Prostate specific membrane antigen (PSMA) ligands

Abstract

The present invention relates generally to the field of dye-labeled radiopharmaceuticals, preferably fluorescent dye-labeled radiopharmaceuticals and their use as tracers, imaging agents in nuclear medicine and their use for the treatment of various disease states of PSMA-expressing cancers, in particular prostate cancers, and metastases thereof, and their use in preoperative PET imaging and fluorescence-guided surgery of cancer, in particular prostate cancer, and metastases thereof.

Description

Technical Field

[0001] The present invention generally relates to the field of dye-labeled, preferably fluorescent dye-labeled radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and their use for the treatment of various disease states of PSMA-expressing cancers, in particular prostate cancer, and their metastases, as well as their use in preoperative PET imaging and fluorescence-guided surgery of cancer, in particular prostate cancer, and its metastases. Background Art

[0002] Prostate cancer (PCa) is the leading cancer in the U.S. and European populations. At least 1 to 2 million men in the Western Hemisphere are living with prostate cancer, and it is estimated that one in six men aged 55 to 85 years will develop the disease. In the United States, more than 300,000 new cases of prostate cancer are diagnosed each year. The mortality rate of the disease is second only to lung cancer. Currently, imaging methods with high-resolution anatomical structures, such as computed tomography (CT), magnetic resonance (MR) imaging, and ultrasound, dominate clinical imaging of prostate cancer. It is estimated that $2 billion is currently spent worldwide each year on surgery, radiation therapy, medical therapy, and minimally invasive treatments for prostate cancer. For the treatment of localized prostate cancer, radical prostatectomy with lymph node dissection is an established treatment strategy. However, precise localization and demarcation of tumor margins and metastases remain challenging. There is currently no effective treatment for recurrent, metastatic, androgen-independent prostate cancer.

[0003] It is well known that tumors may express unique proteins associated with their malignant phenotype or may overexpress normal constitutive proteins more than normal cells. The expression of differential proteins on the surface of tumor cells provides an opportunity to diagnose and characterize the disease by probing the phenotypic identity, biochemical composition and activity of tumors. Radioactive molecules that selectively bind to specific tumor cell surface proteins provide an attractive approach to imaging and treating tumors under non-invasive conditions. A promising series of new low molecular weight imaging agents targets prostate-specific membrane antigen (PSMA) (Mease RC et al. Clin Cancer Res. 2008, 14, 3036-3043; Foss, CA et al. Clin Cancer Res 2005, 11, 4022-4028; Pomper, MG et al. Mol Imaging 2002, 1, 96-101; Zhou, J. et al. Nat Rev Drug Discov 2005, 4, 015-1026; WO 2013 / 022797).

[0004] Several experimental low-molecular-weight PCa imaging agents are currently being investigated clinically, including 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-1-arabinofuranosyl)-5-methyluracil (-[ 18 F]FMAU) (Scher, B. et al. Eur J Nucl Med Mol Imaging 2007, 34, 45-53; Rinnab, L et al. BJU Int 2007, 100, 786,793; Reske, SN et al. J Nucl Med 2006, 47, 1249-1254; Zophel, K. and Kotzerke, J. Eur J Nucl Med Mol Imaging 2004, 31, 756-759; Vees, H. et al. BJU Int 2007, 99, 1415-1420; Larson, SM et al. J Nucl Med 2004, 45, 366-373; Schuster, DM et al. J Nucl Med 2007, 48, 56-63; Tehrani, OS et al. J Nucl Med 2007, 48, 1436-1441). Each works through different mechanisms and has certain advantages, such as [ 11 C] Choline has low urinary excretion and disadvantages such as the short physical half-life of positron-emitting radionuclides.

[0005] PSMA is a transmembrane, 750 amino acid, type II glycoprotein with abundant and restricted expression on the surface of PCa, particularly in androgen-independent, advanced, and metastatic disease (Schulke, N. et al. Proc Natl Acad Sci USA 2003, 100, 12590-12595). The latter is important because, over time, almost all PCa become androgen-independent. PSMA meets the criteria of a promising therapeutic target (Schulke, N. et al. Proc. Natl. Acad. Sci. USA 2003, 100, 12590-12595). The PSMA gene is located on the short arm of chromosome 11 and functions as both a folate hydrolase and a neuropeptidase. It has a neuropeptidase function equivalent to glutamate carboxypeptidase II (GCPII), is called "brain PSMA", and can regulate glutamatergic transmission by cleaving / V-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate (Nan, F. et al. J Med Chem 2000, 43, 772-774). Each cancer cell has up to 10 6 The PSMA molecule was identified in 24 samples, further demonstrating that it is an ideal target for radionuclide-based imaging and therapy (Tasch, J. et al. Crit Rev Immunol 2001, 21, 249-261).

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

[0007] Selective targeting of cancer cells with radiopharmaceuticals, whether for imaging or therapeutic purposes, is challenging. A variety of radionuclides are known to be useful for radioimaging or cancer radiotherapy, including 111 In, 90 Y. 68 Ga, 177 Lu, 99m Tc, 123 I and 131 I. It has recently been shown that some compounds containing a glutamate-urea-glutamate (GUG) or glutamate-urea-lysine (GUL) recognition element linked to a radionuclide-ligand conjugate exhibit high affinity for PSMA.

[0008] New imaging agents with improved tumor targeting properties and pharmacokinetics are described in WO 2015 / 055318. These compounds contain a motif that specifically binds to the cell membrane of cancer cells, wherein the motif contains the prostate specific membrane antigen (PSMA), i.e. the above-mentioned glutamic acid-urea-lysine motif. Preferred molecules described in WO 2015 / 055318 also contain a linker to which the carboxylic acid group of DOTA is bound via an amide bond as a chelating agent. Some of these compounds have been shown to be promising agents for specific targeting of prostate tumors. The compounds are used 177 Lu (for therapeutic purposes) or 68 Ga (for diagnostic purposes) labeling and can be used for visualization and targeting of prostate cancer for radiotherapy purposes.

[0009] However, in the therapeutic application of radiolabeled PSMA inhibitors, organs with physiological PSMA expression have proven to be dose-limiting, thus minimizing the success rate of treatment. In particular, high renal and salivary gland uptake of radiolabeled PSMA inhibitor substances is noteworthy, which can lead to considerable side effects in the case of therapeutic application. Attempts to improve the renal uptake of PSMA inhibitors have led to the development of PSMA-617 [Benesova, M. et al. (2016) J Med Chem 59, 1761-75], which has been used clinically with 177Lu or 225Ac for intracavitary radiotherapy of prostate cancer. However, reduction of salivary and lacrimal gland uptake has not yet been achieved and is still described as critical and dose-limiting in early clinical work. In the first human study of 225Ac-PSMA-617, two patients with very advanced and terminal disease showed complete remission. In both patients, PSA values ​​were below the detectable limit. The complete response was confirmed by the accompanying diagnostic record of 68Ga-PSMA-11.

[0010] As mentioned above, the strong accumulation of PSMA ligands in non-target tissues, in particular the salivary and lacrimal glands, which has been described in numerous scientific publications, leads to considerable side effects. The salivary and lacrimal glands can be severely and partially irreversibly damaged, in particular during alpha treatment with 225Ac. For example, the resulting dry mouth represents a dose-limiting side effect. To address this problem, it has been proposed to improve the tissue specificity of the PSMA ligands, for example in WO 2020 / 165420 A1.

[0011] Therefore, there is still a need for improved PSMA ligands that provide advantageous options for the detection, treatment and management of PSMA-expressing cancers, in particular prostate cancer. The technical problem of the present invention can be seen as providing PSMA ligands and methods in order to meet the above needs. The technical problem is solved by the claims and the embodiments characterized below. Summary of the invention

[0012] The solution of the object is achieved by providing the embodiments characterized in the claims. The inventors have found new compounds which are dye-labeled, preferably fluorescent dye-labeled, complexed PSMA ligands. Thus, the compounds can be used, for example, for intraoperative or diagnostic labeling of cells expressing PSMA, but also as tracers, imaging agents in nuclear medicine and for various disease states for the treatment of PSMA-expressing cancers, in particular prostate cancer. Thus, the PSMA-binding ligands described herein can be used, for example, in preoperative PET imaging and fluorescence-guided surgery of cancers, in particular prostate cancer, and their metastases. These compounds will be 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 linker L BQ , the connector L BQ The at least one amino acid X1 is preferably wherein X1 is an N-alkylated amino acid, more preferably an N-methylated amino acid, in particular wherein X1 is -N(CH3)-CH2-C(=O)-.

[0014] Furthermore, the present invention relates to a complex comprising

[0015] (a) radionuclides, and

[0016] (b) a PSMA-binding ligand as described above and below, or a pharmaceutically acceptable salt or solvate thereof.

[0017] 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.

[0018] Furthermore, the present invention relates to a PSMA-binding ligand as described above or below, or a pharmaceutically acceptable salt or solvate thereof, 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.

[0019] Furthermore, the present invention relates to a PSMA-binding ligand and / or complex as described above or below as a marker for detecting cancerous tissue in a subject.

[0020] As used below, the terms "having", "comprising" or "including" or any grammatical variants thereof are used in a non-exclusive manner. Thus, these terms may refer to the absence of other features in the entity described herein in addition to the features introduced by these terms, or to the presence of one or more other features. For example, the expressions "A has B", "A comprises B" and "A includes B" may refer to the presence of no other elements in A except B (i.e., A is solely and exclusively composed of B), or to the presence of one or more other elements in entity A in addition to B, such as element C, elements C and D or even other elements. Furthermore, as will be appreciated by those skilled in the art, the expressions "comprising a" and "comprising an" preferably refer to "comprising one or more", i.e., equivalent to "comprising at least one".

[0021] In addition, as used below, the terms "preferred", "more preferably", "most preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features without limiting further possibilities. Therefore, the features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. Those skilled in the art will recognize that the present invention can be carried out by using alternative features. Similarly, features introduced by "in one embodiment" or similar expressions are intended to be optional features without any limitation on other embodiments of the invention, without any limitation on the scope of the invention, and without any limitation on the possibility of combining features introduced in this manner with other optional or non-optional features of the invention.

[0022] As used herein, the term "standard conditions" (if not otherwise specified) 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; also preferably, standard conditions include a pH value of 7. In addition, if not otherwise indicated, the term "about" refers to an indicated value with a technical accuracy generally accepted in the relevant field, preferably to an indicated value of ±20%, more preferably ±10%, and most preferably ±5%. In addition, the term "substantially" means that there is no deviation that has an impact on the indicated result or use, i.e., the potential deviation will not cause the indicated result to deviate by more than ±20%, more preferably ±10%, and most preferably ±5%. Therefore, "substantially consisting of..." means including the specified ingredients, but excluding other ingredients (except materials present as impurities, unavoidable materials present due to the process of providing ingredients, and ingredients added for purposes other than achieving the technical effects of the present invention). For example, a composition defined using the phrase "substantially consisting of..." encompasses any known acceptable additives, excipients, diluents, carriers, etc. Preferably, a composition consisting essentially of one group of components will contain less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1% by weight, and most preferably less than 0.1% by weight of the non-specified component or components.

[0023] As mentioned herein, the use of a PSMA ligand and / or complex labeling compound comprises at least the administration of a labeling dose of said labeling compound. However, said use may also comprise further steps before, accompanying and / or after said administration as deemed appropriate by said skilled person. Said use, preferably, further comprises at least one step as described herein, in particular the step of use and / or the step of the method as described herein. Preferably, said use comprises intraoperative identification of cancerous tissue.

[0024] 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 .

[0025] Preferably, the PSMA-binding ligand has the structure

[0026]

[0027] (I)

[0028] Where Q is the PSMA binding motif,

[0029] A is a chelating agent residue,

[0030] Z is a dye group,

[0031] B is a branching group,

[0032] LBQ is a linker connecting Q and B, the linker comprising at least one amino acid X1,

[0033] L BZ is a connector, where n bz is 0 or 1,

[0034] And L BA is a connector, where n ba Is either 0 or 1.

[0035] PSMA binding motif Q

[0036] The PSMA-binding motif Q preferably has the structure

[0037]

[0038] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2. More preferably, R 2 , R 3 and R 4 is CO2H. In particular, R 1 is H and R 2 , R 3 and R 4 It is CO2H. The wavy line indicates the connector L BQ connection site.

[0039] Chelating agent residue A

[0040] 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-triazacyclononane (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-triazacyclononanephosphinic 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] Pentadecane-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 (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

[0041] The term "chelator residue" and generally the term "chelator residue derived from a chelator selected from the group" is intended to mean the above-mentioned chelator, thus generally defined in said "group", which has been linked to the rest of the PSMA-binding ligand via a suitable functional group, preferably to a linker L. BA .

[0042] More preferably, the chelating agent defined in the "group" has been linked to the NH group of the rest of the PSMA molecule via the former carboxylic acid group of said chelating agent, for example to the amine group L BA , thereby forming an amide bond between the chelator and the rest of the PSMA-binding ligand, such as having and L BA An amide bond is formed between them.

[0043] Preferably, A is a chelator residue having a structure selected from the group consisting of:

[0044] , and ;

[0045] Most preferably, A has the structure

[0046] .

[0047] At least one connector L BQ :

[0048] As described above, the PSMA ligand preferably comprises at least one linker L comprising at least one amino acid X1. BQ .

[0049] It should be understood that the term amino acid includes all naturally occurring and non-naturally occurring amino acids, including all stereoisomers of these amino acids, such as enantiomers and diastereomers. Most preferably, the amino acid is an α-amino acid. In terms of chirality, L-amino acids are preferred.

[0050] Preferably X1 is

[0051] - neutral amino acids, or

[0052] - N-alkylated amino acids, preferably N-methylated amino acids.

[0053] More preferably, X1 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.

[0054] The term "neutral amino acid" as used within the meaning of the present invention includes each and every amino acid that has no net charge at pH 7. It is to be understood that the term includes all naturally occurring and non-naturally occurring amino acids, including all stereoisomers, such as enantiomers and diastereomers of these amino acids, such as glycine, alanine, valine, isoleucine, phenylalanine, β-alanine, as well as non-natural amino acids comprising a neutral linker between the N and C termini, such as at least one -(CH2-CH2-O)- group between the N and C termini, and N-alkylated amino acids, such as N-methylated amino acids, whereby the amino acid comprises an alkyl or methyl group attached to the amino group of the amino acid in place of the proton -H.

[0055] Preferably, amino acid X1 is an N-alkylated amino acid. This term refers to an amino acid that contains an alkyl group (e.g., a methyl group) replacing a proton H, which is attached to the amino group of the amino acid. N-alkyl amino acids are also referred to below as N-alkylated or alkylated amino acids. N-methyl amino acids are also referred to below as N-methylated or methylated amino acids.

[0056] 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.

[0057] More preferably, amino acid X1 is an N-methylated amino acid, preferably a neutral N-methylated amino acid.

[0058] It should be understood that the term also includes all naturally occurring and non-naturally occurring N-methyl derivatives of amino acids, including all stereoisomers of these amino acids, such as enantiomers and diastereomers. Most preferably, the amino acid is an N-methyl alpha amino acid. In terms of chirality, L-amino acids are preferred.

