "C 3~7 Cycloalkyl" or "C 3~7"Cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen of the cycloalkyl carbon may be replaced by a substituent as further specified herein. "C 3~5 Cycloalkyl" or "C 3~5 Cycloalkyl ring" is defined accordingly. "Halogen" means fluoro, chloro, bromo or iodo. Halogen is generally preferably fluoro or chloro. Within the scope of the meaning described herein, the term "aromatic ring" means a carbocyclic or heterocyclic aromatic ring. Examples are benzene, naphthalene, 5- to 6-membered aromatic heterocycles and 9- to 11-membered aromatic heterobicyclics. "3- to 7-membered heterocyclyl" or "3- to 7-membered heterocycle", when used in the context of this application, is a ring (fully, partially saturated or unsaturated aromatic or non-aromatic ring) having 3, 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds, with at least 1 ring atom to a maximum of 4 ring atoms being sulfur (-S(O)-, -S(O) 2is replaced by a heteroatom selected from the group consisting of oxygen and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples of 3- to 7-membered heterocycles are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocyclic ring" is defined accordingly. The term "5- to 6-membered heterocyclyl" or "5- to 6-membered heterocyclic ring" is defined accordingly. "5- to 6-membered aromatic heterocyclyl" or "5- to 6-membered aromatic heterocyclic ring" is a heterocyclic ring derived from cyclopentadienyl or benzene, in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O) 2 is replaced by a heteroatom selected from the group consisting of oxygen and nitrogen (including =N(O)-), and means a heterocyclic ring in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O) 2-containing), and is meant to be replaced by a heteroatom selected from the group consisting of oxygen and nitrogen (=N(O)-containing). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, and tetrazole. "7- to 11-membered heterobicyclic" or "7- to 11-membered hetero-bicyclic" is a heterocyclic system of two rings having 7 to 11 ring atoms, which may contain double bonds up to the maximum number, (a fully, partially saturated or unsaturated aromatic or non-aromatic ring), wherein at least one ring atom is shared by both rings, and from at least one ring atom up to 6 ring atoms are sulfur (-S(O)-, -S(O) 2is replaced by a heteroatom selected from the group consisting of oxygen and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples of 7- to 11-membered hetero-bicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 7- to 11-membered hetero-bicycle also includes spiro structures of two rings, such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl, or bridged heterocycles, such as 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8-diazabicyclo[3.2.1]octane. "9- to 11-membered aromatic heterobicyclyl" or "9- to 11-membered aromatic hetero-bicycle" is a heterocyclic system of two rings (fully or partially aromatic) that may contain double bonds up to the maximum number, with at least one ring being aromatic, the heterocyclic ring system having 9 to 11 ring atoms, two ring atoms being shared by both rings, and from at least one ring atom up to 6 ring atoms being sulfur (-S(O)-, -S(O) 2is replaced by a heteroatom selected from the group consisting of oxygen and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples of 9- to 11-membered aromatic heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The terms "9- to 10-membered aromatic heterobicyclic" or "9- to 10-membered aromatic heterocyclic" are defined accordingly.

[0149] Accordingly, one of the residues R 1z 、R 2z 、R 3z 、R 4z 、R 5z 、R 6z 、R 7z functions as a connecting group, atom or bond of the dye Z to the group -(L BZ )n bz -B (L z -) c Z 0 .

[0150] Preferably, R 3 or R 4 represents (L z -) c Z 0 . More preferably, R 3z is (L z -) c Z 0 .

[0151] Preferably, in formula (C), X 1z and X 4z are the same, preferably C(R 6z ), more preferably CH.

[0152] Preferably, in formula (C), X 2zand X 3z is the same, preferably C(R 6 R 7 ) and more preferably, R 6 and R 7 are the same, even more preferably L z -Z z where L z =C 1~10 is alkylene and even more preferably L z =CH 2 and Z z =H.

[0153] Preferably, R 9 is H.

[0154] Preferably, in formula (C), Y z does not contain (L z -), preferably, Y c Z 0 is z - -(C(R 9az )=C(R 9az )-) g -

[0155]

Chemical Formula

[0156] Preferably, Y z is

[0157] [Chemical formula] or -(C(R 9az )=C(R 9az )-) g -, g = 2, and each R 9az = H.

[0158] Preferably, in formula (C), az and bz are the same, preferably 1, more preferably, R 1z and R 2z = SO 3 - is.

[0159] Preferably, in formula (C), az and bz are the same, 2, preferably, two adjacent Rs 1z and two adjacent Rs 2z form a phenyl ring.

[0160] Preferably, in formula (C), one of R 3z and R 4z is (L z -) c Z Z0 and the other is (L z -) c Z z where L z - = C 1~10 alkylene, Z z = H or SO 3 - and preferably c = 1.

[0161] Preferably, (L z -) c Z 0 is the group -(LBZ )n bz -C connected to -B 1~10 Alkylene-C(O)-(c = 1, Z 0 chemical bond), preferably C 3~7 Alkylene-C(O)-, more preferably C 5 is Alkylene--C(O)-

[0162] In a highly preferred embodiment, the structure -C(=O)-C 1 has, and C 1 is the following structure

[0163]

Chemical formula

[0164] The most preferred Z is -C(=O)-C 1 and C 1 is

[0165]

Chemical formula

[0166] Also, Y+ is a pharmaceutically acceptable counterion as described above and below

[0167] Preferably, the dye is SulfoCy5

[0168] The pharmaceutically acceptable negatively charged counterion X - can be understood in the broadest sense as shown above. Similarly, the pharmaceutically acceptable positively charged counterion Y+ may have any valence. Thus, Y + may, by way of example, have a charge of +1, +2, +3 or +4, preferably +1 or +2. Y + may be any pharmaceutically acceptable positively charged ion. Preferably, the ion is very soluble in an aqueous liquid. By way of example, Y + is a cation of an alkali metal (e.g., Na + K + Li + ), a cation of an alkaline earth metal (e.g., Mg 2+ Ca 2+ ), Al 3+ NH 4 + H + , and may be selected from the group consisting of cations of organically bound amines. Further, it is understood that the counterion typically depends on the surrounding liquid, e.g., that contained in the buffer in which the compound is dissolved and the body fluid after injection in vivo. One of the in vivo, extracellular, but not the only, major positively charged counterions is Na + .

[0169] Preferably, the PSMA ligand has a structure selected from the structures shown in FIGS. 1, 2, and 3.

[0170] Most preferably, the PSMA ligand has a structure as shown in FIG. 2.

[0171] Complex As described above, the present invention relates to (a) a radionuclide, and (b) a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof as described above or below comprising a complex.

[0172] Typical pharmaceutically acceptable salts include salts prepared by reacting the PSMA binding ligand of the present invention with a pharmaceutically acceptable mineral acid or organic acid or organic or inorganic base. Such salts are known as acid addition salts and base addition salts. Acids commonly used to form acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc., and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc. Examples of such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc. Preferred pharmaceutically acceptable acid addition salts are those formed from mineral acids such as hydrochloric acid and hydrobromic acid, and those formed from organic acids such as maleic acid and methanesulfonic acid. Salts of amine groups can also include quaternary ammonium salts in which the amino nitrogen has a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety. Base addition salts include those derived from inorganic bases such as ammonium or hydroxides, carbonates, bicarbonates of alkali metals or alkaline earth metals, etc.Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. Potassium salt and sodium salt forms are particularly preferred. The specific counterions that form part of any salt of this invention are generally recognized not to be of critical nature as long as the salt is pharmaceutically acceptable as a whole and the counterions do not impart undesirable qualities to the salt as a whole.

[0173] The term "pharmaceutically acceptable solvate" also encompasses suitable solvates of the PSMA-binding ligand of the present invention, where the PSMA-binding ligand combines with a solvent such as water, methanol, ethanol, DMSO, acetonitrile, or a mixture thereof to form a suitable solvate such as the corresponding hydrate, methanolate, ethanolate, DMSO solvate, or acetonitrilate.

[0174] Radionuclide Depending on whether the PSMA-binding ligand of the present invention is to be used as a radioimaging agent or a radiopharmaceutical, different radionuclides are complexed to the chelating agent.

[0175] The complex of the present invention can contain one or more radionuclides, preferably one radionuclide. These radionuclides are preferably suitable for use as a radioimaging agent or as a therapeutic agent for the treatment of proliferating cells such as PSMA-expressing cancer cells, particularly PSMA-expressing prostate cancer cells. According to the present invention, they are referred to as "metal complexes" or "radiopharmaceuticals".