[0059] 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-methylglutamate, N-methylserine, N-methylthreonine, N-methylasparagine, N-methylglutamine, N-methylcysteine, selenocysteine, N-methylglycine, N-methylproline, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methylleucine, N-methylmethionine, N-methylphenylalanine, N-methyltyrosine, and N-methyltryptophan.

[0060] 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.

[0061] 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.

[0062] More preferably, the methylated amino acid is N-methylalanine or N-methylglycine (sarcosine), more preferably N-methylglycine, and thus at least one amino acid preferably has the structure -N(CH3)-CH2-C(=O)- or -N(CH3)-CH(CH3)-C(=O)-, more preferably -N(CH3)-CH2-C(=O)-.

[0063] Preferably, the connector L BQ Contains structural unit (X1) n1wherein n1 is in the range of from 2 to 25. In case the linker comprises more than one amino acid, these amino acids may be identical or different from each other. Preferably, the amino acid sequence AA consists of the unit (X1) n1 composition, wherein all amino acids X1 are identical. Thus, the linker may, for example, comprise -N(CH3)-CH2-C(=O)- and -N(CH3)-CH(CH3)-C(=O)- groups, or only -N(CH3)-CH2-C(=O)- or -N(CH3)-CH(CH3)-C(=O)- groups, or only -N(CH3)-CH2-C(=O)- groups.

[0064] Preferably, the linker comprises at least 3, preferably 3 to 25 methylated amino acids, which may be the same or different.

[0065] According to a preferred embodiment, at least two N-methylated amino acids are attached to each other.

[0066] Preferably, the linker comprises the structural unit -(X1)n1, wherein X 1 Preferably, X is N-alkylated, preferably methylated, more preferably neutral methylated, more preferably wherein X 1 It is -N(CH3)-CH2-C(=O)-, and wherein n1 is an integer from 1 to 25, more preferably 3 to 20, more preferably 5 to 15, for example 5, 6, 7, 8, 9, 10, 11, 12, 23, 24, 15, more preferably 5 or 10, especially 10.

[0067] Preferably, the PSMA-binding ligand, in particular the linker L BQ , also includes except X1 or (X1) n1 At least one amino acid structural unit AS a and / or at least one amino acid structural unit AS b .

[0068] Amino acid structural unit AS a

[0069] Amino acid structural unit AS a Preferably, it has the following structure:

[0070]

[0071] Where Q 1 Selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl.

[0072] 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 aromatic groups. As examples, optionally substituted phenyl groups or naphthyl groups may be mentioned. Polycyclic aromatic groups may also contain non-aromatic rings.

[0073] The term "alkylaryl" as used in the context of the present invention refers to an aryl group wherein at least one proton has been replaced by an alkyl group (alkyl-aryl-).

[0074] The term "arylalkyl" as used in the context of the present invention refers to an aryl group attached through an alkyl group (aryl-alkyl-).

[0075] The term "heteroaryl" 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, such as tricyclic or bicyclic aromatic groups, containing one or more, such as 1 to 4, such as 1, 2, 3 or 4 heteroatoms in the ring system. If more than one heteroatom is present in the ring system, at least two 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 mentioned as non-limiting examples: benzodioxolyl, pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothienyl, methylenedioxyphenyl, naphthyridinyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0076] The term "alkylheteroaryl" as used in the context of the present invention refers to a heteroaryl group wherein at least one proton has been replaced by an alkyl group (alkyl-heteroaryl-).

[0077] The term "heteroarylalkyl" as used in the context of the present invention refers to a heteroaryl group attached via an alkyl group (heteroaryl-alkyl-).

[0078] In the context of the present invention, the term "cycloalkyl" refers to optionally substituted cycloalkyl residues, where they may be monocyclic or polycyclic groups. Optionally substituted cyclohexyl may be mentioned as a preferred example of a cycloalkyl residue.

[0079] The term "heterocycloalkyl" as used in the context of the present invention refers to an optionally substituted cycloalkyl residue having at least one heteroatom, such as O, N or S, in the ring, wherein the cycloalkyl residue may be a monocyclic or polycyclic group.

[0080] The term "substituted cycloalkyl residue" or "cycloheteroalkyl" as used in the context of the present invention refers to a cycloalkyl residue or cycloheteroalkyl residue in which at least one H has been replaced by a suitable substituent.

[0081] 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 Select from the group consisting of:

[0082] , , , , , , and ,

[0083] Where Q 1 Most preferably

[0084] .

[0085] Amino acid building blocks AS b

[0086] Amino acid structural unit AS b Preferably having structure (b)

[0087] (b)

[0088] Where Q 2 Selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl.

[0089] The term "aryl" as used in the context of the present invention refers to optionally substituted five-membered and six-membered aromatic rings and substituted or unsubstituted polycyclic aromatic groups (aryl groups), such as tricyclic or bicyclic aromatic groups (-aryl-). As examples, optionally substituted phenyl groups or naphthyl groups may be mentioned. Polycyclic aromatic groups may also contain non-aromatic rings, i.e. aryl groups in the context of the present invention.

[0090] The term "alkylaryl" as used in the context of the present invention refers to an aryl group in which at least one proton has been replaced by an alkyl group (-alkyl-aryl-), and the aryl group is linked to a -CH2- group via the alkyl group and to a carbonyl group via the aryl group.

[0091] The term "arylalkyl" as used in the context of the present invention refers to an aryl group which is linked via an alkyl group to a carbonyl group and via an aryl group to a -CH2- group (-aryl-alkyl-).

[0092] The term "heteroaryl" (-heteroaryl-) 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, such as tricyclic or bicyclic aromatic groups, containing one or more, such as 1 to 4, such as 1, 2, 3 or 4 heteroatoms in the ring system. If more than one heteroatom is present in the ring system, at least two 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 mentioned as non-limiting examples: benzodioxolyl, pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothienyl, methylenedioxyphenyl, naphthyridinyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0093] The term "alkylheteroaryl" as used in the context of the present invention refers to an aryl group in which at least one proton has been replaced by an alkyl group (-alkyl-heteroaryl-), and the aryl group is linked via the alkyl group to a -CH2- group and via the heteroaryl group to a carbonyl group.

[0094] The term "heteroarylalkyl" as used in the context of the present invention refers to a heteroaryl group (-aryl-alkyl-) which is linked via an alkyl group to a carbonyl group and via a heteroaryl group to a -CH2- group.

[0095] The term "cycloalkyl" (-cycloalkyl-) in the context of the present invention refers to optionally substituted cycloalkyl radicals, where they may be monocyclic or polycyclic radicals. Optionally substituted cyclohexyl may be mentioned as a preferred example of a cycloalkyl radical.

[0096] The term "heterocycloalkyl" as used in the context of the present invention refers to an optionally substituted cycloalkyl residue having at least one heteroatom, such as O, N or S, in the ring, wherein the cycloalkyl residue may be a monocyclic or polycyclic group.

[0097] The term "substituted cycloalkyl residue" or "cycloheteroalkyl" as used in the context of the present invention refers to a cycloalkyl residue or cycloheteroalkyl residue in which at least one H has been replaced by a suitable substituent.

[0098] Preferably, Q 2is an aryl group or a cycloalkyl group, more preferably

[0099] or ,

[0100] Best choice .

[0101] I understand that Q 2 Any stereoisomers of are possible and included. 2 for In the case of , it is to be understood that this includes both cis and trans isomers, with the trans isomer being particularly preferred.

[0102] Preferably, the PSMA-binding ligand described above and below, preferably the linker L BQ , comprising at least one amino acid structural unit AS a and at least one amino acid structural unit AS b , where AS a With structure

[0103] ,

[0104] Where Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, and wherein AS b With structure (b)

[0105] (b)

[0106] Where Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably wherein Q 2 for

[0107] or ,

[0108] Best choice

[0109] ,

[0110] Preferably, the PSMA-binding ligand comprises a linker unit - (AS b ) q -AS a -, wherein q is an integer from 0 to 3, preferably wherein q is 1.

[0111] Preferably, the PSMA binding motif Q is linked to the group –(AS b ) q, more preferably connected to the moiety –(AS b ) q -AS a Therefore, the PSMA-binding ligand preferably comprises the structural unit

[0112] -–(AS b ) q -AS a -Q.

[0113] More preferably, the structural unit -L BQ –Q contains the structural unit -(X 1 ) n1 –(AS b ) q -AS a --Q, preferably composed of the structural unit -(X 1 ) n1 –(AS b ) q -AS a --Q composition, especially having the following structure

[0114] ,

[0115] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0116] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0117] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0118] and wherein q is an integer from 0 to 3,

[0119] Where X 1 As mentioned above, preferably wherein X 1 is a methylated amino acid, more preferably a neutral N-methyl amino acid, wherein X 1 is more preferably wherein X 1is -N(CH3)-CH2-C(=O)-, and wherein n1 is an integer from 1 to 25, more preferably 3 to 20, more preferably 5 to 15, for example 5, 6, 7, 8, 9, 10, 11, 12, 23, 24, 15, more preferably 5 or 10, in particular 10.

[0120] Branching group B

[0121] As mentioned above, the present invention preferably relates to a PSMA-binding ligand having the following structure:

[0122]

[0123] (I)

[0124] Wherein B is a branching group. As used herein, the term "branching group" refers to a group that divides a molecular chain into at least two molecular chains. Preferably, the branching group is an amino acid having a side chain having a group -(L BZ ) bz -Z or -(L BA ) ba - a suitable functional group to which A can be attached. Preferably, group B has the structure (B1)

[0125]

[0126] (B1)

[0127] Wherein R5 is an alkyl group, preferably -(CH2)1- 10 group, more preferably –(CH2) 2-4 group, and Y B To connect R5 to the group -(L BZ ) bz -Z or -(L BA ) ba -A functional group, where Y B Preferably, it is a group -NH-, -O-, -S-, -NH-NH-, -NH-NH-C(=O)-, -C(=O)-NH-NH- or C(=O)-, more preferably NH- or -C(=O)-. Most preferably, R5 is (CH2)4, and Y B It is –NH-.

[0128] Preferably, the PSMA-binding ligand thus has one of the following structures (Ia) or (Ib), preferably structure (Ia)

[0129]

[0130] Wherein R5 is an alkyl group, preferably -(CH2)1- 10group, more preferably –(CH2) 2-4 group, and Y B To connect R5 to the group -(L BZ ) bz -Z or -(L BA ) ba -A functional group, where Y B Preferably, it is a group -NH-, -O-, -S-, -NH-NH-, -NH-NH-C(=O)-, -C(=O)-NH-NH- or C(=O)-, more preferably NH- or -C(=O)-. Most preferably, R5 is (CH2)4, and Y B It is –NH-.

[0131] More preferably, the PSMA ligand has structure (IIa) or (IIb)

[0132]

[0133] (IIa)

[0134] (IIb)

[0135] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2, 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, and wherein q is an integer from 0 to 3, wherein X 1 As mentioned above, preferably a methylated amino acid, more preferably a neutral methylated amino acid, more preferably wherein X 1 is -N(CH3)-CH2-C(=O)-, and n1 is an integer from 1 to 25, wherein

[0136] Z is a dye group,

[0137] L BZ is a connector, where n bz is 0 or 1,

[0138] And L BA is a connector, where n ba is 0 or 1, wherein R5 is an alkyl group, preferably -(CH2) 2-4 group, and YB is to connect R5 to the group -(L BA ) ba -A or group-(L BZ ) bz -Z functional group, where Y B Preferred is a group -NH- or -C(=O)-, more preferred is a -NH- group.

[0139] Therefore, the PSMA ligand preferably has structure (IIIa) or (IIIb)

[0140]

[0141] (IIIa)

[0142]

[0143] (IIIb),

[0144] More preferably, structure (IVa) or (IVb)

[0145]

[0146] (IVa)

[0147]

[0148] (IVb).

[0149] Connector L BQ and / or L Bz

[0150] Any linker suitable for attaching Z and A, respectively, to the branching group B, preferably to the amino group of structure (B1) may be used. Preferably, the linker L BQ and / or L BZ The invention comprises at least one amino acid. This includes all naturally occurring and non-naturally occurring amino acids, including all stereoisomers of these amino acids, such as enantiomers and diastereomers. Most preferably, the amino acid is an α-amino acid. In terms of chirality, L-amino acids are preferred. Preferably, the linker L BQ and / or L BZ It comprises 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(CH3)-CH2-C(=O)-.

[0151] 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 it 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(CH3)-CH2-C(=O)-.

[0152] Preferably, Z is attached to L BZ N-terminal or L BZ The functional groups of the amino acid side chains present in BZ Connect to L BZ In the case of an amino acid side chain present in the N-terminus of the amino acid chain, the N-terminus of the amino acid chain is preferably terminated with the group -C(=O)-R z Acylation, where R z Preference is given to C10-C20 alkyl chains.

[0153] According to a preferred embodiment, Z is attached to the N-terminus of the amino acid chain. In this case, L BZ Preferably comprises a 2bz ) n2bz -(X 1bz ) n1bz -amino acid sequence, more preferably having the structure -(X 2bz ) n2bz -(X 1bz ) n1bz -, and Z is attached to -(X 2bz ) n2bz -(X 1bz ) n1bz At the N-terminus of 1bz Preferably, it is a methylated amino acid, more preferably wherein X 1bz is -N(CH3)-CH2-C(=O)-, and n1bz is 1 to 20, preferably 4 to 10, more preferably 5, and wherein X 2bz Preferably it is a neutral amino acid, more preferably β-Ala, and n2bz is from 1 to 20, preferably 1. In this case, the PSMA ligand preferably has the structure

[0154] (Va1)

[0155] 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 -, and where X 1bz Preferably, it is a methylated amino acid, more preferably wherein X 1zis -N(CH3)-CH2-C(=O)-, and n1bz is 1 to 20, preferably 4 to 10, more preferably 5, and wherein X 2bz is glutamic acid or lysine, preferably lysine, and Z is attached to 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 a group -C(=O)-R z Acylation, where R z Preferably, it is a C10-C20 alkyl chain. In this case, the PSMA ligand preferably has the structure (Va2), more preferably (VIa2)

[0156] (Va2)

[0157] (VIa2)

[0158] According to a second preferred embodiment, the PSMA ligand has structure (Ib), preferably (IIb), more preferably (IIIb), more preferably (IVb). In this case, L BA Preferably, it comprises an amino acid sequence, said sequence preferably comprising at least one methylated amino acid, preferably -N(CH3)-CH2-C(=O)-. Preferably, L BA Contains the amino acid sequence, and A is attached to L BA N-terminal or L BA The functional groups of the amino acid side chains present in BA In the case of attachment to a side chain, the N-terminus is preferably attached with the group -C(=O)-R z Acylation, where R z Preferably, L BA Contains the amino acid sequence -(X 2a ) n2a -(X 1ba ) n1ba -, preferably consisting of the amino acid sequence -(X 2a ) n2a -(X 1ba ) n1ba -composed, and A is attached to -(X 2ba ) n2ba -(X 1ba ) n1ba - the N-terminus, and wherein X 1ba Preferably, it is a methylated amino acid, more preferably wherein X 1ba is -N(CH3)-CH2-C(=O)-, and n1a is 1 to 20, preferably 4 to 10, more preferably 5, and wherein X 2bais a neutral amino acid, preferably β-Ala, and n2a is 1 to 20, preferably 1.