[0176] Preferred imaging methods are positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0177] Preferably, at least one 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, 153 Sm, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Er, 52 Fe, 59 Fe, and radionuclides of Pb (e.g., 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb) selected from the group consisting of.

[0178] More preferably, at least one radionuclide is 90 Y, 68 Ga, 177 Lu, 225 Ac, and 213 Bi selected from the group consisting of. More preferably, the radionuclide is 177 Lu or 225 Ac.

[0179] Preferably, the radionuclide has a half-life of at least 30 minutes, more preferably at least 1 hour, even more preferably at least 12 hours, still more preferably at least 1 day, and most preferably at least 5 days, and preferably, the radionuclide has a half-life of at most 1 year, more preferably at most 6 months, even more preferably at most 1 month, still more preferably at most 14 days. Thus, preferably, the radionuclide has a half-life of from 30 minutes to 1 year, more preferably from 12 hours to 6 months, still more preferably from 1 day to 1 month, and most preferably from 5 days to 14 days.

[0180] Preferably, the radionuclide is an α- and / or β-emitter, i.e., the radionuclide preferably emits α-particles (α-emitter) and / or β-radiation (β-emitter).

[0181] Preferably, when the radionuclide is an α-emitter, the α-particles have an energy of from 1 to 10 MeV, more preferably from 2 to 8 MeV, and most preferably from 4 to 7 MeV.

[0182] Preferably, when the radionuclide is a β-emitter, the β-radiation has an energy of from 0.1 to 10 MeV, more preferably from 0.25 to 5 MeV, and most preferably from 0.4 to 2 MeV.

[0183] Preferred radionuclides that emit β-radiation are 90 Y, 177 Lu, 59 Fe, 66 Cu, 67 Cu, 161 Tb, 153 Sm, 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 selected from the group consisting of Pb, and highly preferred radionuclides that emit β-radiation are 177 Lu or 90 Y, most preferably 177 Lu. Preferably, in this case, the use is for diagnosis or treatment.

[0184] Preferred radionuclides that emit α-radiation are, for example, 213 Bi, 225 Ac, 149 Tb, 230 U and 223 Ra, 213 Bi, 230 selected from the group consisting of U, and more preferably, the radionuclide is 225 Ac and / or 213 Bi. A highly preferred radionuclide that emits α-radiation is, for example 225 Ac. Preferably, in this case, the use is for treatment.

[0185] According to a further embodiment, the radionuclide is a positron emitter. In this case, the radionuclide is preferably 89 Zr, 44 Sc, 66 Ga, 68 Ga and 64 selected from the group consisting of Cu. In this case, the use is preferably for PET diagnosis.

[0186] According to a more preferred embodiment, the radionuclide is a gamma emitter. In this case, the radionuclide is preferably 111 In, 67 Ga, 99m Tc, 155 Tb, 165 Er and 203 selected from the group consisting of Pb. In this case, the use is preferably for SPECT diagnosis.

[0187] According to a more preferred embodiment, the radionuclide emits Auger electrons and preferably decays by electron capture. In this case, the radionuclide is preferably 67 Ga, 155 Tb, 153 Gd, 165 Er and 203 selected from the group consisting of Pb. In this case, the use is preferably for treatment.

[0188] Pharmaceutical Composition As described above, the present invention also relates to a pharmaceutical composition comprising a PSMA binding ligand as described above or below or a complex as described above or below. The pharmaceutical composition should preferably be understood to comprise a therapeutically effective amount of each of the PSMA binding ligand and / or the complex. The pharmaceutical composition may further comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0189] The terms "medicine" and "pharmaceutical composition" as used herein relate to the PSMA binding ligand and / or complex of the present invention and optionally one or more pharmaceutically acceptable carriers, i.e., excipients. The PSMA binding ligand of the present invention can be formulated as a pharmaceutically acceptable salt, and the salts are described above herein. The pharmaceutical composition is preferably administered locally (e.g., intratumorally), topically or systemically. Suitable routes of administration conventionally used for drug administration are oral, intravenous or parenteral administration, and inhalation. The preferred route of administration is parenteral administration. "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, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, intrathecal, intramedullary and intrasternal injections and infusions. Preferably, the administration is by intravenous administration or infusion. However, depending on the nature and mode of action of the PSMA binding ligand, the pharmaceutical composition may be administered by other routes as well.

[0190] Furthermore, the PSMA binding ligand can be administered in combination with other drugs either in a common pharmaceutical composition or as separate pharmaceutical compositions, where the separate pharmaceutical compositions may be provided in the form of a component kit. The PSMA binding ligand is preferably administered in a conventional dosage form prepared by combining the drug with a standard pharmaceutical carrier according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation. It is recognized that the form and characteristics of the pharmaceutically acceptable carrier or diluent are determined by the amount of active ingredient to be combined, the route of administration and other well-known variables.

[0191] Excipients must be acceptable in the sense of being compatible with the other ingredients of the formulation and being suitable for use in contact with the tissues of the patient within the scope of sound medical judgment, with an acceptable benefit / risk ratio, without excessive toxicity, irritation, allergic response, or other problems or complications. Preferably, the excipient is not harmful to its recipient. The excipients used may be, for example, solid, gel, or liquid carriers. Exemplary solid carriers are lactose, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, etc. Exemplary liquid carriers are phosphate buffered saline aqueous solutions, syrups, oils such as peanut oil and olive oil, water, emulsions, various types of wetting agents, sterile solutions, etc. Similarly, the carrier or diluent may contain time-delay materials well known in the art, such as glyceryl monostearate or glyceryl distearate, alone or together with waxes. The suitable carriers include those described above and others well known in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc. When solutions for infusion or injection are used, they are preferably aqueous solutions or suspensions, which can be produced from lyophilized preparations containing, for example, the active substance as such or together with a carrier such as mannitol, lactose, glucose, albumin, etc., prior to use. The ready-made solutions are sterilized and, where appropriate, mixed with excipients such as preservatives, stabilizers, emulsifiers, solubilizers, buffers, and / or salts for adjusting the osmotic pressure. Sterilization can be obtained by sterile filtration using a filter with a small pore size, and, where appropriate, the composition can be lyophilized accordingly. A small amount of antibiotic can also be added to ensure the maintenance of sterility.

[0192] As will be understood by those skilled in the art, the dosage of the PSMA binding ligand depends on a variety of factors. As is well known in the medical art, the dosage for any one patient can depend on many factors, including the patient's size, body surface area, age, the particular PSMA binding ligand to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Further, the dosage of the PSMA binding ligand typically also depends on the intended use, e.g., diagnostic and / or therapeutic use, and, if any, the detection method used.

[0193] In diagnostic use, in particular, the administration of a labeled dose is preferred, and the term "labeled dose" relates to the dose of a PSMA-binding ligand that enables the labeling of PSMA-expressing tissue, preferably specifically labeling PSMA-expressing tissue, more preferably enabling the distinction between cancerous and non-cancerous tissue. For example, during surgery, when the PSMA-binding ligand is detected by its dye moiety, preferably, the labeled dose is at least 200 μg per subject, preferably at least 500 μg, more preferably at least 1 mg of the labeled compound. Preferably, the labeled dose is 0.2 mg to 100 mg per subject, more preferably 0.5 to 25 mg, even more preferably 1 mg to 10 mg, and most preferably 1 mg to 5 mg of said labeled compound. Thus, the labeled dose can be, for example, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, or about 1.5 mg per subject. The aforementioned labeled dose is preferably the labeled dose for a human subject. Thus preferably, the labeled dose is preferably 3 μg / kg body weight to 300 μg / kg body weight, more preferably 5 μg / kg body weight to 100 μg / kg body weight, even more preferably 7.5 μg / kg body weight to 50 μg / kg body weight, and further preferably about 15 μg / kg body weight. Thus preferably, the dose is preferably administered as a single dose, i.e., exactly one dose, within a time frame of at least 12 hours, preferably at least 1 day, more preferably at least 2 days, and thus, within the aforementioned time frame, preferably, no further dose of the labeled compound is administered. Preferably, the said labeled dose is administered to the patient 0.25 hours to 48 hours before diagnosis and / or detection of the PSMA-binding ligand. When the PSMA-binding ligand is a complex as described elsewhere herein and is detected in diagnostic use by the bound radionuclide, the dose is calculated as the activity dose as specified elsewhere herein.With respect to the dosage of the compound, the dosage strongly depends on the specific activity of the radionuclide and generally can be approximately 5 to 1000 times lower compared to the diagnostic dosages specified above herein for detection by the dye moiety.