[0159] Dye group Z

[0160] As used in the context of the present invention, the terms "dye group", "dye moiety", "label" and "stain" 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 colored moiety, particularly preferably the dye is a fluorescent dye.

[0161] Fluorescent dyes as used herein can be understood in the broadest sense as any dye moiety capable of fluorescence detection. Preferably, such fluorescence detection is in the range of 350 to 1000 nm, i.e. in the visible spectrum and near infrared (NIR) spectrum, 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 is well distinguished from the autofluorescence of cancer and surrounding tissue. Many fluorescent dye moieties are known in the art, and will be apparent to ordinary technicians. Many fluorescent dyes are commercially available, wherein the activated group is used to react with protein side chains or other compounds (e.g., precursor compounds for preparing the compounds of the present invention). Preferably, the dye can be detected by fluorescence with a wavelength of from 350 to 1000 nm, i.e. in the visible spectrum and near infrared (NIR) spectrum, preferably from 400 to 850 nm, such as 600 nm to 850 nm, preferably 700 nm to 780 nm, and / or allows detection of fluorescence by the eye and / or a wavelength in the range of from 780 nm to 850 nm.

[0162] Additionally or alternatively, the dye may also be colored, i.e., provoke color perception when illuminated by any light. Such a chromatic effect may be stimulated by absorbing light of one or more specific wavelength ranges in the visible light range (i.e., in the range from about 350 nm to about 800 nm) and / or by emitting light of one or more specific wavelength ranges in the visible light range. Preferably, the color is different from the tumor formation and surrounding tissue to be examined. Therefore, when not used for fluorescence detection, the dye portion is preferably not red or brown, but preferably blue or green. When the dye is prepared for fluorescence detection, as long as fluorescence can be detected under the background of autofluorescence, the difference in color will generally play a secondary role. Preferably, the colored dye portion in the context of the present invention is a small molecule dye, i.e., a dye portion with a molecular weight (MW) of no more than 1000 Da, preferably no more than 750 Da, and particularly no more than 500 Da.

[0163] Depending on the chemical nature of the fluorescent dye in the compound of the invention and the presence of one or more fluorophores and / or quenchers on the target cell surface (i.e., the cell membrane of the corresponding cancer cell), after the binding of the compound according to the invention to the cell membrane, it is also possible to observe, for example, fluorescence energy transfer (FRET) and / or fluorescence quenching effects. Additionally or alternatively, the presence of a fluorescent dye relationship can also be further examined based on fluorescence methods, such as fluorescence recovery after photobleaching (FRAP), fluorescence loss in photobleaching (FLIP). These methods can provide information about the mobility of the compound or its salt that is bound or associated with the cell membrane of the cancer cell.

[0164] Preferably, neither the chemical groups present in the PSMA ligand nor the complexed radiometal quench the intensity of the fluorescent signal obtained by dye Z at its emission maximum in an aqueous environment at approximately neutral pH (ie pH 6-8, particularly 6.5-7.5) by more than 50%.

[0165] Preferably, the dye Z is suitable for luminescence in an aqueous environment at approximately neutral pH, ie pH 6-8, in particular 6.5-7.5, especially pH 7.0-7.5.

[0166] In a preferred embodiment, the dye Z is a fluorescent dye having an emission maximum in the range from 350 nm to 1000 nm, preferably 400 nm to 850 nm.

[0167] 5, AlexaFluor 550, AlexaFluor 514, AlexaFluor 532, AlexaFluor 546, AlexaFluor 555, AlexaFluor 568, AlexaFluor 594, AlexaFluor 610, AlexaFluor 633, AlexaFluor 647, AlexaFluor 660, AlexaFluor 680, AlexaFluor 700 and AlexaFluor 750, Cy2, Cy3, Cy3B, Cy3.5, Cy5, sulfoCy5, 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)-carboxamide cadaverine), 5-FAM cadaverine (fluorescein-5-carboxamide cadaverine), 5(6)-FAM ethylenediamine (fluorescein-5(6)-carboxamide ethylenediamine), 5-FAM ethylenediamine (fluorescein-5(6)-carboxamide ethylenediamine), 5-FITC (FITC isomer I; fluorescein-5-isothiocyanate), 5-FITC cadaverine; fluorescein-5-maleimide;5-IAF (5-iodoacetamide fluorescein), 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 ethyl diamine, 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), dansylcadaverine (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);Fluorescein (4-phenylspiro-[furan-2(3H),1-benzofuran]-3,3'-dione (1-phthalan]-3,3′-dion)), NBD (4-chloro-7-nitro-benzo-2-oxa-1,3-diazole), pyrromethene, Texas Red (1H,5H,11H,15H-xanthen[2,3,4-ij:5,6,7-i'j']biquinolizin-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-sulfonyl-, 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-methocy, 610CP, SiR-methyl, ATTO 390, ATTO 425, ATTO 465, ATTO 488, ATTO 495, ATTO 514, ATTO 520, ATTO532, ATTO Rho6G, ATTO 550, ATTO 565, ATTO Rho3B, ATTO Rho11, ATTO Rho12, ATTOThio12, 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 its derivatives. ;

[0168] 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).

[0169] Thus, according to a preferred embodiment, Z is Atto590 (CAS No. 670269-33-7 for NHS-ester, where it is understood that the NHS-O group is not present in the group Z when attached) having the following structure, wherein "*" indicates that the NHS-O group is not present in the group Z. 2 The connection site:

[0170] .

[0171] According to another preferred embodiment, Z is Alexa594 (6-[2,4 (or 2,5)-dicarboxyphenyl]-1,2,10,11-tetrahydro-1,2,2,10,10,11-hexamethyl-4,8-bis(sulfomethyl)-pyrano[3,2-g:5,6-g]diquinolin-13-ium) having the following structure, wherein "*" indicates that the same 2 The connection site:

[0172] .

[0173] According to another preferred embodiment, Z is STAR600 (available, for example, from Abberior) having the following structure, wherein "R" represents a 2 Chemical bonds:

[0174] .

[0175] According to another preferred embodiment, Z is STAR635P (available, for example, from Abberior, see Wurm, CA, Kolmakov, K., Göttfert, F. et al. Novel red fluorophores with superior performance in STED microscopy. Opt Nano 1, 7 (2012)) having the following structure, wherein "R" represents a 2 Chemical bonds:

[0176] .

[0177] According to another preferred embodiment, Z is a STAR RED having the following structure (e.g. available from Abberior, see Wurm, CA, Kolmakov, K., Göttfert, F. et al. Novel red fluorophores with superior performance in STED microscopy. Opt Nano 1, 7 (2012)), wherein "R" represents a 2 Chemical bonds:

[0178] .

[0179] According to another preferred embodiment, Z is ATTO647N having the following structure, wherein "*" represents the same 2 Chemical bonds:

[0180] .

[0181] According to another preferred embodiment, Z is Bodipy650-X (CAS 04-0; 1616842-78-4 of NHS-ester, wherein it is understood that when attached, no NHS-O group is present in the Z group, see Mitronova, GY et al., Sci Rep 712319 (2017)) having the following structure, wherein "*" indicates that the Z group is identical to L. 2 The connection site:

[0182] .

[0183] According to another preferred embodiment, Z is 580CP-methoxy (N. Butkevich, GY Mitronova, SC Sidenstein, JL Klocke, D. Kamin, DNH Meineke, E.D'Este, P.-T. Kraemer, JG Danzl, VN Belov, SW Hell, Angew. Chem. Int. Ed. 2016, 55, 3290) having the following structure, wherein "R" represents a 580CP-methoxy group with L 2 Chemical bonds:

[0184] .

[0185] According to another preferred embodiment, Z is 610CP (CAS 1877282-17-1, see N. Butkevich, GY Mitronova, SC Sidenstein, JL Klocke, D. Kamin, DNH Meineke, E. D'Este, P.-T. Kraemer, JG Danzl, VN Belov, SW Hell, Angew. Chem. Int. Ed. 2016, 55, 3290) having the following structure, wherein "R" represents a molecule identical to L. 2 Chemical bonds:

[0186] .

[0187] According to another preferred embodiment, Z is SiR-methyl having the following structure (see Lukinavičius, G., et al. Nature Chem 5, 132-139 (2013)), wherein "R" represents a residue with L 2 Chemical bonds:

[0188] .

[0189] According to another preferred embodiment, Z is IRDye800CW (CAS 1088919-86-1) having the following structure, wherein "*" indicates that L 2 The connection site:

[0190] .

[0191] According to another preferred embodiment, Z is ICG (3599-32-4) having the following structure:

[0192] .

[0193] According to another preferred embodiment, Z is a compound having the structure -C(=O)-C 1 sulfoCy5 (CAS 1144107-82-3 (potassium salt), CAS 1121756-16-8 (inner salt), CAS 2098639-31-5 (sodium salt)), where C 1 yes

[0194] ,

[0195] And where Y + It is a suitable pharmaceutically acceptable salt, preferably Na+ or K+, more preferably Na+.

[0196] According to another preferred embodiment, Z has the formula (C)

[0197] ,

[0198] (C)

[0199] in

[0200] X 1z and X 4z Independently selected from -N=, -N(R 5z ) = and -C(R 6z ) = composed of groups;

[0201] X 2z and X 3z Independently selected from O, S, Se, N (R 5z ) and C(R 6z R 7z ) are preferably all C(CH3)2;

[0202] Y z is a linker that connects the two parts of (C) and allows electrons to be delocalized between the parts, where Y z Optionally contains a group (L z -) c Z 0 ;

[0203] az and bz are independently selected from the group consisting of 1, 2 and 3;

[0204] Each R 1z and each R 2z Independently selected from (L z -) cc Z z , (L z -) c Z 0 and H; and two adjacent R 1z and / or two adjacent R 2z It is also possible to form an aromatic ring, which is optionally substituted by one or more (L z -) c Z z or (L z -) c Z 0 replace;

[0205] R 3z , R 4z , R 5z , R 6z , R 7z , R 9zIndependently selected from (L z -) c Z z ,(L z -) c Z 0 and H composed of groups;

[0206] Each c is independently 0 or 1;

[0207] Each L z Independently for 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, which is optionally substituted with one or more of -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)O- and T 1 interruption and / or termination;

[0208] T 1 is phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, decahydronaphthyl, adamantyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl or 7- to 11-membered heterobicyclyl, wherein T 1 Optionally, one or more selected from halogen, CN, C(O)R 8z 、COOR 8z , OR 8z 、C(O)N(R 8z R 8az )、S(O)2N(R 8z R 8az )、S(O)N(R 8z R 8az )、S(O)2R 8z 、N(R 8z )S(O)2N(R 8az R 8bz ), SR 8z 、N(R 8z R 8az ), NO2; OC(O)R 8z 、N(R 8z )C(O)R 8az 、N(R 8z )S(O)2R 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) (wherein the ring is at least partially saturated) or C 1-6 Alkyl is substituted by a substituent consisting of a group consisting of 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different;

[0209] Each Z Z are 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)2OR 8 z、S(O)2O - 、S(O)2N(R 8z R 8az )、S(O)N(R 8z R 8az )、S(O)2R 8z 、S(O)R 8z 、N(R z )S(O)2N(R 8az R 8bz ), SR 8z 、N(R 8z R 8az )、NO2;P(O)(OR 8z )2、P(O)(OR 8z ) - 、OC(O)R 8z 、N(R 8z )C(O)R 8az 、N(R 8z )S(O)2R 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 orOC(O)N(R 8z R 8az );

[0210] R 8z , R8az , R 8bz Independently selected from H or C 1-6 The group consisting of alkyl groups, where C 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different;

[0211] Z 0 is to connect the dye Z to the group –(L BZ ) bz -B's chemical bond,

[0212] The premise is R 1z , R 2z , R 3z , R 4z , R 5z , R 6z , R 7z , R 9z One of them is (L z -) c Z 0 or Y z Contains (L-) c Z 0 .

[0213] The term "optionally substituted" refers to unsubstituted or substituted. Generally, but not limited to, "one or more substituents" refers to one, two or three, preferably one or two substituents, and more preferably one substituent. Generally, these substituents can be the same or different. "Alkyl" refers to a straight or branched hydrocarbon chain. Each hydrogen of an alkyl carbon can be replaced by a substituent as further specified herein. As used in the context of the present application, the terms "alkyl", "alkyl residue" and "alkyl group" and "alkyl moiety" can be understood as a straight or branched saturated hydrocarbon chain. "Straight chain" can also be designated as "unbranched" or "linear". Preferably, the alkyl is a straight chain. As used in the context of the present application, the term "alkylene" refers to a straight or branched saturated hydrocarbon chain, in which the two parts of the molecule are connected by an alkylene residue. "Straight chain" can also be designated as "unbranched" or "linear". As further specified herein, each hydrogen of an alkylene carbon can be replaced by or may not be replaced by a substituent (i.e., can be substituted or unsubstituted).

[0214] “C 1-4 "Alkyl" refers to an alkyl chain having 1 to 4 carbon atoms, for example, if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, for example, when two parts of the molecule are connected via an alkyl group, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. C1-4 Each hydrogen of an alkyl carbon may be replaced by a substituent as further defined herein. 1-6 "Alkyl" refers to an alkyl chain having 1 to 6 carbon atoms, for example, if present at the end of a molecule: C 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or, for example, when the two parts of the molecule are connected by an alkyl group, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1-6 Each hydrogen of an alkyl carbon may be replaced by a substituent as further defined herein. 1-8 "Alkylene residue" refers to an alkylene chain having 1 to 8 carbon atoms, for example, when two parts of the molecule are connected by an alkylene group, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, -CH2-C(CH3)2-, -C(CH2-CH3)2-, -CH(CH2-CH3)-, -CH2-CH(CH3)(CH2-CH3)-, -CH(CH3)(CH2-CH3)-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, etc. The term "C 4-8 "C6 alkylene" and "C6 alkylene" are defined accordingly. The term "C 3-7 "C5 (C4) alkylene" and "C5 (C4) alkylene" are defined accordingly. The term "C 1-10 "Alkylene group" refers to a divalent straight or branched hydrocarbon chain having 1 to 10 carbon atoms. Each hydrogen of the alkyl carbon may be replaced by a substituent as further defined herein. Examples are methylene (-CH2-)-CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. 1-10 Each hydrogen of a carbon of an alkylene group may be replaced by a substituent as further defined herein. Thus, "C 1-10 "Alkylene residue" refers to an alkylene chain having 1 to 10 carbon atoms (when two parts of the molecule are connected via an alkylene group). Preferably, but not necessarily, C in the context of the residue f of the spacer y 1-10 The alkylene residue is a straight chain, i.e., unbranched, C 1-10Alkylene residues, wherein optionally one or more hydrogens are replaced and / or wherein optionally one or more -CH2- moieties may be replaced by -O- or -NH-. The expression "one or more -CH2- moieties may optionally be replaced by" means that the specified number of CH2 groups can be replaced by the atoms or groups specified herein. In addition, one or more hydrogens as specified herein can be replaced by substituents. 1-10 An alkylene group is "optionally interrupted and / or terminated" means that the alkylene chain is interrupted between two carbon atoms by an atom or chemical group as defined herein, or that the alkylene group is terminated by said atom or group after at least one carbon at one end of the alkylene chain, or that the alkylene chain is interrupted and terminated at the same time, or that the alkylene chain is neither interrupted nor terminated. As an example, but not limited to this example, a C3 alkylene group optionally interrupted and / or terminated by one or more Xs may have the sequence CCC, CCCX, XCCC, XCCCX, CXCC, CCXC, CXCXC, XCCXC, XCXCXC, XCXCCX, XCXCXCX.

[0215] The term "carbocycle" 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 ring. Preferred carbocyclic rings having 5, 6 or 7 carbon atoms are cyclopentene, cyclohexene, phenyl, cycloheptane, in particular cyclohexane. 3-7 Cycloalkyl" or "C 3-7 "Cycloalkyl ring" refers to a cyclic alkyl chain having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further defined herein. The term "C 3-5 Cycloalkyl" or "C 3-5"Cycloalkyl ring" is defined accordingly. "Halogen" refers to fluorine, chlorine, bromine or iodine. Generally preferably, halogen is fluorine or chlorine. Within the meaning of the present specification, the term "aromatic ring" refers to a carbocyclic or heterocyclic aromatic ring. Examples are benzene, naphthalene, 5- to 6-membered aromatic heterocycles and 9- to 11-membered aromatic heterobicyclic groups. "3- to 7-membered heterocyclyl" or "3- to 7-membered heterocycle" as used in the context of the present application refers to a ring with 3, 4, 5, 6 or 7 ring atoms, which may contain up to the maximum number of double bonds (fully, partially or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom to 4 ring atoms are selected from sulfur (including -S(O)-, ... The 3- to 7-membered heterocyclic rings are substituted with a heteroatom selected from the group consisting of: (O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule via a carbon or nitrogen atom. Examples of 3- to 7-membered heterocyclic rings are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolidine, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyrrolidine, imidazole, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyrrolidine, pyrrolidine, imidazole, imidazoline, pyrrolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyrrolidine ... The term "4 to 7 membered heterocyclyl" or "4 to 7 membered heterocycle" is defined accordingly. The term "5 to 6 membered heterocyclyl" or "5 to 6 membered heterocycle" is defined accordingly. "5 to 6 membered aromatic heterocyclyl" or "5 to 6 membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl or benzene, wherein at least one carbon atom is selected from sulfur (including S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and the like. )-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine. "5-membered aromatic heterocyclic group" or "5-membered aromatic heterocycle" refers to a heterocycle derived from a cyclopentadienyl group, wherein at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole."7- to 11-membered heterobicyclyl" or "7- to 11-membered heterobicyclic ring" refers to a heterocyclic ring system of two rings having 7 to 11 ring atoms, wherein at least one ring atom is common to both rings, and may contain up to the maximum number of double bonds (fully, partially or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom to 6 ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), wherein the ring is attached to the rest of the molecule through a carbon or nitrogen atom. Examples of 7- to 11-membered heterobicyclic rings are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 7- to 11-membered heterobicycle also includes spiro structures of two rings, such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptane-6-yl or 2,6-diazaspiro[3.3]heptane-6-yl or bridged heterocycles, such as 8-azabicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octane-2-yl or 3,8-diazabicyclo[3.2.1]octane. "9- to 11-membered aromatic heterobicyclyl" or "9- to 11-membered aromatic heterobicyclic ring" refers to a heterocyclic ring system consisting of two rings, at least one of which is aromatic, wherein the heterocyclic ring system has 9 to 11 ring atoms, wherein two ring atoms are common to both rings, and may contain up to the maximum number of double bonds (fully or partially aromatic), wherein at least one ring atom to up to 6 ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is attached to the rest of the molecule through a carbon or nitrogen atom. Examples of 9- to 11-membered aromatic heterobicyclic rings are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazol, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term "9- to 10-membered aromatic heterobicyclic ring" or "9- to 10-membered aromatic heterobicyclic ring" is defined accordingly.

[0216] Therefore, residue R 1z , R 2z , R 3z , R 4z , R 5z , R 6z , R 7z One of them acts as a dye Z and the group –(L BZ ) bz-B's connecting group, atom or bond (L z -) c Z 0 .

[0217] Preferably, R 3 or R 4 Indicates (L z -) c Z 0 More preferably, R 3z Yes (L z -) c Z 0 .

[0218] Preferably, in formula (C), X 1z and X 4z are the same and preferably C(R 6z ), more preferably CH.

[0219] Preferably, in formula (C), X 2z and X 3z are identical and preferably C(R 6 R 7 ), more preferably R 6 and R 7 are the same and even more preferably L z -Z z , where L z = C 1-10 alkylene, and even more preferably L z = CH2, and Z z =H.

[0220] Preferably, R 9 It's H.

[0221] Preferably, in formula (C), Y z Not included (L z -) c Z 0 , and preferably Y z yes

[0222] -(C(R 9az )=C(R 9az )-) g -

[0223] ,

[0224] wherein g is 1, 2, 3 or 4 (preferably 2 or 3, more preferably 3), and each R 9az =L z -) c Z z or H; and two R9az It is also possible to form a carbocyclic ring or a 4- to 7-membered heterocyclic ring having 5, 6 or 7 carbon atoms;

[0225] Each c is independently 0 or 1;

[0226] Each L z Independently for 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, which is optionally substituted by -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)O- and T 1 one or more interruptions and / or terminations;

[0227] T 1 is phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, decahydronaphthyl, adamantyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl or 7- to 11-membered heterobicyclyl, wherein T 1 Optionally, one or more selected from halogen, CN, C(O)R 8z 、COOR 8z , OR 8z 、C(O)N(R 8z R 8az )、S(O)2N(R 8z R 8az )、S(O)N(R 8z R 8az )、S(O)2R 8z 、N(R 8z )S(O)2N(R 8az R 8bz ), SR 8z 、N(R 8z R 8az ), NO2; OC(O)R 8z 、N(R 8z )C(O)R 8az 、N(R 8z )S(O)2R 8az 、N(R 8z )S(O)R 8az 、N(R 8z )C(O)N(R 8az R 8bz )、N(R8z )C(O)OR 8az 、OC(O)N(R 8z R 8az ), oxo (═O) (wherein the ring is at least partially saturated) or C 1-6 Alkyl is substituted by a substituent consisting of a group consisting of 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different;

[0228] R 8z , R 8az , R 8bz Independently selected from H or C 1-6 The group consisting of alkyl groups, where C 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different;

[0229] Each Z z are 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)2OR 8z 、S(O)2O - 、S(O)2N(R 8z R 8az )、S(O)N(R 8z R 8az )、S(O)2R 8z 、S(O)R 8z 、N(R 8z )S(O)2N(R 8az R 8bz ), SR 8z 、N(R 8z R 8az )、NO2; P(O)(OR 8z )2、P(O)(OR 8z ) - 、OC(O)R 8z 、N(R 8z )C(O)R 8az 、N(R 8z )S(O)2R 8az 、N(R 8z )S(O)R 8az 、N(R 8z )C(O)N(R 8az R 8bz )、N(R 8z )C(O)OR 8azorOC(O)N(R 8z R 8az ).

[0230] Preferably, Y z for

[0231] or -(C(R 9az )=C(R 9az )-) g -

[0232] where g = 2 and each R 9az =H.

[0233] Preferably, in formula (C), az and bz are the same and are preferably 1, more preferably R 1z and R 2z = SO3 - .

[0234] Preferably, in formula (C), az and bz are the same and are 2, preferably wherein two adjacent R 1z and two adjacent R 2z Forming a benzene ring.

[0235] Preferably, in formula (C), R 3z and R 4z One of them is (L z -) c Z Z0 , and the other is (L z -) c Z z , where L z - = C 1-10 Alkylene, and Z z = H or SO3 - And c is preferably = 1.

[0236] Preferably, (L z -) c Z 0 It is C 1-10 Alkylene-C(O)-(C=1,Z 0 chemical bond), preferably C 3-7 Alkylene-C(O), more preferably C5 alkylene--C(O)-, connecting (C) to the group –(L BZ ) bz -B.

[0237] In a highly preferred embodiment, the structure -C(=O)-C 1 , and C 1 Selected from the group consisting of:

[0238] , , and ,

[0239] Where X - is a pharmaceutically acceptable negatively charged counter ion;

[0240] where Y + is a pharmaceutically acceptable positively charged counterion; and

[0241] The wavy line indicates the conjugation site of the group –C(=O), which is attached to the group –(L BZ ) bz -B.

[0242] The most preferred Z is -C(=O)-C 1 , where C 1 yes

[0243] .

[0244] and as described above and below, where Y + It is a pharmaceutically acceptable counter ion.

[0245] Preferably, the dye is sulfoCy5.

[0246] As mentioned above, a pharmaceutically acceptable negatively charged counterion X may be understood in the broadest sense. - Likewise, the pharmaceutically acceptable positively charged counterion Y + can also have any valence. Therefore, Y + It may exemplarily have a charge of +1, +2, +3 or +4, preferably a charge of +1 or +2. + It can be any pharmaceutically acceptable positively charged ion. Preferably, the ion has good solubility in the aqueous phase liquid. For example, Y + The cations may be selected from alkali metals (e.g. Na + , K + , Li + ), alkaline earth metal cations (such as Mg 2+ , Ca 2+ )、Al 3+ NH4 + , H + and the cations of organically bound amines. Furthermore, it is understood that the counterion is often dependent on the surrounding fluid, such as the fluid in which the compound is dissolved in a buffer and the body fluid after in vivo injection. In vivo, outside the cell, one of the major, but not the only, positively charged counterions is Na +.

[0247] Preferably, the PSMA ligand has a Figure 1 , Figure 2 and Figure 3 The structure of the structure shown.

[0248] Most preferably, the PSMA ligand has Figure 2 The structure shown

[0249] Complex

[0250] As mentioned above, the present invention relates to a complex comprising

[0251] (a) radionuclides, and

[0252] (b) a PSMA-binding ligand as described above or below, or a pharmaceutically acceptable salt or solvate thereof.

[0253] Typical pharmaceutically acceptable salts include those prepared by reaction of the PSMA binding ligands of the present invention with pharmaceutically acceptable mineral or organic acids or organic or inorganic bases. These salts are referred to as acid addition salts and base addition salts. Acids commonly used to form acid addition salts are 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 are sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, hydrochlorides, dihydrochlorides, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, hydroxybenzoates, methoxybenzoates, phthalates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed by mineral acids such as hydrochloric acid and hydrobromic acid, and those formed by organic acids such as maleic acid and methanesulfonic acid. The salt of an amine group may also include a quaternary ammonium salt, in which the amino nitrogen carries 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 alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc. Such bases for preparing salts of the present invention therefore include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, etc. Particularly preferred are potassium salt and sodium salt forms. It should be appreciated that the specific counterions forming a part of any salt of the present invention generally do not have a critical property, as long as the salt is pharmacologically acceptable as a whole, and as long as the counterions do not produce undesirable qualities to the salt as a whole.

[0254] The term "pharmaceutically acceptable solvate" also encompasses suitable solvates of the PSMA-binding ligand of the present invention, wherein the PSMA-binding ligand is combined with a solvent such as water, methanol, ethanol, DMSO, acetonitrile or a mixture thereof to form a suitable solvate, e.g., the corresponding hydrate, methanolate, ethanolate, DMSO solvate or acetonitrile.

[0255] Radionuclides

[0256] Depending on whether the PSMA binding ligand of the present invention is used as a radioactive imaging agent or as a radiopharmaceutical, different radionuclides are complexed to the chelating agent.

[0257] The complexes of the invention may contain one or more radionuclides, preferably one radionuclide. These radionuclides are preferably suitable for use as radioactive imaging agents or as therapeutic agents for the treatment of proliferating cells, such as PSMA-expressing cancer cells, in particular PSMA-expressing prostate cancer cells. According to the invention, they are referred to as "metal complexes" or "radiopharmaceuticals".

[0258] Preferred imaging methods are positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0259] Preferably, at least one radionuclide is selected from 89 Zr, 44 Sc, 111 ln, 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 2. 52 Fe, 59 Radionuclides of Fe and Pb (e.g. 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb) group.

[0260] More preferably, the at least one radionuclide is selected from 90 Y.68 Ga, 177 Lu, 225 Ac and 213 More preferably, the radionuclide is 177 Lu or 225 Ac.

[0261] Preferably, the radionuclide has a half-life of at least 30 minutes, more preferably at least 1 hour, more preferably at least 12 hours, even more preferably at least 1 day, most preferably at least 5 days; also preferably, the radionuclide has a half-life of at most 1 year, more preferably at most 6 months, still more preferably at most 1 month, even more preferably at most 14 days. Therefore, preferably, the radionuclide has a half-life of from 30 minutes to 1 year, more preferably from 12 hours to 6 months, even more preferably from 1 day to 1 month, most preferably from 5 days to 14 days.

[0262] Preferably, the radionuclide is an alpha- and / or beta-emitter, ie the radionuclide preferably emits alpha-particles (alpha-emitter) and / or beta-radiation (beta-emitter).

[0263] Preferably, where the radionuclide is an alpha emitter, the alpha-particles have an energy of from 1 to 10 MeV, more preferably from 2 to 8 MeV, most preferably from 4 to 7 MeV.

[0264] Preferably, where the radionuclide is a beta-emitter, the beta-radiation has an energy of from 0.1 to 10 MeV, more preferably from 0.25 to 5 MeV, most preferably from 0.4 to 2 MeV.

[0265] Preferred radionuclides emitting beta radiation are selected from the group consisting of 90 Y. 177 Lu, 59 Fe, 66 Cu, 67 Cu, 161 Tb, 153 Sm, 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 The group consisting of Pb. Very preferred radionuclides emitting beta radiation are 177 Lu or 90 Y, most preferred 177 Lu. Preferably in this case the use is diagnostic or therapeutic.

[0266] Preferred radionuclides emitting alpha radiation are, for example, selected from 213 Bi, 225 Ac,149 Tb, 230 U and 223 The group formed by Ra. 213 Bi, 230 U, more preferably the radionuclide is 225 Ac and / or 213 Bi. Very preferred radionuclides emitting α-radiation are, for example 225 Ac. Preferably in this case the use is therapeutic.

[0267] According to another embodiment, the radionuclide is a positron emitter. In this case, the radionuclide is preferably selected from 89 Zr, 44 Sc, 66 Ga, 68 Ga and 64 In this case, the use is preferably PET diagnostics.

[0268] According to another preferred embodiment, the radionuclide is a gamma emitter. In this case, the radionuclide is preferably selected from 111 In, 67 Ga, 99m Tc, 155 Tb, 165 Er and 203 In this case, the use is preferably SPECT diagnosis.

[0269] According to another preferred embodiment, the radionuclide emits Auger electrons and preferably decays by electron capture. In this case, the radionuclide is preferably selected from 67 Ga, 155 Tb, 153 Gd, 165 Er and 203 In this case, the use is preferably therapeutic.