[0194] A therapeutically effective dosage refers to the amount of the PSMA-binding ligand to be used in the pharmaceutical composition of the present invention for preventing, ameliorating, or treating the symptoms associated with the diseases or conditions mentioned in this specification. The therapeutic efficacy and toxicity of such PSMA-binding ligands can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED50 (the therapeutically effective dosage in 50% of the population) and LD50 (the lethal dosage in 50% of the population). The dosage ratio between the therapeutic effect and the toxic effect is the therapeutic index, which can be expressed as the ratio of LD50 / ED50. As understood by those skilled in the art, the dosage in radiotherapy is typically indicated as the active dosage as specified elsewhere in this specification. Progression can be monitored by periodic assessments. The pharmaceutical compositions and formulations mentioned in this specification are administered at least once for treating or preventing the diseases or conditions listed in this specification. However, the said pharmaceutical compositions may be administered two or more times, for example, 1 to 10 times. Preferably, the pharmaceutical composition may be administered at a frequency of once every 1 to 6 months, more preferably once every 2 to 4 months. Specific pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and contain at least one active PSMA-binding ligand mentioned above herein, in association with an additive mixture or otherwise a pharmaceutically acceptable carrier or diluent. To prepare those specific pharmaceutical compositions, the active compound is usually mixed with a carrier or diluent or enclosed or encapsulated in capsules, sachets, cachets, paper, or other suitable containers or vehicles. The resulting formulations should be adapted to the mode of administration, i.e., in the form of tablets, capsules, suppositories, solutions, suspensions, etc. Dosage recommendations shall be as indicated in the prescriber or user instructions to predict dosage adjustments depending on the recipient considered.

[0195] As used herein, the term "patient" relates to vertebrates, preferably mammals, more preferably humans, monkeys, female cows, horses, cats or dogs. Preferably, the mammal is a primate, more preferably a monkey, and most preferably a human.

[0196] The dosage of the PSMA-binding ligand administered to the patient is preferably defined as the compound dosage, i.e., the amount of the PSMA-binding ligand administered to the patient. A preferred diagnostic compound dosage is a total dosage of 1 - 10 nmol / patient, and thus, preferably, the diagnostic compound dosage is 0.02 - 0.1 nmol / kg body weight. A preferred therapeutic compound dosage is a total dosage of 10 - 100 nmol / patient, and thus, preferably, the therapeutic compound dosage is 0.2 - 1 nmol / kg body weight.

[0197] As will be understood by those skilled in the art, the dosage of the complex as specified herein, i.e., the complex comprising and preferably consisting of a radionuclide and a PSMA-binding ligand, is preferably expressed as the compound dosage as specified above, and the preferred dosage is the same as that specified above. More preferably, the dosage of the complex is expressed as the activity dosage, i.e., the amount of radioactivity administered to the patient. Preferably, the activity dosage is adjusted to avoid adverse effects as specified elsewhere herein. Preferably, the patient-specific dosage, preferably the patient-specific activity dosage, is determined taking into account the relevant factors as specified elsewhere herein, in particular, taking into account the treatment progression and / or adverse effects observed for each patient. Thus, preferably, the activity dosage is adjusted such that the organ-specific dosage in the salivary gland is at most 30 Sv, more preferably less than 20 Sv, even more preferably less than 10 Sv, and most preferably less than 5 Sv.

[0198] The effective amount may be administered in a single dose (single dose) at an activity dose of about 2 MBq to about 30 MBq, preferably 4 to 30 MBq, more preferably 6 to 30 MBq, more preferably 8 to 30 MBq, more preferably 10 to 30 MBq, more preferably 15 to 30 MBq, preferably 20 to 30 MBq per patient. Accordingly, the preferred therapeutic dose in such cases is 2 MBq to about 30 MBq / patient, preferably 4 to 30 MBq / patient, more preferably 6 to 30 MBq / patient, more preferably 8 to 30 MBq / patient, more preferably 10 to 30 MBq / patient, more preferably 15 to 30 MBq / patient, preferably 20 to 30 MBq / patient. Preferably, the activity dose is about 10 to 30 MBq per administration, for example, about 10 MBq, 11 MBq, 12 MBq, 13 MBq, 14 MBq, 15 MBq, 16 MBq, 17 MBq, 18 MBq, 19 MBq, 20 MBq, 21 MBq, 22 MBq, 23 MBq, 24 MBq, 25 MBq, 26 MBq, 27 MBq, 28 MBq, 29 MBq or 30 MBq, or any range between any two of the above values, etc. However, as specified hereinafter in this specification, higher or lower doses may be expected depending on the type and / or use of the radiation emitted by the radionuclide. The phrase "effective amount" or "therapeutically effective amount" as used herein means the amount of a PSMA-binding ligand, a material or composition comprising the PSMA-binding ligand of the present invention, or other active ingredient that is effective to produce some desired therapeutic effect in at least a subpopulation of cells in a patient at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutically effective amount with respect to the PSMA-binding ligand of the present invention means the amount of the therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment or prevention of a disease. The term as used in connection with the PSMA-binding ligand of the present invention can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of the disease, or enhances the therapeutic effectiveness or synergistic effect with another therapeutic agent.

[0199] According to a preferred embodiment, the radionuclide is a β-emitter as specified above herein, more preferably177 is Lu, the use is for diagnosis, and in such a case, the activity dosage of the complex is preferably at least 100 kBq / kg body weight, more preferably at least 500 kBq / kg body weight, and most preferably at least 1 MBq / kg body weight. More preferably, the radionuclide is a β-emitter as specified above herein, and more preferably 177 is Lu, the use is for treatment, preferably for the treatment of prostate cancer tumors as specified elsewhere herein, and in such a case, the activity dosage of the complex is preferably at least 25 MBq / kg body weight, more preferably at least 50 MBq / kg body weight, and most preferably at least 80 MBq / kg body weight. Thus, the preferred treatment dosage in such a case is 2 - 10 Gbq / patient, more preferably 4 - 8 GBq / patient, and most preferably about 6 GBq / patient.

[0200] More preferably, the radionuclide is an α-emitter as specified above herein, and more preferably 225 is Ac, the use is for treatment, preferably for the treatment of prostate cancer tumors as specified elsewhere herein, and in such a case, the activity dosage of the complex is preferably in the range of 25 kBq / kg to about 500 kBq / kg of the patient's body weight, more preferably, the activity dosage of the complex is at least 75 kBq / kg body weight, more preferably at least 100 kBq / kg body weight, still more preferably at least 150 kBq / kg body weight, and most preferably at least 200 kBq / kg body weight. Thus, preferably, in such a case, the activity dosage of the complex is 75 - 500 kBq / kg body weight, more preferably 100 - 400 kBq / kg body weight, still more preferably 150 - 350 kBq / kg body weight, and most preferably 200 - 300 kBq / kg body weight.

[0201] The present invention also relates to a PSMA-binding ligand as described above or below, a complex as described above or below, or a pharmaceutical composition as described above herein, for use in diagnosis, preferably for diagnosing a cell proliferative disease or disorder, particularly prostate cancer and / or its metastases. Furthermore, the present invention also relates to a PSMA-binding ligand as described above or below, a complex as described above or below, or a pharmaceutical composition as described above or below, for use in medicine, preferably for treating or preventing a cell proliferative disease or disorder, particularly prostate cancer and / or its metastases.

[0202] As used herein, the term "diagnosing" refers to determining whether a subject has or does not have a disease or disorder, preferably a cell proliferative disease or disorder. As will be understood by those skilled in the art, such determination is preferably correct for 100% of the subjects being investigated, but will usually not be correct for 100% of the subjects being investigated. However, the term requires that a statistically significant proportion of the subjects be correctly determined and thus be diagnosable. Whether a portion is statistically significant can be readily determined by those skilled in the art using a variety of well-known statistical evaluation tools, such as determination of confidence intervals, p-value determination, Student's t-test, Mann-Whitney test, etc. Details can be found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983. Preferred confidence intervals are at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%. The p-value is preferably 0.2, 0.1, or 0.05. As will be understood by those skilled in the art, diagnosing can include further diagnostic determinations, such as visual and / or manual examination, determination of tumor biomarker concentration in a sample of the subject, x-ray examination, etc. The term includes not only the individual diagnosis of a patient, but also the continuous monitoring of a patient. Monitoring the presence or absence of a cell proliferative disease or symptoms associated therewith at various times, i.e., diagnosing, includes not only monitoring patients known to have a cell proliferative disease, but also monitoring subjects known to be at risk of developing a cell proliferative disease. Further, monitoring can also be used to determine whether a patient is being successfully treated or whether at least the symptoms of a cell proliferative disease can be improved over time by a particular treatment. Further, the term also includes classifying a subject according to a normal classification scheme, such as the T1-T4 staging known to those skilled in the art. Thus, diagnosing can include determining metastases, the number and location of affected lymph nodes, etc.

[0203] The terms "treating" and "treatment" refer to a significant degree of improvement of a disease or disorder or a symptom associated therewith mentioned herein. The treating, as used herein, also includes the restoration of overall health with respect to the disease or disorder mentioned herein. It should be understood that treating may not be effective in all subjects to be treated when the term is used herein. However, the term preferably requires that a statistically significant proportion of subjects suffering from the disease or disorder mentioned herein can be successfully treated. Whether a portion is statistically significant can be readily determined by one of ordinary skill in the art using various well-known statistical evaluation tools as specified above herein. The terms "preventing" and "prevention" refer to maintaining health in a subject for a particular period of time with respect to the disease or disorder mentioned herein. It is understood that the time period may be dependent on the amount of the administered pharmaceutical compound and the individual factors of the subject considered elsewhere in this specification. Prevention may not be effective in all subjects treated with a PSMA-binding ligand according to the present invention. However, the term preferably requires that a statistically significant proportion of a cohort or population of subjects be effectively prevented from suffering from the disease or disorder or a symptom associated therewith mentioned herein. Preferably, a cohort or population of subjects that would otherwise develop the disease or disorder mentioned herein in the absence of the preventive measures according to the present invention is contemplated in this context. Whether a portion is statistically significant can be readily determined by one of ordinary skill in the art using various well-known statistical evaluation tools considered above herein.

[0204] Preferably, the treatment and / or prevention comprises administration of at least one PSMA-binding ligand and / or at least one complex as specified elsewhere herein, more preferably at an active dosage and / or a compound dosage as specified above herein.

[0205] As used herein, the term "proliferative cell disorder" relates to a disease in animals, including humans, characterized by uncontrolled growth by a population of somatic cells ("cancer cells"). This uncontrolled growth may be accompanied by invasion and destruction (infiltration) of the surrounding tissues by the cancer cells and possibly its spread (metastasis) to other locations in the body. Preferably, recurrence is included under the term cancer. Thus, preferably, cancer is a solid tumor, metastasis, or recurrence thereof. Preferably, the proliferative cell disorder is an uncontrolled proliferation of cells, including cells expressing PSMA.

[0206] Accordingly, preferably, the cell proliferative disorder is a PSMA-expressing cancer. The term "PSMA-expressing cancer" refers to any cancer in which cancerous cells express prostate-specific membrane antigen (PSMA). Preferably, the cancer (or cancer cells) that can be treated according to the present invention is selected from prostate cancer, conventional renal cell cancer, transitional cell cancer of the bladder, lung cancer, testicular embryonal cancer, neuroendocrine cancer, colon cancer, brain tumor, and breast cancer, more preferably selected from PSMA-positive prostate cancer, PSMA-positive renal cell cancer, PSMA-positive cancer of transitional cells of the bladder, PSMA-positive lung cancer, PSMA-positive testicular embryonal cancer, PSMA-positive neuroendocrine cancer, PSMA-positive colon cancer, PSMA-positive brain tumor, and PSMA-positive breast cancer. Whether a cancer is PSMA-positive can be determined by those skilled in the art by methods known in the art, for example, in vitro by immunostaining of cancer samples, or in vivo, for example, by PSMA scintigraphy, preferably both as established as described by Kratochwil et al. (2017, J Nucl Med 58(10):1624). In a particularly preferred embodiment of the present invention, the PSMA-expressing cancer is prostate cancer or breast cancer, more preferably prostate cancer, even more preferably advanced stage prostate cancer. Accordingly, preferably, the cell proliferative disorder is prostate cancer stage T2, more preferably stage T3, most preferably stage T4. Preferably, the cell proliferative disorder is metastatic prostate cancer, more preferably metastatic castration-resistant prostate cancer. Advantageously, administration of the PSMA-binding ligand and / or complex of the present invention to a patient results in an improved pharmacokinetic profile, particularly improved renal excretion, with essentially unchanged enrichment in the target tissue, preferably the cell proliferative tissue, more preferably the cancer tissue, as compared to, for example, PSMA-617 commonly used on the one hand, as shown in the studies underlying the present invention. The improved excretion can avoid and / or reduce the adverse side effects on non-target tissues, particularly the salivary gland and / or lacrimal gland. This is advantageous because the adverse side effects on the salivary gland are considered as dose-limiting (see Kratochwil et al. (2017, J Nucl Med 58(10):1624)).Based on the findings of the present invention, a larger amount of the compound and / or complex, and in particular, a higher dose of radioactivity, can be administered to a patient when compared to the compounds and complexes described in the art. Thus, the therapeutic window is wider than that using the compounds currently in use. Advantageously further, the PSMA-binding ligands of the present invention provide an improved diagnosis, as co-labeling of non-related tissues and organs, in particular the salivary glands, lacrimal glands and / or kidneys, is reduced. Moreover, the improved renal excretion reduces background and / or false positive labeling in diagnostic applications, preferably resulting in a clearer identification of PSMA-expressing tissues.

[0207] Accordingly, the PSMA-binding ligands and / or complexes of the present invention enable the treatment of PSMA-expressing cancers, in particular prostate cancer, and its metastases, and / or the diagnosis of PSMA-expressing cancers, in particular prostate cancer, and its metastases, and the PSMA-binding ligands and / or complexes exhibit an advantageous renal excretion profile, preferably with a favorable acceleration of clearance. Thus, the harmful side effects on the patient's kidneys are reduced. Accordingly, the present invention relates to a PSMA-binding ligand and / or complex, or a pharmaceutical composition as described above, for treating and / or preventing PSMA-expressing cancer, in particular prostate cancer and / or its metastases, in a patient in need thereof, wherein the subject suffers from renal insufficiency.

[0208] As described above and in detail in the Examples herein, the compounds as specified herein provide accelerated excretion while maintaining essentially the same enrichment in the target tissue, for example, as PSMA-617, and thus, the harmful effects on non-target tissues, preferably the salivary glands and / or lacrimal glands, are avoided or reduced. Thus, the treatment and / or diagnosis as specified herein has less or less severe harmful side effects on, for example, the salivary glands and / or lacrimal glands, or preferably, is free of harmful side effects, particularly on the salivary glands and / or lacrimal glands.

[0209] Preferably, the PSMA-binding ligand of the present invention enables the reduction and / or avoidance of adverse side effects, e.g., on the salivary gland and / or lacrimal gland, while maintaining essentially unchanged therapeutic efficacy. As will be understood by those skilled in the art in view of the above, the PSMA-binding ligand as specified herein preferably further enables the use of higher concentrations of the compound and / or higher doses of radioactivity without at least increasing adverse effects, which may be particularly useful, for example, in diagnostic applications for detecting e.g. minor metastases or small amounts of residual tumor tissue, and / or in therapy.

[0210] Accordingly, the PSMA-binding ligand and / or complex of the present invention enables the treatment of PSMA-expressing cancers, particularly prostate cancer, and its metastases, and / or the diagnosis of PSMA-expressing cancers, particularly prostate cancer, and its metastases, in which xerostomia symptoms are avoided.

[0211] Preferably, the PSMA-binding ligand as described above or below, or the complex as described above or below, or the pharmaceutical composition as described above or below is used for in vivo imaging and radiotherapy. Suitable pharmaceutical compositions may contain a radiopharmaceutical agent or a radiotherapy agent having a radionuclide either as an element, i.e., radioactive iodine, or as a radioactive metal chelate complex of a PSMA-binding ligand in an amount sufficient for imaging, together with a pharmaceutically acceptable radiological vehicle. The radiological vehicle should be suitable for injection or aspiration and may be, for example, human serum albumin; buffered aqueous solutions, e.g., buffers of tris(hydroxymethyl)-aminomethane (and its salts), phosphate buffer, citrate buffer, bicarbonate buffer, etc.; sterile water, physiological saline; and balanced ion solutions containing chloride salts and / or dicarbonate salts, or normal plasma cations such as calcium, potassium, sodium and magnesium.