[0270] Pharmaceutical composition

[0271] As mentioned 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. It should be understood that the pharmaceutical composition preferably comprises a therapeutically effective amount of a PSMA-binding ligand and / or a complex, respectively. The pharmaceutical composition may further comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0272] As used herein, the terms "medicament" and "pharmaceutical composition" refer to the PSMA-binding ligand and / or complex of the invention and optionally one or more pharmaceutically acceptable carriers, i.e., excipients. The PSMA-binding ligand of the invention can be formulated as a pharmaceutically acceptable salt; such salts have been described above. The pharmaceutical composition is preferably administered regionally (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 administration route" refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Preferably, 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 also be administered by other routes.

[0273] In addition, the PSMA-binding ligands can be administered in combination with other drugs in a common pharmaceutical composition or as separate pharmaceutical compositions, wherein the separate pharmaceutical compositions can be provided in the form of a kit of parts. The PSMA-binding ligands are preferably administered in conventional dosage forms prepared by combining the drugs with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate for the desired formulation. It should be understood that the form and nature of the pharmaceutically acceptable carrier or diluent depends on the amount of active ingredient combined therewith, the route of administration, and other well-known variables.

[0274] One or more excipients must be acceptable in the sense of being compatible with the other ingredients of the preparation, and within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio. Preferably, the excipient is harmless to its recipient. The excipient used can be, for example, a solid, gel or liquid carrier. Exemplary solid carriers are lactose, terra alba, sucrose, talcum, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. Exemplary liquid carriers are phosphate buffered saline solutions, syrups, oils (e.g., peanut oil and olive oil), water, emulsions, various types of wetting agents, sterile solutions, etc. Similarly, the carrier or diluent can include time-delay materials well known in the art, such as single or with glyceryl monostearate or glyceryl distearate with wax. The suitable carrier includes those mentioned above and other carriers well known in the art, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. One or more diluents are selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, glucose solution and Hank's solution. In addition, the pharmaceutical composition or preparation may also include other carriers, adjuvants or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc. When using solutions for infusion or injection, they are preferably aqueous solutions or suspensions, which may be produced before use, such as from freeze-dried preparations containing active substances themselves or active substances with carriers (such as mannitol, lactose, glucose, albumin, etc.). Ready-made solutions are sterilized and mixed with excipients where appropriate, such as preservatives, stabilizers, emulsifiers, solubilizers, buffers and / or salts for regulating osmotic pressure. The sterilization can be obtained by aseptic filtration using a filter with a small pore size according to the composition that can be lyophilized where appropriate. A small amount of antibiotics can also be added to ensure sterile maintenance.

[0275] As will be appreciated by the skilled artisan, the dosage of the PSMA-binding ligand depends on a variety of factors. As is well known in the medical field, the dosage for any one patient may depend on many factors, including the patient's size, body surface area, age, the specific PSMA-binding ligand to be administered, sex, time and route of administration, general health, and other drugs administered concurrently. In addition, the dosage of the PSMA-binding ligand will generally also depend on the intended application, such as diagnostic and / or therapeutic applications, and the detection method used (if any).

[0276] In diagnostic applications, in particular, administration of a labeling dose is preferred, the term "labeling dose" relates to a dose of a PSMA-binding ligand capable of labeling PSMA-expressing tissues, preferably, specifically labeling PSMA-expressing tissues, more preferably capable of distinguishing cancerous tissues from non-cancerous tissues. In the case of detecting the PSMA-binding ligand by the dye portion of the PSMA-binding ligand, for example during surgery, preferably, the labeling dose is at least 200 μg, preferably at least 500 μg, more preferably at least 1 mg of the labeling compound per subject. Preferably, the labeling dose is from 0.2 mg to 100 mg, more preferably from 0.5 mg to 25 mg, more preferably from 1 mg to 10 mg, and most preferably from 1 mg to 5 mg of the labeling compound per subject. Thus, the labeled dose may 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 above labeled dose is preferably a labeled dose for human subjects. Also preferably, the labeled dose is preferably from 3µg / kg body weight to 300µg / kg body weight, more preferably from 5µg / kg body weight to 100µg / kg body weight, even more preferably from 7,5µg / kg body weight to 50µg / kg body weight, and even more preferably about 15µg / kg body weight. Also preferably, the dose is a single dose, i.e., exactly one dose, preferably administered within a time frame of at least 12 hours, preferably at least one day, more preferably at least two days; therefore, within the above time frame, preferably no further dose of the labeled compound is administered. Preferably, the labeling dose is administered to the patient from 0.25 hours to 48 hours prior to diagnosis and / or detection of the PSMA-binding ligand. In the case where the PSMA-binding ligand is a complex as described elsewhere herein and the PSMA-binding ligand is detected in a diagnostic application by binding to a radionuclide, the dose is calculated as the active dose as specified elsewhere herein. In the case of compound doses, the dose will depend largely on the specific activity of the radionuclide and may generally be about 5-fold to 1000-fold lower than the diagnostic doses specified above for detection by the dye moiety.

[0277] The therapeutically effective dose refers to the amount of PSMA-binding ligand used in the pharmaceutical composition of the present invention, which prevents, ameliorates or treats the symptoms associated with the diseases or conditions referred to in this specification. The therapeutic efficacy and toxicity of such PSMA-binding ligands can be determined by standard pharmaceutical procedures in cell culture or experimental animals, such as ED50 (the dose that is therapeutically effective in 50% of the population) and LD50 (the dose that is lethal to 50% of the population). The dose ratio between the therapeutic effect and the toxic effect is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. As understood by those skilled in the art, the dose in radiation therapy is usually expressed as an active dose, as described elsewhere herein. Progress can be monitored by regular assessment. The pharmaceutical compositions and formulations described herein are administered at least once to treat or prevent the diseases or conditions listed in this specification. However, the pharmaceutical composition may be administered more than once, for example one to ten times. Preferably, the frequency of the pharmaceutical composition may be administered once every one to six months, more preferably once every two to four months. Specific pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and contain at least one active PSMA-binding ligand as mentioned above in a mixture or otherwise in association with a pharmaceutically acceptable carrier or diluent. To prepare these specific pharmaceutical compositions, one or more active compounds are usually mixed with a carrier or diluent, or enclosed or wrapped in a capsule, sachet, cachet, paper or other suitable container or excipient. The resulting formulation should be adapted to the mode of administration, i.e. in the form of tablets, capsules, suppositories, solutions, suspensions, etc. Dosage recommendations should be indicated in the prescription instructions or instructions for use so that dosage adjustments can be made in advance according to the recipient under consideration.

[0278] The term "patient", as used herein, refers to a vertebrate, preferably a mammal, more preferably a human, monkey, cow, horse, cat or dog. Preferably, the mammal is a primate, more preferably a monkey, most preferably a human.

[0279] The dose of PSMA-binding ligand administered to a patient is preferably defined as the compound dose, i.e., the amount of PSMA-binding ligand administered to a patient. A preferred diagnostic compound dose is a total dose of 1-10 nmol / patient; thus, preferably, the diagnostic compound dose is from 0.02 to 0.1 nmol / kg body weight. A preferred therapeutic compound dose is a total dose of 10 to 100 nmol / patient; thus, preferably, the therapeutic compound dose is from 0.2 to 1 nmol / kg body weight.

[0280] As will be appreciated by the skilled person, the dose of the complex specified herein, i.e. the complex comprising, preferably consisting of, a radionuclide and a PSMA binding ligand, is preferably expressed as a compound dose as described above, preferably the same dose as described above. More preferably, the dose of the complex is expressed as an active dose, i.e. the amount of radioactivity administered to the patient. Preferably, the active dose is adjusted to avoid adverse reactions as described elsewhere herein. Taking into account the relevant factors specified elsewhere herein, in particular taking into account the treatment progress and / or adverse reactions observed for the individual patient, preferably a patient-specific dose, preferably a patient-specific active dose, is determined. Thus, preferably, the active dose is adjusted so that the organ-specific dose 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.

[0281] The effective amount can be administered to the patient at one time (single dose) at an active dose of from 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. Therefore, the preferred therapeutic dose in such a case is from 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 active dose ranges from about 10 to 30 MBq per administration, such as, for example, about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 MBq, or any range between any two of the above values. However, as described below, higher or lower doses are contemplated depending on the type of radiation emitted by the radionuclide and / or depending on the application. As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a PSMA-binding ligand, material, or composition comprising a PSMA-binding ligand of the invention, or an amount of other active ingredients, that is effective for producing 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. A therapeutically effective amount with respect to a PSMA-binding ligand of the invention means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. Used in connection with the PSMA-binding ligands of the invention, the term can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of another therapeutic agent or acts synergistically with another therapeutic agent.

[0282] According to a preferred embodiment, the radionuclide is a beta-emitter as described above, more preferably 177 Lu, and the use is diagnostic; in such a case, the active dose of the complex is preferably 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. More preferably, the radionuclide is a β-emitter as described above, more preferably 177 Lu, and for use in treatment, preferably the treatment of prostate cancer as described elsewhere herein; in such cases, the active dose of the complex is preferably at least 25 MBq / kg body weight, more preferably at least 50 MBq / kg body weight, most preferably at least 80 MBq / kg body weight. Thus, the preferred therapeutic dose in such cases is from 2 to 10 Gbq / patient, more preferably from 4 to 8 GBq / patient, most preferably about 6 GBq / patient.

[0283] More preferably, the radionuclide is an alpha-emitter as described above, more preferably 225 Ac, and the use is treatment, preferably the treatment of prostate cancer as described elsewhere herein; in such a case, the active dose of the complex is preferably in the range of from 25 kBq / kg to about 500 kBq / kg of the patient's body weight, more preferably, the active dose 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, most preferably at least 200 kBq / kg body weight. Therefore, preferably, in such a case, the active dose of the complex is from 75 to 500 kBq / kg body weight, more preferably from 100 to 400 kBq / kg body weight, still more preferably from 150 to 350 kBq / kg body weight, most preferably from 200 to 300 kBq / kg body weight.

[0284] 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, for use in diagnosis, preferably for diagnosis of a cell proliferative disease or disorder, in particular prostate cancer and / or its metastasis. 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 treatment or prevention of a cell proliferative disease or disorder, in particular prostate cancer and / or its metastasis.

[0285] As used herein, the term "diagnosis" refers to assessing whether a subject has a disease or condition, preferably a cell proliferative disease or condition. As will be appreciated by those skilled in the art, this assessment, although preferably so, may not generally be correct for 100% of the subjects being investigated. However, the term requires that a preferably statistically significant portion of the subject be correctly assessed to make a diagnosis. Those skilled in the art can use various well-known statistical evaluation tools (e.g., determination of confidence intervals, determination of p-values, Student's t-test, Mann-Whitney test, etc.) to effortlessly determine whether a portion is statistically significant. For details, see 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, diagnosis may include further diagnostic assessments, such as visual and / or manual inspection, determination of tumor biomarker concentrations in samples from the subject, X-ray examination, and the like. The term includes individual diagnosis of the patient as well as ongoing monitoring of the patient. Monitoring, i.e., diagnosing the presence or absence of a cell proliferative disease or symptoms associated with it at different time points, includes monitoring patients known to have a cell proliferative disease and monitoring subjects known to be at risk of developing a cell proliferative disease. In addition, monitoring may also be used to determine whether the patient has been successfully treated, or whether at least the symptoms of the cell proliferative disease can be improved over time by a certain therapy. In addition, the term also includes classifying the subject according to conventional classification schemes known to those skilled in the art (e.g., T1 to T4 staging). Accordingly, diagnosis may include determining the number and location of metastases, affected lymph nodes, and the like.

[0286] The terms "treating" and "treatment" refer to improving to a great extent the disease or condition referred to herein or the symptoms accompanying it. The treatment as used herein also includes complete restoration of health for the disease or condition described herein. It should be understood that, as the term is used herein, treatment may not be effective in all subjects to be treated. However, the term should require that, preferably, a statistically significant portion of the subjects suffering from the disease or condition described herein can be successfully treated. Without further explanation, a person skilled in the art can use various well-known statistical evaluation tools as described above to determine whether a portion is statistically significant. The terms "preventing" and "prevention" refer to maintaining health relative to the disease or condition described herein in a subject for a certain period of time. It is understood that the time period may depend on the amount of drug compound that has been administered and the individual factors of the subject discussed elsewhere in this specification. It should be understood that prevention may not be effective in all subjects treated with the PSMA-binding ligand according to the present invention. However, the term requires that, preferably, a statistically significant portion of the subjects of the cohort or population are effectively prevented from suffering from the disease or condition described herein or its accompanying symptoms. Preferably, in this case a cohort or population of subjects is envisioned that would normally (i.e. without the preventive measures according to the invention) develop a disease or condition as described herein. A person skilled in the art can readily determine whether a portion is statistically significant using the various well-known statistical evaluation tools discussed above.

[0287] Preferably, the treatment and / or prevention comprises administration of at least one PSMA-binding ligand and / or at least one complex as described elsewhere herein, more preferably at an active dose and / or compound dose as described above.

[0288] As used herein, the term "cell proliferative disorder" refers to a disease of animals, including humans, characterized by the uncontrolled growth of groups of somatic cells ("cancer cells"). This uncontrolled growth may be accompanied by invasion and destruction of surrounding tissues (infiltration), and may spread the cancer cells to other sites in the body (metastasis). Preferably, the term cancer also includes recurrence. Thus, preferably, the cancer is a solid cancer, a metastasis thereof, or a recurrence. Preferably, the cell proliferative disorder is an uncontrolled proliferation of cells, including cells expressing PSMA.

[0289] Thus, preferably, the cell proliferative disease is a PSMA-expressing cancer. The term "PSMA-expressing cancer" refers to any cancer whose cancer cells express prostate-specific membrane antigen (PSMA). Preferably, the cancer (or cancer cell) that can be treated according to the present invention is selected from prostate cancer, conventional renal cell carcinoma, bladder transitional cell carcinoma, lung cancer, testis-embryo carcinoma, neuroendocrine cancer, colon cancer, brain tumors and breast cancer, more preferably selected from PSMA-positive prostate cancer, PSMA-positive renal cell carcinoma, PSMA-positive bladder transitional cell carcinoma, PSMA-positive lung cancer, PSMA-positive testis-embryo carcinoma, PSMA-positive neuroendocrine cancer, PSMA-positive colon cancer, PSMA-positive brain tumors and PSMA-positive breast cancer. Whether a cancer is PSMA-positive can be established by a skilled person by methods known in the art, for example in vitro by immunostaining of a cancer sample, or in vivo, for example by PSMA scintigraphy, preferably both as described by Kratochwil et al. (2017, J Nucl Med 58(10):1624). In a particularly preferred aspect of the present invention, the PSMA-expressing cancer is prostate cancer or breast cancer, more preferably prostate cancer; even more preferably advanced prostate cancer. Thus, preferably, the cell proliferative disease is prostate cancer stage T2, more preferably stage T3, and most preferably stage T4. Preferably, the cell proliferative disease is metastatic prostate cancer, more preferably metastatic castration-resistant prostate cancer. Advantageously, it has been shown in the studies of the present invention that administration of the PSMA-binding ligands and / or complexes of the present invention to patients results in improved pharmacokinetic characteristics, in particular improved renal excretion, with substantially unchanged enrichment in target tissues, preferably cell proliferative tissues, more preferably cancerous tissues, compared to, for example, PSMA-617, which is commonly used at the same time. Due to the improved excretion, adverse side effects on non-target tissues, in particular salivary glands and / or lacrimal glands, can be avoided and / or reduced. This is advantageous because adverse side effects on the salivary glands are believed to be dose limiting (see Kratochwil et al. (2017, J Nucl Med 58(10):1624). Based on the findings of the present invention, larger amounts of compounds and / or complexes, in particular higher doses of radioactivity, can be administered to patients compared to compounds and complexes described in the art. Thus, the therapeutic window is wider than with currently used compounds. Also advantageously, the PSMA-binding ligands of the present invention provide improved diagnostics because of reduced co-labeling of irrelevant tissues and organs, in particular salivary glands, lacrimal glands and / or kidneys. Furthermore, by means of improved renal excretion, background and / or false positive labeling in diagnostic applications is reduced, preferably resulting in clearer identification of tissues expressing PSMA.