[0212] The concentration of the imaging agent or therapeutic agent in the radiological vehicle should be sufficient to provide satisfactory imaging. Appropriate dosages are described above herein. The imaging agent or therapeutic agent should be administered such that it remains in the patient for between about 1 hour and 10 days, although both longer and shorter time periods are acceptable. Conveniently, ampoules containing 1 - 10 mL of an aqueous solution can be prepared.

[0213] Imaging can be carried out in a manner known to those skilled in the art, for example, by injecting a sufficient amount of the imaging composition to provide appropriate imaging, and then scanning with a suitable imaging or scanning machine, such as a tomography or gamma camera. In certain embodiments, a method of imaging a region in a patient comprises the following steps: (i) administering to the patient a diagnostically effective amount of a PSMA-binding ligand complexed with a radionuclide, (ii) 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 PSMA-binding ligand and complex target the PSMA protein.

[0214] Accordingly, in some embodiments, there is provided a method of imaging a tissue, such as spleen tissue, kidney tissue, or PSMA-expressing tumor tissue, comprising contacting the tissue with a complex synthesized by contacting a radionuclide and a PSMA-binding ligand as described above.

[0215] The amount of the PSMA-binding ligand of the present invention, or a formulation comprising a complex or a salt, solvate, stereoisomer, or tautomer thereof, of the PSMA-binding ligand, administered to a patient depends on several physiological factors. These factors, including the nature of the imaging to be performed, the tissue to be targeted for imaging or treatment, and the body weight and medical history of the patient to be imaged or treated using the radiopharmaceutical, are known to a physician.

[0216] Furthermore, the present invention relates to a PSMA-binding ligand and / or complex as described above or below as a labeling agent for detecting cancerous tissue in a subject.

[0217] The term "labeling agent" is understood by those skilled in the art. Preferably, the term relates to a compound that labels PSMA-expressing tissue, more preferably that specifically labels PSMA-expressing cancer tissue. The term "specific labeling" of PSMA-expressing tissue preferably relates to labeling that enables a distinction between PSMA-expressing tissue and non-PSMA-expressing tissue, such as cancer-adjacent tissue. Preferably, said distinction is possible in vitro and / or in vivo, more preferably in vivo. Thus, preferably, the labeling enables a distinction between adjacent cancerous and non-cancerous tissue, for example in the surgical area. Thus, specific labeling does not necessarily have to enable a distinction between PSMA-expressing tissue and any non-PSMA-expressing tissue in a subject, and preferably it is sufficient if the PSMA-expressing tissue can be distinguished from non-PSMA-expressing tissue in the vicinity of the PSMA-expressing tissue. Thus, the distinction can preferably be between cancerous and non-cancerous tissue in the abdominal cavity, more preferably within at most 10 cm, more preferably within at most 5 cm, even more preferably within at most 2 cm from the cancerous tissue. Moreover, preferably, it is not required that the distinction be possible from intact structures that are easily distinguishable in a subject, such as the kidney, liver, etc. The distinction can preferably be made, for example, by visual inspection, for example by a physician, or be assisted or effected by an optical device adapted to detect a label comprised in the labeling compound. Preferably, specific labeling is a labeling that is at least 2-fold, more preferably at least 5-fold, even more preferably at least 10-fold, still more preferably at least 25-fold, more preferably at least 100-fold stronger in PSMA-expressing tissue, preferably cancer cells, compared to non-PSMA-expressing tissue. The labeling agent may be a PSMA-binding ligand or a metal chelate thereof described herein, in particular a radioactive metal chelate thereof.

[0218] Furthermore, the present invention also relates to a PSMA binding ligand, complex, or pharmaceutical composition as specified above herein for use in fluorescence-guided surgery.

[0219] In view of the above, the present invention also 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 or below. Specifically, cell proliferative diseases or disorders to be treated or imaged using a PSMA binding ligand, pharmaceutical composition or radiopharmaceutical according to the present invention are, for example, cancers in the lung, liver, kidney, bone, brain, spinal cord, bladder, etc., such as prostate cancer and / or prostate cancer metastases.

[0220] The PSMA binding ligands of the present invention can be synthesized, for example, not only in solution but also on a solid phase using, for example, standard peptide coupling procedures, such as Fmoc solid phase coupling procedures. Preferably, the chelating agent is coupled to the remainder of the molecule in the last coupling step, followed by a deprotection step and, in the case of solid phase chemistry, cleavage from the resin. However, other synthetic procedures are possible and are known to those skilled in the art. The preferred synthesis of the PSMA binding ligands of the present invention is described in detail in the Examples section.

[0221] Furthermore, the present invention also relates to a method of labeling PSMA-expressing tissue in a subject, comprising the step of administering a PSMA binding ligand to the subject.

[0222] The present invention relates to a method for identifying PSMA-expressing tissue in a subject, comprising: (a) labeling PSMA-expressing tissue by administering a PSMA-binding ligand to the subject; and (b) identifying the labeled PSMA-expressing tissue in situ, and a method for removing cancerous tissue from the subject, comprising: (a) labeling cancerous tissue by administering a PSMA-binding ligand to the subject; (b) identifying the labeled PSMA-expressing tissue in situ; and (c) removing the cancerous tissue.

[0223] Furthermore, the present invention relates to the use of a PSMA-binding ligand as specified hereinabove in the manufacture of a diagnostic composition for labeling PSMA-expressing tissue, preferably for labeling cancerous tissue in vivo, and / or in the manufacture of a therapeutic composition for the treatment of PSA-expressing cell proliferation.

[0224] Summarizing the findings of the present invention, the following embodiments are preferred: 1. A PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising a PSMA-binding motif Q, a chelating agent residue A, a dye group Z, and at least one linker L comprising at least one amino acid X 1 wherein BQ - X is preferably a neutral amino acid or 1 - X is preferably an N-alkylated amino acid, preferably an N-methylated amino acid, 1 more preferably X is a neutral N-alkylated amino acid, more preferably a neutral N-methylated amino acid, and more preferably X 1 is -N(CH 1 )-CH 3 -C(=O)-, a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof. 2

[0225] 2. Structure

[0226] [Chemical formula] (wherein Q is a PSMA binding motif, A is a chelating agent residue, Z is a dye group, B is a branching group, L BQ is a linker connecting Q to B, and the linker contains at least one amino acid X 1 and L BZ is a linker, n bz is 0 or 1, L BA is a linker, n ba is 0 or 1) The PSMA binding ligand according to Embodiment 1 having

[0227] 3. B has the structure

[0228] [Chemical formula] (wherein R 5 is an alkyl group, preferably -(CH 2 ) 2~4 group, Y B is a functional group connecting R 5 to the group -(L BZ )n bz -Z or -(L BA )n ba -A, and Y B is preferably the group -NH- or -C(=O)-) The PSMA binding ligand according to Embodiment 2 having

[0229] 4. One of the following structures (Ia) or (Ib), preferably structure (Ia)

[0230] [Chemical formula] The PSMA binding ligand according to Embodiment 4 having

[0231] 5. The PSMA-binding motif Q has a structure

[0232]

Chemical formula

[0233] 6. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 or 5, which is a chelating agent residue derived from a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (=DOTA), N,N''-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N''-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

[0234] 7. A is from the group consisting of

[0235] [Chemistry] The PSMA-binding ligand according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, which is a chelating agent residue having a structure selected from

[0236] 8. A is a structure

[0237] [Chemistry] The PSMA-binding ligand according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, which is a chelating agent residue having

[0238] 9. Structure (Ia)

[0239] [Chemistry] (wherein R 5 is an alkyl group, preferably a -(CH 2 ) 1~10 group, more preferably a -(CH 2 ) 2~4 group, Y B is a functional group that links R 5 to the group -(L BZ )n bz -Z or -(L BA )n ba -A, and Y B is preferably the group -NH- or -C(=O)-, more preferably -NH-) The PSMA-binding ligand according to Embodiment 7 or 8, having

[0240] 10. The PSMA-binding ligand according to any one of Embodiments 1 to 9, wherein the dye group Z is a fluorescent dye containing a fluorophore having excitation and emission spectra in the range of about 350 to 100 nm, preferably 400 nm to about 850 nm.