[0290] Thus, the PSMA-binding ligands and / or complexes of the present invention allow for the treatment of PSMA-expressing cancers (particularly prostate cancer) and their metastases, and / or for the diagnosis of PSMA-expressing cancers (particularly prostate cancer) and their metastases, wherein the PSMA-binding ligands and / or complexes show a favorable renal excretion profile, preferably with a favorable acceleration of clearance. Thus, adverse side effects on the kidneys of the patient are reduced. Therefore, the present invention also relates to the PSMA-binding ligands and / or complexes or pharmaceutical compositions of the present invention as described above for use in the treatment and / or prevention of PSMA-expressing cancers (particularly prostate cancer) and / or their metastases in a patient in need thereof, said subject suffering from renal failure.

[0291] As described above and in the Examples, the compounds described herein provide accelerated excretion while maintaining substantially the same enrichment in target tissues as, for example, PSMA-617, thereby avoiding or reducing adverse reactions in non-target tissues, preferably salivary glands and / or lacrimal glands. Thus, the treatments and / or diagnoses described herein have fewer or less severe adverse side effects, for example, on salivary glands and / or lacrimal glands, or are preferably not accompanied by adverse side effects, particularly on salivary glands and / or lacrimal glands.

[0292] Preferably, the PSMA-binding ligands of the present invention allow for reduction and / or avoidance of adverse side effects, such as on the salivary glands and / or lacrimal glands, while maintaining substantially unchanged therapeutic efficacy. In view of the above, one skilled in the art will appreciate that the PSMA-binding ligands described herein preferably further enable the use of higher concentrations of the compound and / or higher doses of radioactivity without at least increasing adverse reactions, which may be particularly useful in diagnostic applications to detect, for example, small metastases or small amounts of remaining tumor tissue, and / or may be particularly useful in therapy.

[0293] Thus, the PSMA-binding ligands and / or complexes of the present invention allow for the treatment of PSMA-expressing cancers, in particular prostate cancer, and their metastases, and / or for the diagnosis of PSMA-expressing cancers, in particular prostate cancer, and their metastases, wherein xerostomia is avoided.

[0294] 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 radioactive imaging agent in an amount sufficient for imaging, or a radiotherapeutic agent having a radionuclide as an element (i.e., radioiodine), or a radiometal chelate of the PSMA binding ligand, and a pharmaceutically acceptable radioactive excipient. The radioactive excipient should be suitable for injection or aspiration, such as human serum albumin; buffered aqueous solutions, such as tris (hydroxymethyl (hydromethyl)) -aminomethane (and its salts), phosphates, citrates, bicarbonates, etc.; sterile water saline; and counterion solutions containing chloride and or bicarbonate, or normal plasma cations such as calcium, potassium, sodium and magnesium.

[0295] The concentration of the imaging agent or therapeutic agent in the radioactive excipient should be sufficient to provide satisfactory imaging. Appropriate dosages have been described above. The imaging agent or therapeutic agent should be administered so as to remain in the patient's body for about 1 hour to 10 days, although longer and shorter time periods are acceptable. Thus, a convenient ampoule containing 1 to 10 mL of aqueous solution can be prepared.

[0296] Imaging can be performed in a manner known to those skilled in the art, such as by injecting a sufficient amount of the imaging composition to provide adequate imaging, followed by scanning using a suitable imaging or scanning machine (e.g., a tomography scanner or a gamma camera). In certain embodiments, a method of imaging an area of ​​a patient comprises the steps of: (i) administering to the patient a diagnostically effective amount of a PSMA-binding ligand complexed with a radionuclide; (ii) exposing the area of ​​the patient to a scanning device; and (ii) obtaining an image of the area of ​​the patient. In certain embodiments, the imaged area is the head or chest. In other embodiments, the PSMA-binding ligand and the complex target the PSMA protein. Thus, in some embodiments, a method of imaging a tissue (e.g., spleen tissue, kidney tissue, or tumor tissue expressing PSMA) is provided, comprising contacting the tissue with a complex synthesized by contacting a radionuclide and a PSMA-binding ligand, as described above.

[0297] The amount of a PSMA-binding ligand of the invention, or a complex comprising a PSMA-binding ligand, or a salt, solvate, stereoisomer, or tautomer thereof, administered to a patient depends on a number of physiological factors, which are known to the physician, including the nature of the imaging to be performed, the tissue being targeted for imaging or treatment, and the weight and medical history of the patient to be imaged or treated with the radiopharmaceutical.

[0298] Furthermore, the present invention relates to a PSMA-binding ligand and / or complex as described above or below as a marker for detecting cancerous tissue in a subject.

[0299] The term "marking agent" is understood by the skilled person. Preferably, the term relates to a compound that marks a PSMA-expressing tissue, more preferably a PSMA-expressing cancer tissue. The term "specific marker" of a PSMA-expressing tissue preferably relates to a marker that is able to distinguish between a PSMA-expressing tissue and a non-PSMA-expressing tissue (e.g., paracancerous tissue). Preferably, the distinction is achieved in vitro and / or in vivo, more preferably in vivo. Thus, preferably, the marker is able to distinguish between adjacent cancerous and non-cancerous tissues, for example, in the surgical field. Thus, a specific marker does not necessarily have to be able to distinguish between a PSMA-expressing tissue and any non-PSMA-expressing tissue in a subject; it is preferably sufficient if a PSMA-expressing tissue can be distinguished from a non-PSMA-expressing tissue adjacent to a PSMA-expressing tissue. Thus, the distinction can preferably be between cancerous and non-cancerous tissue in the abdominal cavity, more preferably within a range of up to 10 cm, more preferably up to 5 cm, even more preferably up to 2 cm from the cancerous tissue. Furthermore, it is preferably not required that the distinction be made in intact structures that can be easily identified from a subject (e.g., kidneys, liver, etc.). The differentiation is preferably performed by visual inspection (e.g. by a physician) or may be assisted by or performed by an optical device suitable for detecting the label contained in the labeling compound. Preferably, the specific labeling is a labeling of PSMA-expressing tissue, preferably a labeling of cancer cells, at least 2 times, more preferably at least 5 times, even more preferably at least 10 times, still more preferably at least 25 times, more preferably at least 100 times more intense than non-PSMA-expressing tissue. The labeling agent may be a PSMA-binding ligand as described herein or a metal chelator thereof, in particular a radioactive chelator thereof.

[0300] Furthermore, the present invention relates to PSMA-binding ligands, complexes or pharmaceutical compositions (all as described above) for use in fluorescence-guided surgery.

[0301] In view of the above, the present invention also provides methods of treating a patient by administering to the patient a therapeutically effective amount of a complex (as described above or below) to treat a patient suffering from a cell proliferative disease or disorder. In particular, the cell proliferative disease or disorder treated or imaged using a PSMA-binding ligand, pharmaceutical composition or radiopharmaceutical according to the present invention is cancer, such as prostate cancer and / or prostate cancer metastasis, such as in the lung, liver, kidney, bone, brain, spinal cord, bladder, etc.

[0302] The PSMA-binding ligands of the invention can be synthesized, for example, in solution as well as on solid phase using, for example, standard peptide coupling procedures (e.g., Fmoc solid phase coupling procedures). Preferably, in the last coupling step, the chelator is coupled to the remainder of the molecule, followed by a deprotection step and, in the case of solid phase chemistry, cleavage from the resin. However, other synthesis procedures are possible and known to the skilled person. A preferred synthesis of the PSMA-binding ligands of the invention is described in detail in the Examples section.

[0303] Furthermore, the invention relates to a method of marking PSMA-expressing tissue in a subject, comprising administering a PSMA-binding ligand to the subject.

[0304] The present invention also relates to a method for identifying PSMA-expressing tissue in a subject, comprising (a) marking the 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 a subject, comprising (a) marking the 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.

[0305] Furthermore, the present invention relates to the use of a PSMA binding ligand as described above in the manufacture of a diagnostic composition for marking PSMA expressing tissue, preferably marking cancer tissue in vivo and / or for the manufacture of a therapeutic composition for treating the proliferation of PSA expressing cells.

[0306] Summarizing the findings of the present invention, the following embodiments are preferred:

[0307] 1. 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 linker L comprising at least one amino acid X1 BQ ,in

[0308] - X1 is preferably a neutral amino acid, or

[0309] - X1 is preferably an N-alkylated amino acid, preferably an N-methylated amino acid,

[0310] More preferably, X1 is a neutral N-alkylated amino acid, more preferably a neutral N-methylated amino acid, and more preferably X1 is -N(CH3)-CH2-C(=O)-.

[0311] 2. A PSMA-binding ligand according to embodiment 1, having the structure

[0312]

[0313] (I)

[0314] Where Q is the PSMA binding motif,

[0315] A is a chelating agent residue,

[0316] Z is a dye group,

[0317] B is a branching group,

[0318] L BQ is a linker connecting Q and B, the linker comprising at least one amino acid X1,

[0319] L BZ is a connector, where n bz is 0 or 1,

[0320] And L BA is a connector, where n ba Is either 0 or 1.

[0321] 3. The PSMA-binding ligand according to embodiment 2, wherein B has the structure

[0322]

[0323] Wherein R5 is an alkyl group, preferably -(CH2) 2-4 group, and Y B To connect R5 and group -(L BZ ) bz -Z or -(L BA ) ba -A functional group, where Y B Preferred is -NH- or C(=O)-.

[0324] 4. The PSMA-binding ligand according to embodiment 4, which has one of the following structures (Ia) or (Ib), preferably structure (Ia): .

[0325] 5. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 5, wherein the PSMA-binding motif Q has the structure

[0326]

[0327] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2.

[0328] 6. The PSMA-binding ligand according to any one of embodiments 1 or 5, or a pharmaceutically acceptable salt or solvate thereof,

[0329] wherein 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-triazacyclononane-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononanephosphinic acid (TRAP), 1,4,7-triazacyclononanephosphinic 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 ]pentadecan-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 (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

[0330] 7. The PSMA-binding ligand according to any one of embodiments 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a chelator residue having a structure selected from the group consisting of:

[0331] , , and .

[0332] 8. The PSMA-binding ligand according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a chelator residue having the following structure:

[0333] .

[0334] 9. The PSMA-binding ligand according to embodiment 7 or 8, which has the structure (Ia)

[0335]

[0336] Wherein R5 is an alkyl group, preferably -(CH2)1- 10 group, more preferably –(CH2) 2-4 group, and Y B To connect R5 and group -(L BZ ) bz -Z or -(L BA ) ba -A functional group, where Y B Preferred is the group -NH- or -C(=O)-, more preferably -NH-.

[0337] 10. The PSMA-binding ligand according to any one of embodiments 1 to 9, wherein the dye group Z is a fluorescent dye comprising a fluorophore having excitation and emission spectra in the range of about 350 to 100 nm, preferably 400 nm to about 850 nm.

[0338] 11. The PSMA-binding ligand according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein the dye group Z is a fluorescent dye Z selected from the group consisting of AlexaFluor 3, AlexaFluor 5, AlexaFluor 350, AlexaFluor 405, AlexaFluor 430, AlexaFluor 488, AlexaFluor 500, AlexaFluor 514, AlexaFluor 532, AlexaFluor 546, AlexaFluor 555, AlexaFluor 568, AlexaFluor 594, AlexaFluor 610, AlexaFluor 633, AlexaFluor 647, AlexaFluor 660, AlexaFluor 680, AlexaFluor 700, and AlexaFluor 710. 750, Cy2, Cy3, Cy3B, Cy3.5, Cy5, sulfoCy5, Cy5.5 and Cy7, DyLight 350, DyLight 405, DyLight488, 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-dichlorotriazinyl)aminofluorescein), 6-FAM (6-carboxyfluorescein), 5(6)-FAM cadaverine (fluorescein-5(6)-carboxamide cadaverine), 5-FAM cadaverine (fluorescein-5-carboxamide cadaverine), 5(6)-FAM ethylenediamine (fluorescein-5(6)-carboxamide ethylenediamine), 5-FAM ethylenediamine (fluorescein-5(6)-carboxamide ethylenediamine), 5-FITC (FITC isomer I; fluorescein-5-isothiocyanate), 5-FITC cadaverine; fluorescein-5-maleimide; 5-IAF (5-iodoacetamide fluorescein), 6-JOE (6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein), 5-CR110 (5-carboxy Rhodamine 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), dansylcadaverine (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-benzofuran]-3,3'-dione), NBD (4-chloro-7-nitro-benzo-2-oxa-1,3-diazole), pyrromethene, Texas Red (1H,5H,11H,15H-xanthen[2,3,4-ij:5,6,7-i'j']biquinolizin-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-sulfonyl-, 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 methocy, 610CP, SiR-methyl, ATTO 390, ATTO 425, ATTO 465, ATTO 488, ATTO 495, ATTO 514, ATTO 520, ATTO532, ATTO Rho6G, ATTO 550, ATTO 565, ATTO Rho3B, ATTO Rho11, ATTO 14, ATTO 633, ATTO 647, ATTO 647N, ATTO 655, ATTO Oxa12, ATTO 665, ATTO 680, ATTO 700, ATTO 725, ATTO647N, STAR 600, STAR 635 P, STAR RED, 580CP-methoxy and derivatives thereof, preferably Z is selected from Atto590, Alexa594, STAR600, STAR 635P, STAR RED, 580CP-methoxy and derivatives thereof. The group consisting of RED, Atto647N, fluoroboron 650-X, 580CP-methoxy, 610CP, SiR-methyl, sulfoCy5, IRDye800CW and indocyanine green (ICG) and their derivatives, more preferably Z is sulfoCy5.

[0339] 12. The PSMA-binding ligand according to any one of embodiments 1 to 10, having the structure

[0340]

[0341] (I)

[0342] Where Q is the PSMA binding motif

[0343] A is a chelating agent residue,

[0344] Z is a dye group,

[0345] B is a branching group,

[0346] L BQis a linker connecting Q and B, the linker comprising at least one amino acid X1,

[0347] L BZ is a connector, where n bz is 0 or 1

[0348] And L BA is a connector, where n ba is 0 or 1,

[0349] And wherein the dye group Z is a fluorescent dye Z, which comprises the following structure or consists of the following structure: ,

[0350] in:

[0351] X 1z and X 4z Independently selected from -N=, -N(R 5z ) = and -C(R 6z ) = composed of groups;

[0352] X 2z and X 3z Independently selected from O, S, Se, N (R 5z ) and C(R 6z R 7z ) are preferably all C(CH3)2;

[0353] Y z is a linker that connects the two parts of (C) and allows electrons to be delocalized between the parts, where Y z Optionally contains a group (L z -) c Z 0 ;

[0354] az and bz are independently selected from the group consisting of 1, 2 and 3;

[0355] Each R 1z and each R 2z Independently selected from (L z -) c Z z , (L z -) c Z 0 and H; and two adjacent R 1z and / or two adjacent R 2z Aromatic rings may also be formed, which are optionally substituted by one or more (L z -) c Z z or (L z -) c Z 0replace;

[0356] R 3z , R 4z , R 5z , R 6z , R 7z , R 9z Independently selected from (L z -) c Z z ,(L z -) c Z 0 and H composed of groups;

[0357] Each c is independently 0 or 1;

[0358] Each L z Independently for 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, which is optionally substituted by -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)O- and T 1 one or more interruptions and / or terminations;

[0359] T 1 is phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, decahydronaphthyl, adamantyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl or 7- to 11-membered heterobicyclyl, wherein T 1 Optionally, one or more selected from halogen, CN, C(O)R 8z 、COOR 8z , OR 8z 、C(O)N(R 8z R 8az )、S(O)2N(R 8z R 8az )、S(O)N(R 8z R 8az )、S(O)2R 8z 、N(R 8z )S(O)2N(R 8az R 8bz ), SR 8z 、N(R 8z R 8az ), NO2; OC(O)R8z 、N(R 8z )C(O)R 8az 、N(R 8z )S(O)2R 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) (wherein the ring is at least partially saturated) or C 1-6 Alkyl is substituted by a substituent consisting of a group consisting of 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different;

[0360] Each Z z are 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)2OR 8 z、S(O)2O - 、S(O)2N(R 8z R 8az )、S(O)N(R 8z R 8az )、S(O)2R 8z 、S(O)R 8z 、N(R z )S(O)2N(R 8az R 8bz ), SR 8z 、N(R 8z R 8az )、NO2;P(O)(OR 8z )2、P(O)(OR 8z ) - 、OC(O)R 8z 、N(R 8z )C(O)R 8az 、N(R 8z )S(O)2R 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 orOC(O)N(R 8z R 8az );

[0361] R 8z , R 8az , R 8bz Independently selected from H or C 1-6 The group consisting of alkyl groups, where C 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different;

[0362] Z 0 is to connect the dye Z to the group –(L BZ ) bz -B's chemical bond,

[0363] The premise is R 1z , R 2z , R 3z , R 4z , R 5z , R 6z , R 7z , R 9z One of them is (L z -) c Z 0 or Y z Contains (L-) c Z 0 .

[0364] 13. The PSMA-binding ligand according to any one of embodiments 12, wherein the dye group Z has the structure -C(=O)-C 1 , and C 1 Selected from the group consisting of:

[0365] , , and ,

[0366] Where X - is a pharmaceutically acceptable negatively charged counterion; and wherein Y + It is a pharmaceutically acceptable positively charged counter ion.

[0367] 14. The PSMA-binding ligand according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein the PSMA ligand, preferably the linker L BQ , further comprising at least one amino acid structural unit AS a , where AS a Has the following structure:

[0368]

[0369] Where Q 1 Selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl.

[0370] 15. The PSMA-binding ligand according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the PSMA ligand, preferably the linker L BQ , comprising at least one amino acid structural unit AS b , where AS b With structure (b)

[0371] (b)

[0372] Where Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably Q 2 for

[0373] or

[0374] More preferably

[0375] .

[0376] 16. The PSMA-binding ligand according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein the linker L BQ Also contains at least one amino acid structural unit AS a and at least one amino acid structural unit AS b , where AS a With structure

[0377]

[0378] Where Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, and AS b With structure (b)

[0379] (b)

[0380] Where Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably wherein Q 2 for

[0381] or

[0382] More preferably

[0383] ,

[0384] Preferably, wherein the linker L BQ Also includes connection unit – (AS b ) q -AS a -, wherein q is an integer from 0 to 3, preferably wherein q is 1.

[0385] 17. The PSMA-binding ligand according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is linked to -(AS b ) q -AS a -, the PSMA-binding ligand comprises a structural unit

[0386] -–(AS b ) q -AS a -Q.

[0387] 18. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to embodiment 12, wherein the structural unit - L BQ –Q contains a structural unit having the following structure-(X 1 ) n1 –(AS b ) q -AS a --Q, preferably composed of a structural unit having the following structure:-(X 1 ) n1 –(AS b ) q -AS a --Q composition, 19.

[0389]

[0390] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0391] Q 1is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0392] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0393] and wherein q is an integer from 0 to 3,

[0394] And where X 1 is a methylated amino acid, preferably wherein X 1 is -N(CH3)-CH2-C(=O)-, and n1 is an integer from 0 to 25, preferably 5 to 15, more preferably 5 or 10, especially 10.

[0395] 20. The PSMA-binding ligand according to embodiment 13, or a pharmaceutically acceptable salt or solvate thereof, wherein Q 1 Preferably, Q comprises a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl. More preferably, Q 1 Selected from the group consisting of:

[0396] , , , , , , and ,

[0397] Preferably, Q 1 for .

[0398] 21. The PSMA-binding ligand according to any one of embodiments 13 or 14, wherein R 3 , R 2 and R 4 is –CO2H and R 1 For H.

[0399] 22. The PSMA-binding ligand according to any one of embodiments 13 to 15, wherein Q 2 for

[0400] or

[0401] Best .

[0402] 23. The PSMA-binding ligand according to any one of embodiments 1 to 22, wherein the ligand has the structure

[0403]

[0404] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0405] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0406] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0407] and wherein q is an integer from 0 to 3,

[0408] Where X 1 is a methylated amino acid, preferably wherein X 1 is -N(CH3)-CH2-C(=O)-, and n1 is an integer from 1 to 25, wherein

[0409] Z is a dye group,

[0410] L BZ is a connector, where n bz is 0 or 1

[0411] And L BA is a connector, where n ba is 0 or 1, preferably 0,

[0412] and wherein R5 is an alkyl group, preferably -(CH2) 2-4 group, and Y B To connect R5 and group -(L BA ) ba -A functional group, where Y B Preferred are the groups -NH- or -C(=O)-, more preferred are the -NH- groups.

[0413] 24. The PSMA-binding ligand according to any one of embodiments 1 to 22, wherein the ligand has the structure

[0414]

[0415] Where R1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0416] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0417] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0418] and wherein q is an integer from 0 to 3,

[0419] Where X 1 is a methylated amino acid, preferably wherein X 1 is -N(CH3)-CH2-C(=O)-, and n1 is an integer from 1 to 25,

[0420] And among them

[0421] Z is a dye group,

[0422] L BZ is a connector, where n bz is 0 or 1

[0423] And L BA is a connector, where n ba is 0 or 1,

[0424] and wherein R5 is an alkyl group, preferably -(CH2) 2-4 group, and Y B To connect R5 and group -(L BZ ) bz -Z functional group, where Y B Preferred are the groups -NH- or -C(=O)-, more preferred are the -NH- groups.

[0425] 25. The PSMA-binding ligand according to any one of embodiments 23 or 24, wherein L BQ and / or L Bz Contains at least one methylated amino acid.

[0426] 26. The PSMA-binding ligand according to embodiment 23, wherein the ligand has structure (IIIa)

[0427]

[0428] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0429] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0430] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0431] and wherein q is an integer from 0 to 3,

[0432] Where X 1 is a methylated amino acid, preferably wherein X 1 is -N(CH3)-CH2-C(=O)-, and n1 is an integer from 1 to 25, preferably 5 to 10, more preferably 10.

[0433] And among them

[0434] Z is a dye group,

[0435] L BZ is a connector, where n bz is 0 or 1

[0436] and wherein R5 is an alkyl group, preferably -(CH2) 2-4 Group.

[0437] 27. The PSMA-binding ligand according to embodiment 26, wherein L BZ comprising an amino acid sequence, and wherein Z is attached to L BZ N-terminus or attached to L BZ The functional group of the side chain of the amino acid present in the ester, provided that in the case where LBZ is attached to the side chain, the N-terminus is preferably acylated with the group -C(=O)-Rz, R z Preference is given to C10-C20 alkyl chains.

[0438] 28. The PSMA-binding ligand according to embodiment 26, wherein the amino acid sequence has the structure -(X 2bz ) n2bz -(X 1bz ) n1bz - and Z is attached to the N-terminus, and wherein X1z is a methylated amino acid, preferably wherein X 1z is -N(CH3)-CH2-C(=O)-, and n1bz is from 1 to 20, preferably 4 to 10, more preferably 5, and wherein X 2bz is a neutral amino acid, preferably β-Ala, and n2bz is from 1 to 20, preferably 1.

[0439] 29. The PSMA-binding ligand according to embodiment 26, wherein the amino acid sequence has the structure –(X 3bz ) n3bz -(X 1bz ) n1bz - and where X 1bz is a methylated amino acid, preferably wherein X 1bz is -N(CH3)-CH2-C(=O)-, and n1z is 1 to 20, preferably 4 to 10, more preferably 5, and wherein X 2bz is glutamic acid or lysine, preferably lysine and Z is attached to X 2bz , and n2bz is 1 to 20, preferably 1, and wherein the N terminus is preferably acylated.

[0440] 30. The PSMA-binding ligand according to any one of Embodiments 24, said ligand having structure (IIIb)

[0441]

[0442] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 and R 4 are independently selected from the group consisting of CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0443] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0444] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0445] and wherein q is an integer from 0 to 3,

[0446] Where X 1 is a methylated amino acid, preferably wherein X 1 is -N(CH3)-CH2-C(=O)-, and n1 is an integer from 1 to 25,

[0447] And among them

[0448] Z is a dye group,

[0449] L BZ is a connector, where n bz is 0 or 1, preferably 0,

[0450] And L BA is a connector, where n ba is 0 or 1,

[0451] and wherein R5 is an alkyl group, preferably -(CH2) 2-4 Group.

[0452] 31. A PSMA-binding ligand according to embodiment 30, wherein L BA comprising an amino acid sequence, and wherein A is attached to L BA N-terminus or attached to L BA The functional groups of the amino acid side chains present in BA In the case of attachment to a side chain, the N-terminus is preferably attached with a group -C(=O)-R z Acylation, R z Preference is given to C10-C20 alkyl chains.

[0453] 32. The PSMA-binding ligand according to embodiment 31, wherein the amino acid sequence has the structure -(X 2ba ) n2ba -(X 1ba ) n1ba - and A is attached to the N-terminus, and wherein X 1ba is a methylated amino acid, preferably wherein X 1ba is -N(CH3)-CH2-C(=O)-, and n1ba is from 1 to 20, preferably 4 to 10, more preferably 5, and wherein X 2ba is a neutral amino acid, preferably β-Ala, and n2ba is from 1 to 20, preferably 1.

[0454] 33. The PSMA ligand according to embodiment 1 has Figure 1 , Figure 2 or Figure 3 , preferably Figure 2 The structure shown is shown.

[0455] 34. A complex comprising

[0456] (a) radionuclides, and

[0457] (b) A PSMA-binding ligand according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt or solvate thereof.

[0458] 35. The complex according to embodiment 34, wherein the radionuclide is selected from the group consisting of: 89 Zr, 44 Sc, 111 ln, 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 Radionuclides of Fe and Pb (e.g. 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb).

[0459] 36. A pharmaceutical composition comprising a PSMA-binding ligand according to any one of embodiments 1 to 33 or a complex according to embodiment 34 or 35.

[0460] 37. 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 medicine, preferably for the treatment and / or prevention of PSMA-expressing cancers, in particular prostate cancer, and / or metastases thereof.

[0461] 38. The PSMA-binding ligand, complex or pharmaceutical composition for use according to embodiment 37, wherein adverse side effects on the kidney are reduced and / or avoided.

[0462] 39. The complex or pharmaceutical composition for use according to embodiment 37 or 38, wherein the radionuclide is an alpha-emitter, more preferably 225 Ac, and wherein preferably the active dose of the complex is at least 75 kBq / kg body weight, more preferably at least 100 kBq / kg body weight.

[0463] 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 diagnosis.

[0464] 41. A PSMA-binding ligand for use 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 metastases thereof.

[0465] 42. The complex or pharmaceutical composition for use according to embodiment 40 or 41, wherein the radionuclide is a β-emitter, more preferably 177 Lu, and wherein preferably the active dose 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.

[0466] 43. A PSMA-binding ligand for use 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.

[0467] 44. A method for identifying tumor tissue to be removed by surgery++++, the method comprising detecting the presence of fluorescence in tissue of a patient to which a PSMA-binding ligand or complex or pharmaceutical composition according to claim 23 has been administered.

[0468] 45. The PSMA ligand according to embodiment 1, which has one of the following structures:

[0469]

[0470]

[0471] . BRIEF DESCRIPTION OF THE DRAWINGS

[0472] Figure 1: Structure of Glu-urea-Lys-2-Nal-Chx-Sar5-Lys(DOTA)-Sar5-bAla-sulfoCy5 (BP-1).

[0473] Figure 2 : Structure of Glu-urea-Lys-2-Nal-Chx-Sar5-Lys(DOTA)-Sar5-bAla-sulfoCy5 (BP-2).

[0474] Figure 3 : Structure of Glu-urea-Lys-2-Nal-Chx-Sar5-Lys(sulfoCy5)-Sar5-bAla-DOTA (BP-4).

[0475] Figure 4a -c: Pharmacokinetic study using small animal PET imaging. 0.5 nmol was injected into LNCaP and PC-3 tumor-bearing athymic nude mice (right torso) 68 Time-activity curves of non-target organs and tumors after Ga-labeled BP-2, up to 60 min post pi. SUV = standardized uptake value.

[0476] Figure 5 : Optical imaging of tumor anatomy. BALB / c nu / nu mice (n=1) bearing LNCaP (A) and PC-3 (B) tumors were injected with 0.5 nmol 68 Optical imaging was performed after Ga-labeled BP-2. Mice were sacrificed 2 h pi after PET imaging, and fluorescence was detected using the Odyssey CLx system (excitation wavelength 700 nm). Fluorescence intensity is represented in the heat map coloring. Tissue located on the imaging system surface during fluorescence detection explains minor artifacts in the fluorescence images. PSMA + -Tumors show high fluorescence signal ( Figure 5 A), while in PSMA - -Tumors ( Figure 5 B) Only negligible fluorescence signal of BP-2 was detected. DETAILED DESCRIPTION

[0477] The following examples are only used to illustrate the present invention. In any case, they should not be interpreted as limiting the scope of the present invention.