[0241] 11. The pigment group Z is Alexa Fluor 3, Alexa Fluor 5, Alexa Fluor 350, Alexa Fluor 405, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 500, Alexa Fluor 514, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 555, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 610, Alexa Fluor 633, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor 700, and Alexa Fluor 750, Cy2, Cy3, Cy3B, Cy3.5, Cy5, Sulfo Cy5, Cy5.5 and Cy7, DyLight 350, DyLight 405, DyLight 488, DyLight 550, DyLight 594, DyLight 633, DyLight 650, DyLight 680, DyLight 750 and DyLight 800, FluoProbes 390, FluoProbes 488, FluoProbes 532, FluoProbes 547H, FluoProbes 594, FluoProbes 647H, FluoProbes 682, FluoProbes 752 and FluoProbes 782, AMCA, DEAC (7-diethylaminocoumarin-3-carboxylic acid), 7-hydroxy-4-methylcoumarin-3, 7-hydroxycoumarin-3-carboxylic acid (Pubchem SID 135727263), MCA (7-methoxycoumarin-4-acetic acid) (Pubchem CID 342221), 7-methoxycoumarin-3, AMF (4'-(aminomethyl)fluorescein), 5-DTAF (5-(4,6-dichlorotriazinyl)aminofluorescein), 6-DTAF (6-(4,6-Dichlorotriazinyl)aminofluorescein), 6-FAM (6-Carboxyfluorescein), 5(6)-FAM Cadaverine (Fluorescein-5(6)-carboxamidocadaverine), 5-FAM Cadaverine (Fluorescein-5-carboxamidocadaverine), 5(6)-FAM Ethylenediamine (Fluorescein-5(6)-carboxamidoethylenediamine), 5-FAM Ethylenediamine (Fluorescein-5(6)-carboxamidoethylenediamine), 5-FITC (FITC Isomer I; Fluorescein-5-isothiocyanate), 5-FITC Cadaverine; Fluorescein-5-maleimide; 5-IAF (5-Iodoacetamidofluorescein), 6-JOE (6-Carboxy-4',5'-dichloro-2',7'-Dimethoxyfluorescein), 5-CR110 (5-carboxyrhodamine 110), 6-CR110 (6-carboxyrhodamine 110), 5-CR6G (5-carboxyrhodamine 6G); 6-CR6G (6-carboxyrhodamine 6G), 5(6)-carboxyrhodamine 6G cadaverine; 5(6)-carboxyrhodamine 6G ethylenediamine, 5-ROX (5-carboxy-X-rhodamine), 6-ROX (6-carboxy-X-rhodamine); 5-TAMRA (5-carboxytetramethylrhodamine), 6-TAMRA (6-carboxytetramethylrhodamine), 5-TAMRA cadaverine, 6-TAMRA cadaverine, 5-TAMRA ethylenediamine (5-carboxytetramethylrhodamine ethylenediamine), 6-TAMRA ethylenediamine (6-carboxytetramethylrhodamine ethylenediamine), 5-TMR C6 maleimide, 6-TMR C6 maleimide, TR C2 maleimide, TR cadaverine, 5-TRITC (tetramethylrhodamine-5-(and -6)-isothiocyanate), 6-TRITC, R isomer (tetramethylrhodamine-6-isothiocyanate), dansyl cadaverine (5-dimethylaminonaphthalene-1-(N-(5-aminopentyl))sulfonamide), EDANS C2 maleimide (5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid C2 maleimide), EDANS acid (5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid); fluorescamine (4-phenylspiro-[furan-2(3H),1-phthalane]-3,3'-dione), NBD (4-chloro-7-nitro-benzo-2-oxa-1,3-diazole), pyromethene, Texas Red (1H,5H,11H,15H-xantheno[2,3,4-ij:5,6,7-i'j']diquinolidin-18-ium, 9-[2(or 4)-(chlorosulfonyl)-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-, inner salt), Cy5, Cy5 succinimidyl ester (3H-indolium, 2-[5-[1-[6-[(2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]-1,3-dihydro-3,3-dimethyl-5-sulfo-2H-indol-2-ylidene]-1,3-Pentadien-1-yl]-1-ethyl-3,3-dimethyl-5-sulfo-, inner salt), Cy5 acridine orange, 2,7-dichlorofluorescein, eosin, rose bengal, 1,2-dihydroxyanthraquinone, 1,4-dihydroxyanthraquinone, 1,8-dihydroxyanthraquinone, 1,3,8-trihydroxy-6-ethylanthraquinone, 1,2,5,8-tetrahydroxyanthraquinone, 1-aminonaphthalene, 2-aminonaphthalene, indocyanine green (ICG), IRDye800CW, Bodipy650-X, CF680R, 580CP-methoxy, 610CP, SiR-methyl, ATTO 390, ATTO 425, ATTO 465, ATTO 488, ATTO 495, ATTO 514, ATTO 520, ATTO 532, ATTO Rho6G, ATTO 550, ATTO 565, ATTO Rho3B, ATTO Rho11, ATTO Rho12, ATTO Thio12, ATTO Rho101, ATTO 590, ATTO Rho13, ATTO 594, ATTO 610, ATTO 620, ATTO Rho14, ATTO 633, ATTO 647, ATTO 647N, ATTO 655, ATTO Oxa12, ATTO 665, ATTO 680, ATTO 700, ATTO 725, ATTO647N, STAR 600, STAR635 P, STAR RED, 580CP-methoxy and derivatives thereof, and is a fluorescent dye Z selected from the group consisting of, preferably, Z is selected from the group consisting of Atto590, Alexa594, STAR600, STAR 635P, STAR RED, Atto647N, Bodipy650-X, 580CP-methoxy, 610CP, SiR-methyl, sulfoCy5, IRDye800CW and indocyanine green (ICG) and derivatives thereof, more preferably, Z is sulfoCy5, the PSMA-binding ligand according to any one of embodiments 1 to 10 or a pharmaceutically acceptable salt or solvate thereof.,

[0242] 12. Structure

[0243]

Chemical formula

[0244]

Chemical formula

[0245] 13. The dye group Z has the structure -C(=O)-C 1 having, and C 1 is the following structure

[0246]

Chemical formula

[0247] 14. The PSMA ligand, preferably the linker L BQ further comprises at least one amino acid building block AS a wherein AS a has the structure

[0248]

Chemical formula

[0249] 15. The PSMA ligand, preferably the linker L BQ comprises at least one amino acid building block AS b wherein AS b has the structure (b)

[0250]

Chem.

[0251]

Chem.

[0252]

Chem.

[0253] 16. Linker L BQ further comprises at least one amino acid building block AS a and at least one amino acid building block AS b wherein AS a has the structure

[0254]

Chem.

[0255]

Chem.

[0256]

Chemical formula

[0257]

Chemical formula

[0258] 17. Q is linked to -(AS b ) q -AS a and the PSMA-binding ligand comprises the building block --(AS b ) q -AS a -Q The PSMA-binding ligand according to any one of embodiments 1 to 11 or a pharmaceutically acceptable salt or solvate thereof.

[0259] 18. The building block -L BQ -Q has the structure

[0260]

Chemical formula

[0261] 20. Q 1 preferably contains a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl, more preferably, Q 1 is from the group consisting of

[0262]

Chemical Structure

[0263]

Chem.

[0264] 21. R 3 , R 2 and R 4 are -CO 2 H, and R 1 is H, the PSMA-binding ligand according to any one of Embodiments 13 or 14.

[0265] 22. Q 2 is

[0266]

Chem.

[0267]

Chem.

[0268] 23. The ligand has the structure

[0269]

Chem.

[0270] 24. The ligand has the structure

[0271]

Chemical formula

[0272] 25. L BQ and / or L Bz is the PSMA-binding ligand according to any one of embodiments 23 or 24, comprising at least one methylated amino acid.

[0273] 26. The ligand has the structure (IIIa)

[0274]

Chemical formula

[0275] 27. L BZ contains an amino acid sequence, Z is at the N-terminus of L BZ or binds to the functional group of the side chain of the amino acid present in L BZ , provided that when LBZ is bound to the side chain, the N-terminus is preferably acylated with the group -C(=O)-Rz, and R z is preferably a C10-C20 alkyl chain, the PSMA-binding ligand according to embodiment 26.

[0276] 28. The amino acid sequence has the structure -(X 2bz ) n2bz -(X 1bz ) n1bz -, Z is bound to the N-terminus, X 1z is a methylated amino acid, preferably X 1z is -N(CH 3 )-CH 2 -C(=O)-, n1bz is 1-20, preferably 4-10, more preferably 5, X 2bz is a neutral amino acid, preferably beta-Ala, and n2bz is 1-20, preferably 1, the PSMA-binding ligand according to embodiment 26.

[0277] 29. The amino acid sequence has the structure -(X 3bz ) n3bz -(X 1bz ) n1bz -, X 1bz is a methylated amino acid, preferably X 1bz is -N(CH 3 )-CH 2 -C(=O)-, n1z is 1-20, preferably 4-10, more preferably 5, X 2bz is glutamic acid or lysine, preferably lysine, and Z is X 2bzis attached to the side chain, n2bz is from 1 to 20, preferably 1, and the N-terminus is preferably acylated, the PSMA-binding ligand according to embodiment 26.

[0278] 30. The ligand has the structure (IIIb)

[0279]

Chemical formula

[0280] 31. L BA contains an amino acid sequence, A is at the N-terminus of L BA or binds to a functional group of the side chain of an amino acid present in L BA provided that when L BA is bound to the side chain, the N-terminus is preferably acylated with the group -C(=O)-R z and R z is preferably a C10-C20 alkyl chain, the PSMA-binding ligand according to Embodiment 30.

[0281] 32. The amino acid sequence has the structure -(X 2ba ) n2ba -(X 1ba ) n1ba -, A is bound to the N-terminus, X 1ba is a methylated amino acid, preferably X 1ba is -N(CH 3 )-CH 2 -C(=O)-, n1ba is 1 to 20, preferably 4 to 10, more preferably 5, X 2ba is a neutral amino acid, preferably beta-Ala, and n2ba is 1 to 20, preferably 1, the PSMA-binding ligand according to Embodiment 31.

[0282] 33. The PSMA ligand according to Embodiment 1, having a structure as shown in FIG. 1, FIG. 2 or FIG. 3, preferably as shown in FIG. 2.

[0283] 34. (a) A radionuclide, and (b) A PSMA-binding ligand according to any one of Embodiments 1 to 33 or a pharmaceutically acceptable salt or solvate thereof comprising a complex.

[0284] 35. The 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, 153 Sm, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Er, 52 Fe, 59 Fe, and a radionuclide of Pb (for example, 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb), and is the complex according to embodiment 34 selected from the group consisting of

[0285] 36. A pharmaceutical composition comprising the PSMA-binding ligand according to any one of embodiments 1 to 33 or the complex according to embodiment 34 or 35.

[0286] 37. The PSMA-binding ligand according to any one of embodiments 1 to 33, the complex according to embodiment 34 or 35, or the pharmaceutical composition according to claim 36, for use in medicine, preferably for treating and / or preventing PSMA-expressing cancer, particularly prostate cancer and / or its metastases.

[0287] 38. A PSMA-binding ligand, complex, or pharmaceutical composition for use according to embodiment 37, wherein the adverse side effects on the kidney are reduced and / or avoided.

[0288] 39. The radionuclide is an α-emitter, more preferably 225 Ac, and preferably, the active dosage of the complex is at least 75 kBq / kg body weight, more preferably at least 100 kBq / kg body weight. A complex or pharmaceutical composition for use according to embodiment 37 or 38.

[0289] 40. A PSMA-binding ligand according to any one of embodiments 1 to 33, a complex according to embodiment 34 or 35, or a pharmaceutical composition according to claim 36, for use in diagnostics.

[0290] 41. A PSMA-binding ligand according to any one of embodiments 1 to 33, a complex according to embodiment 34 or 35, or a pharmaceutical composition according to claim 36, for use in the diagnosis of cancer, preferably PSMA-expressing cancer, particularly prostate cancer and / or its metastases.

[0291] 42. The radionuclide is a β-emitter, more preferably 177 Lu, and preferably, the active dosage of the complex is at least 100 kBq / kg body weight, more preferably at least 500 kBq / kg body weight, most preferably at least 1 MBq / kg body weight. A complex or pharmaceutical composition for use according to embodiment 40 or 41.

[0292] 43. A PSMA-binding ligand according to any one of embodiments 1 to 33, a complex according to embodiment 34 or 35, or a pharmaceutical composition according to claim 36, for use in fluorescence-guided surgery.

[0293] 44. A method for identifying tumor tissue to be removed by surgery, comprising the step of detecting the presence of fluorescence in the tissue of a patient administered the PSMA-binding ligand or complex or pharmaceutical composition according to claim 23.

[0294] 45. The following structure:

[0295]

Chemical formula

Examples

[0296] The following examples are merely illustrative of the present invention. In any case, they shall not be construed as limiting the scope of the present invention.

[0297] Experimental procedures All commercially available chemical reagents were of analytical grade and used without further purification. 68 Ga (half-life 68 minutes) was 68 obtained from a Ge / 68 Ga generator (Galliapharm® Ge-68 / Ga-68 Generator, Eckert & Ziegler), and 177 Lu (half-life 6.6 days) was purchased from ITG. The compounds were purified using semi-preparative reverse-phase high-performance liquid chromatography (RP-HPLC; Chromolith Semi Prep RP-18e, 100×10 mm; Merck, Darmstadt, Germany). Compound analysis was performed using analytical RP-HPLC (RP-HPLC; Chromolith RP-18e, 100×4.6 mm; Merck, Darmstadt, Germany). The analytical HPLC runs were at a linear gradient from 5% A (0.1% aqueous TFA) to 100% B (CH 3It was carried out using 0.1% TFA in CN. The Agilent Technologies 1200 series system was equipped with variable UV and gamma detectors (Ramona*, Elysia). UV absorbance was measured at 220 and 280 nm respectively. For mass spectrometry, MALDI-MS (Daltonics Microflex, Bruker Daltonics, Bremen, Germany) was used.

[0298] Glu-urea-Lys-2-Nal-Chx-Sar 5 -Lys(DOTA)-Sar 5 -bAla-sulfoCy5(BP-1), Glu-urea-Lys-2-Nal-Chx-Sar 10 -Lys(DOTA)-Sar 5 -bAla-sulfoCy5(BP-2) and Glu-urea-Lys-2-Nal-Chx-Sar 5 -Lys(sulfoCy5)-Sar 5 -bAla-DOTA(BP-4) synthesis The synthesis of the pharmacophore Glu-urea-Lys was carried out as described previously (1). Briefly, the synthesis started with the formation of isocyanate of the glutamyl moiety using triphosgene. Resin immobilized (2-chloro-trityl resin, Merck, Darmstadt) ε-allyloxycarbonyl protected lysine was added and reacted for 16 hours with gentle stirring. The resin was filtered off, and the allyloxy protecting group was removed by reacting twice with Pd(PPh 3 ) 4 (0.3 equivalent) and morpholine (15 equivalents).

[0299] Subsequently, a linker between the PSMA pharmacophore and the chelator / dye was introduced by a standard Fmoc solid-phase protocol. In the first step, Fmoc-2-NaI-OH and N-Fmoc-transamic acid (4 equivalents each) were coupled in DMF using HATU (4 equivalents) and DIPEA (10 equivalents). Depending on the amino acid sequence, Fmoc-sarcosine was coupled 5 and 10 times respectively, followed by coupling of Fmoc-Lys(Alloc)-OH in DMF using HATU (4 equivalents) and DIPEA (10 equivalents). Subsequently, Fmoc-sarcosine was coupled 5 times, followed by coupling of Boc-beta-alanine in DMF using HATU (4 equivalents) and DIPEA (10 equivalents).

[0300] For the synthesis of BP-1 and BP-2, the allyloxy protecting group was removed by reacting twice with Pd(PPh 3 ) 4 (0.3 equivalent) and morpholine (15 equivalents) under ambient conditions (1 hour, room temperature). Subsequently, Bis(tBu)DOTA (bis(tBu)-ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 equivalents) was coupled in DMF using HATU (4 equivalents) and DIPEA (10 equivalents). The precursor was cleaved from the resin using TFA / TIPS / H 2 O (95 / 2.5 / 2.5, v / v / v) at room temperature for 3 hours, purified using RP-HPLC with a Chromolith RP-18e column (100×10 mm; Merck, Darmstadt, Germany), and identified by mass spectrometry. Finally, sulfo Cy5-NHS ester (2.5 mg) was coupled to the precursor in DMF at room temperature for 24 hours, and the final products (BP-1 and BP-2) were purified using RP-HPLC with a Chromolith RP-18e column (100×10 mm; Merck, Darmstadt, Germany) and identified by mass spectrometry.

[0301] For the synthesis of BP-4, Bis(tBu)DOTA (bis(tBu)-ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 equivalents) was coupled to Glu-urea-Lys-2-Nal-Chx-Sar 5 -Lys(Alloc)-Sar 5 -bAla in DMF using HATU (4 equivalents) and DIPEA (10 equivalents). Subsequently, the allyloxy protecting group was removed by reacting twice with Pd(PPh 3 ) 4 (0.3 equivalent) and morpholine (15 equivalents) under ambient conditions (1 h, room temperature). The precursor was cleaved from the resin using TFA / TIPS / H 2 O (95 / 2.5 / 2.5, v / v / v) at room temperature for 3 h and lyophilized. Finally, sulfoCy5-NHS ester (2.5 mg) was coupled to the precursor in DMF at room temperature for 24 h, and the final product (BP-4) was purified using RP-HPLC with a Chromolith RP-18e column (100×10 mm; Merck, Darmstadt, Germany) and identified by mass spectrometry.

[0302] 68 Ga labeling The precursor peptide [5 nmol in HEPES buffer (1 M, pH 4, 40 μL)] was added to 40 μL 68 Ga]Ga 3+ eluate (ca. 40 MBq) and ascorbic acid (5.68 mM, 0.8 μL). The pH was adjusted to 3.8 - 4.2 using 30% NaOH. The reaction mixture was incubated at 95 °C for 15 min. The radiochemical yield (RCY) was determined by RP-HPLC.

[0303] 177 Lu labeling The precursor peptide [2 nmol in HEPES buffer (0.1 M, pH 7, 50 μL)] was added to 10 μL 177 Lu]LuCl 3(Approximately 10 - 30 MBq, 0.04 M HCl) and ascorbic acid (5.68 mM, 0.7 μL) were added. The reaction mixture was incubated at 95 °C for 15 minutes. The radiochemical yield (RCY) was determined by RP-HPLC.

[0304] Cell culture PSMA + LNCaP cells (CRL-1740; ATCC; PSMA positive) and PC-3 cells (CRL-1435; ATCC; PSMA negative) were cultured in RPMI medium supplemented with 10% fetal bovine serum and 2 mmol / L L-glutamine (all from PAA). The cells were grown at 37 °C in humidified air containing 5% CO 2 and were harvested using trypsin-ethylenediaminetetraacetic acid (trypsin-EDTA; 0.25% trypsin, 0.02% EDTA, Invitrogen).

[0305] Cell binding and internalization Competitive cell binding assays and internalization experiments were performed as previously described (2). Briefly, cells (10 5 per well) were incubated with a 0.8 nM solution of 68 Ga-labeled radioligand [Glu-urea-Lys(Ahx)] 2 -HBED-CC (PSMA-10, a precursor ordered from ABX, Radeberg, Germany) in the presence of 12 different concentrations of analyte (0 - 5000 nM, 100 μL / well). After incubation, the mixture was removed and the wells were washed three times with PBS using a multi-screen vacuum manifold (Millipore, Billerica, MA). Cell-bound radioactivity was measured using a gamma counter (Perkin Elmer 2480, Wizard, Gamma Counter). The 50% inhibitory concentration (IC50) values were calculated by fitting the data using a non-linear regression algorithm (GraphPad Software).

[0306] For internalization experiments, 10 cells / well were added 24 h prior to incubation. 5 Cells were seeded on poly-L-lysine coated 24-well cell culture plates. After washing, cells were incubated with 30 nM of radiolabeled compound for 45 min at 37° C. Cell uptake was terminated by washing three times with 1 mL of ice-cold PBS. To remove surface-bound radioactivity, cells were incubated twice for 5 min with 0.5 mL of glycine-HCl in PBS (50 mM, pH=2.8). Cells were washed with 1 mL of ice-cold PBS and lysed using 0.3 N NaOH (0.5 mL). Surface-bound and internalized fractions were measured in a gamma counter. Cell uptake was determined by 10 5 The percentage of the initial radioactivity bound to cells [%ID / 10 5 The number of cells was calculated as [cells].

[0307] Biodistribution For experimental tumor models, 5 x 10 of LNCaP or PC-3 6 Cells (in 50% Matrigel; Becton Dickinson) were implanted subcutaneously in the right torso of 7-8 week old male BALB / c nu / nu mice (Janvier). Tumors were approximately 1 cm in size. 3 It was grown until it became 177 Lu-labeled compounds were injected into the tail vein (1-2 MBq; 60 pmol). Animals were sacrificed 1 or 2 h post-injection (pi). Organs of interest were dissected, blotted dry and weighed. Radioactivity was measured using a gamma counter and calculated as %ID / g. All animal experiments were in accordance with the current legislation of the Federal Republic of Germany.

[0308] PET / MR and Optical Imaging For imaging studies, mice were anesthetized (2% isoflurane) and given 0.5 nmol of DMSO in 0.9% NaCl (pH 7). 68The Ga-labeled compound was injected into the tail vein. PET imaging was performed with a μPET / MRI scanner (BioSpec 3T, Bruker) in a 60-minute dynamic scan. The images were iteratively reconstructed (MLEM 0.5 algorithm, 12 iterations) and converted to SUV images. Quantification was performed using the ROI (region of interest) technique, and the data were presented as time-activity curves as SUV 体重 and plotted. After PET / MR imaging, the mice were sacrificed, and optical imaging of subcutaneous tumors and target organs was performed with an Odyssey CLx system (LI-COR Biosciences, excitation wavelength 700 nm). All animal experiments were conducted in accordance with the current laws of the Federal Republic of Germany.

[0309] Statistical aspects All experiments were performed at least in triplicate and repeated at least three times. Quantitative data were expressed as mean ± SD. When applicable, means were compared using Student's t-test. A P-value < 0.05 was considered statistically significant.

[0310] Results In vitro characterization The final products were identified using reverse-phase HPLC / matrix-assisted laser desorption / ionization mass spectrometry. The 68 Ga and 177 Lu complex formation resulted in radiochemical yields higher than 95%. All compounds showed high PSMA binding affinity in the nanomolar range, which was reduced compared to the reference PSMA-617 (Table 1)(3). Notably, PSMA-specific cell surface binding and specific internalization equivalent to those of PSMA-617 were detected for all 68 Ga-labeled compounds tested.

[0311] [Table 1]

[0312] In vivo characterization All 177The Lu-labeled compound revealed PSMA-specific tumor uptake in LNCaP xenograft tumors (p > 0.05), which was the reference compound at 1 hour after injection 177 Lu-PSMA-617 (8.47 ± 4.09% ID / g) and 68 Ga-Glu-urea-Lys-2-Nal-Chx-Lys (IRDye800CW)-DOTA (4.13 ± 0.15% ID / g) showed no significant difference (Table 2)(4). At the same time, the kidney uptake of 177Lu-BP-2 (19.05 ± 9.52% ID / g) was 177 Lu-PSMA-617 (137.2 ± 77.8% ID / g), 68 Ga-Glu-urea-Lys-2-Nal-Chx-Lys (IRDye800CW)-DOTA (65.64 ± 6.60% ID / g) and other test compounds 177 Lu-BP-1 and 177 Lu-BP-4, surprisingly, was significantly reduced. The uptake of BP-2 in muscle, blood, spleen, lung and liver was found to be equivalent to other test compounds at 1 hour after injection (Table 3). Rapid renal clearance was confirmed by a further decrease in BP-2 uptake found in the kidney (4.61 ± 0.45% ID / g) accompanied by a decrease in uptake in, for example, blood and spleen at 2 hours after injection. Tumor uptake showed no significant difference at 2 hours after injection compared to 1 hour after injection, indicating tracer enrichment over time. The tumor specificity of BP-2 was demonstrated in PC-3 tumor-bearing mice, which showed negligible tumor uptake at 1 hour after injection (Table 2).

[0313]

Table 2

[0314]

Table 3

[0315] The organ distribution findings were confirmed by PET / MR imaging. The pharmacokinetic properties of BP-2 were enhanced compared to PSMA-617, characterized by an accelerated excretion profile. The tumor targeting properties of BP-2 were found to be equivalent to those of the parent reference PSMA-617 (Figure 4).

[0316] Optical imaging confirmed the findings of PSMA-specific tumor enrichment (Figure 5). Here, PSMA + -tumors showed a high fluorescence signal (Figure 5A), while in PSMA - -tumors (Figure 5B), only a negligible fluorescence signal of BP-2 could be detected.

[0317] References TIFF2025516756000078.tif89167

Images