[0478] Experimental procedures

[0479] All commercially available chemicals were of analytical grade and used without further purification. 68 Ge / 68Ga generator (Galliapharm® Ge-68 / Ga-68 generator, Eckert & Ziegler) was obtained 68 Ga (half-life 68 minutes), and 177 Lu (half-life 6.6 d) was purchased from ITG. Compounds were purified using semipreparative reversed-phase high-performance liquid chromatography (RP-HPLC; Chromolith SemiPrep 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). Analytical HPLC runs were performed at 2 mL / min using a linear gradient (5% A (0.1% TFA in water) to 100% B (0.1% TFA in CH3CN)) in 10 min. System Agilent Technologies 1200 series equipped with variable UV and gamma detectors (Ramona*, Elysia). UV absorbance was measured at 220 and 280 nm, respectively. For mass spectrometry analysis, MALDI-MS (Daltonics Microflex, Bruker Daltonics, Bremen, Germany) was used.

[0480] Glu-urea-Lys-2-Nal-Chx-Sar5-Lys(DOTA)-Sar5-bAla-sulfoCy5 (BP-1), Glu-urea-Lys-2-Nal-Chx-Sar 10 Synthesis of -Lys(DOTA)-Sar5-bAla-sulfoCy5 (BP-2) and Glu-urea-Lys-2-Nal-Chx-Sar5-Lys(sulfoCy5)-Sar5-bAla-DOTA (BP-4)

[0481] The synthesis of the pharmacophore Glu-urea-Lys was performed as described previously (1). Briefly, the synthesis began with the formation of the 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 h under gentle stirring. The resin was filtered off and the allyloxy protecting group was removed by reacting twice with Pd(PPh3)4 (0.3 eq) and morpholine (15 eq) under ambient conditions (1 h, RT).

[0482] Subsequently, the linker between the PSMA pharmacophore and the chelator / dye was introduced by a standardized Fmoc solid phase protocol. In the first step, Fmoc-2-NaI-OH and N-Fmoc-tranexamic acid (4 equivalents each) were coupled with HATU (4 equivalents) and DIPEA (10 equivalents) in DMF. Depending on the amino acid sequence, Fmoc-sarcosine was coupled 5 and 10 times, respectively, and then Fmoc-Lys(Alloc)-OH was coupled with HATU (4 equivalents) and DIPEA (10 equivalents) in DMF. Subsequently, Fmoc-sarcosine was coupled five times, and then Boc-β-alanine was coupled with HATU (4 equivalents) and DIPEA (10 equivalents) in DMF.

[0483] For the synthesis of BP-1 and BP-2, the allyloxy protecting group was removed by reacting twice with Pd(PPh3)4 (0.3 eq.) and morpholine (15 eq.) under ambient conditions (1 h, RT). Bis(tBu)DOTA (bis(tBu) ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 eq.) was then coupled with HATU (4 eq.) and DIPEA (10 eq.) in DMF. The precursor was cleaved from the resin using TFA / TIPS / H2O (95 / 2.5 / 2.5, v / v / v) at room temperature for 3 h and purified by RP-HPLC using a Chromolith RP-18e column (100 × 10 mm; Merck, Darmstadt, Germany) and identified by mass spectrometry. Finally, sulfoCy5-NHS ester (2.5 mg) was conjugated to the precursor in DMF at room temperature for 24 h, and the final products (BP-1 and BP-2) were purified by RP-HPLC using a Chromolith RP-18e column (100 × 10 mm; Merck, Darmstadt, Germany) and identified by mass spectrometry.

[0484] To synthesize BP-4, bis(tBu)DOTA (bis(tBu) ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 equiv) was coupled with HATU (4 equiv) and DIPEA (10 equiv) in DMF to form Glu-urea-Lys-2-Nal-Chx-Sar5-Lys(Alloc)-Sar5-bAla. The allyloxy protecting group was then removed by reacting twice with Pd(PPh3)4 (0.3 equiv) and morpholine (15 equiv) under ambient conditions (1 h, RT). The precursor was cleaved from the resin using TFA / TIPS / H2O (95 / 2.5 / 2.5, v / v / v) at room temperature for 3 h and lyophilized. Finally, sulfoCy5-NHS ester (2.5 mg) was conjugated to the precursor in DMF at room temperature for 24 h, and the final product (BP-4) was purified by RP-HPLC using a Chromolith RP-18e column (100 × 10 mm; Merck, Darmstadt, Germany) and identified by mass spectrometry.

[0485] 68 Ga - Mark

[0486] The precursor peptide [5 nmol in HEPES buffer (1 M, pH 4, 40 µL)] was added to 40 µL [ 68 Ga]Ga 3+ The eluent (~40 MBq) and ascorbic acid (5.68 mM, 0.8 µL) were added. The pH was adjusted to 3.8-4.2 with 30% NaOH. The reaction mixture was incubated at 95 °C for 15 min. The radiochemical yield (RCY) was determined by RP-HPLC.

[0487] 177 Lu - Mark

[0488] The precursor peptide [2 nmol in HEPES buffer (0.1 M, pH 7, 50 µL)] was added to 10 µL [ 177 Lu]LuCl3 (~10-30MBq, 0.04 M HCl) and ascorbic acid (5.68 mM, 0.7µL). The reaction mixture was incubated at 95°C for 15 minutes. The radiochemical yield (RCY) was determined by RP-HPLC.

[0489] Cell culture

[0490] PSMA was cultured in RPMI medium supplemented with 10% fetal bovine serum and 2 mmol / L L-glutamine (both from PAA). +LNCaP cells (CRL-1740; ATCC; PSMA positive) and PC-3 cells (CRL-1435; ATCC; PSMA negative) were grown at 37°C in a humidified atmosphere containing 5% CO2 and harvested using trypsin-ethylenediaminetetraacetic acid (trypsin-EDTA; 0.25% trypsin, 0.02% EDTA, Invitrogen).

[0491] Cell binding and internalization

[0492] Competitive cell binding assays and internalization experiments were performed as described previously (2). Briefly, the cells (10 5 cells / well) and 0.8 nM 68 The cells were incubated with a solution of Ga-labeled radioligand [Glu-urea-Lys(Ahx)]2-HBED-CC (PSMA-10, precursor ordered from Radeberg ABX, Germany). After incubation, the mixture was removed and the wells were washed three times with PBS using a multiscreen 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) value was calculated by fitting the data using a nonlinear regression algorithm (GraphPad software).

[0493] For internalization experiments, 10 5 Cells / well were seeded in 24-well cell culture plates coated with poly-L-lysine. After washing, cells were incubated with 30 nM radiolabeled compounds at 37°C for 45 min. Cellular uptake was terminated by washing three times with 1 mL of ice-cold PBS. To remove surface-bound radioactivity, cells were incubated twice with 0.5 mL of glycine-HCl in PBS (50 mM, pH = 2.8) for 5 min. Cells were washed with 1 mL of ice-cold PBS and dissolved with 0.3 N NaOH (0.5 mL). Surface-bound and internalized fractions were measured in a gamma counter. Cellular uptake was measured as binding to 10 5 The percentage of the initial added radioactivity of the cells [%ID / 10 5 cells] calculation.

[0494] Biodistribution

[0495] For experimental tumor models, 5 × 10 6LNCaP or PC-3 (in 50% Matrigel; Becton-Dickinson) cells were inoculated subcutaneously in the right trunk of 7- to 8-week-old male BALB / c nu / nu mice (Janvier). Tumors were allowed to grow to approximately 1 cm 3 Size. 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 performed in accordance with the current legislation of the Federal Republic of Germany.

[0496] PET / MR and optical imaging

[0497] For imaging studies, mice were anesthetized (2% isoflurane) and 0.5 nmol 68 Ga-labeled compounds were injected into the tail vein in 0.9% NaCl (pH 7). PET imaging was performed using a µPET / MRI scanner (BioSpec 3T, Bruker) with dynamic scanning for 60 min. 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 represented in the time-activity curve were used as SUV 体重 Mice were sacrificed after PET / MR imaging, and optical imaging of subcutaneous tumors and organs of interest was performed using the Odyssey CLx system (LI-COR Biosciences, excitation wavelength 700 nm). All animal experiments were performed in accordance with the current laws of the Federal Republic of Germany.

[0498] Statistics

[0499] All experiments were performed at least three times and repeated at least three times. Quantitative data are presented as mean ± SD. Where applicable, mean values ​​were compared using Student's t test. P values ​​< 0.05 were considered statistically significant.

[0500] result

[0501] In vitro characterization

[0502] The final products were identified by reversed-phase HPLC / matrix-assisted laser desorption / ionization mass spectrometry. 68 Ga and 177 Lu complexation resulted in radiochemical yields greater than 95%. All compounds showed high PSMA binding affinity in the nanomolar range, which was reduced compared to the control PSMA-617 (Table 1)(3).68 The Ga-labeled compounds all showed PSMA-specific cell surface binding and specific internalization comparable to that of PSMA-617.

[0503] Table 1. Cellular binding and internalization data of compounds*. Using PSMA + Compound affinity for PSMA and internalization properties of compounds were determined in vitro using LNCaP cells. For all compounds, PSMA-specific internalization and binding affinity to PSMA were detected in the nanomolar range.

[0504]

[0505] *Data are expressed as mean ± SD (n = 3), †68 Ga-labeled compounds; k of PSMA-617 i Values ​​are from Benesova et al. (3). Specific cellular uptake was determined by blocking with 500 µM 2-PMPA. Values ​​are expressed as binding to 10 5 The percentage of applied radioactivity (AR) per cell. ‡ Radioligand: 68 Ga-PSMA-10 (K d : 3.8 ±1.8 nM , c 放射性配体 :0.8 nM)

[0506] In vivo characterization

[0507] All tested 177 Lu-labeled compounds all showed PSMA-specific tumor uptake in LNCaP xenograft tumors (p>0.05), compared with the reference compound 177 Lu-PSMA-617 (8.47 ± 4.09% ID / g) and 68 Compared with Ga-Glu-urea-Lys-2-Nal-Chx-Lys(IRDye800CW)-DOTA(IRDye800CW)-DOTA (4.13 ± 0.15 %ID / g), there was no significant difference at 1 h pi (Table 2) (4). 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 tested compounds 177 Lu-BP-1 and 177The renal uptake of 177Lu-BP-2 (19.05±9.52%ID / g) was surprisingly significantly reduced compared to Lu-BP-4. At 1 h p.i., uptake of BP-2 was found to be comparable to the other tested compounds in muscle, blood, spleen, lung, and liver (Table 3). Rapid renal clearance was confirmed by the further reduction in BP-2 uptake found in the kidney (4.61±0.45%ID / g) accompanied by reduced uptake in, for example, blood and spleen at 2 h p.i. There was no significant difference in tumor uptake at 2 h p.i. compared to 1 h p.i., suggesting enrichment of the tracer over time. Tumor specificity of BP-2 was confirmed in PC-3 tumor-bearing mice, showing only negligible tumor uptake at 1 h p.i. (Table 2).

[0508] Table 2 1 hour 0.06 nmol 177 Organ distribution of Lu-labeled compounds in tumor-bearing BALB / c nu / nu mice*.

[0509]

[0510] *Data are expressed as mean % ID / g tissue ± SD (n = 3, for BP-2 n = 4) and tumor to organ ratio

[0511] Table 3 0.06 nmol 2 hours after pi 177 Organ distribution of Lu-labeled BP-2 in LNCaP-tumor-bearing BALB / c nu / nu mice*.

[0512]

[0513] *Data are expressed as mean %ID / g tissue ± SD (n = 3) and tumor to organ ratio

[0514] Organ distribution was confirmed by PET / MR imaging. BP-2 has enhanced pharmacokinetic properties compared to PSMA-617, which is characterized by accelerated excretion properties. The tumor targeting properties of BP-2 were found to be comparable to the parental control PSMA-617 (Figure 4).

[0515] Optical imaging confirmed the finding of PSMA-specific tumor enrichment ( Figure 5 Here, PSMA + -Tumors show high fluorescence signal ( Figure 5 A), while in PSMA - - In tumors ( Figure 5 B) Only negligible fluorescence signal of BP-2 was detected.

[0516] References

[0517] 1. Schafer M, Bauder-Wust U, Leotta K, et al. A dimerized urea-basedinhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging ofprostate cancer. EJNMMI Res. 2012;2:23.

[0518] 2. Eder M, Schafer M, Bauder-Wust U, et al. (68)Ga-Complexlipophilicity and the targeting property of a urea-based PSMA inhibitor forPET imaging. Bioconjug Chem. 2012;23:688-697.

[0519] 3. Benesova M, Bauder-Wust U, Schafer M, et al. Linker ModificationStrategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targetingand Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors. J MedChem. 2016;59:1761-1775.

[0520] 4. Benesova M, Schafer M, Bauder-Wust U, et al. PreclinicalEvaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with OptimizedLinker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. J NuclMed. 2015;56:914-920.

Claims

1. 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 linker L BQ , the at least one connector L BQ It comprises at least one amino acid X1, preferably at least one N-alkylated amino acid, more preferably wherein the amino acid X1 is -N(CH3)-CH2-C(=O)-.

2. The PSMA-binding ligand according to claim 1, having the structure （I） wherein Q is the PSMA binding motif, A is the chelating agent residue, Z is the dye group, B is a branching group, L BQ is a linker connecting Q and B, the linker comprising at least one amino acid X1, L BZ is a connector, where n bz is 0 or 1, And L BA is a connector, where n ba Is either 0 or 1.

3. The PSMA-binding ligand according to claim 2, wherein B has the structure Wherein R5 is an alkyl group, preferably -(CH2) 2-4 group, and Y B To connect R5 and group -(L BZ ) bz -Z or -(L BA ) ba -A functional group, where Y B Preferred is the group -NH- or C(=O)-.

4. The PSMA-binding ligand according to claim 3, which has one of the following structures (Ia) or (Ib), preferably structure (Ia): .

5. The PSMA-binding ligand according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein 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-triazacyclononane-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononanephosphinic acid (TRAP), 1,4,7-triazacyclononanephosphinic 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 ]pentadecan-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 (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

6. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 5, wherein A is a chelator residue having the structure 。 7. The PSMA ligand according to claim 2, wherein the dye group Z is a fluorescent dye Z, and the fluorescent dye Z comprises the following structure, preferably consists of the following structure: ， in: X 1z and X 4z Independently selected from -N=, -N(R 5z ) = and -C(R 6z ) = composed of groups; X 2z and X 3z Independently selected from O, S, Se, N (R 5z ) and C(R 6z R 7z ), preferably both are C(CH3)2; Y z is a linker that connects the two parts of (C) and allows electron delocalization between the parts, where Y z Optionally contains a 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 Independently selected from (L z -) c Z z ,(L z -) c Z 0 and H; and two adjacent R 1z and / or two adjacent R 2z It is also possible to form an aromatic ring, which is optionally substituted by one or more (L z -) c Z z or (L z -) c Z 0 replace; R 3z , R 4z , R 5z , R 6z , R 7z , R 9z Independently selected from (L z -) c Z z ,(L z -) c Z 0 and H composed of groups; Each c is independently 0 or 1; Each L z Independently for 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, which is optionally substituted by -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)O- and T 1 one or more interruptions and / or terminations; T 1 is phenyl, naphthyl, indenyl, indanyl, tetrahydronaphthyl, decahydronaphthyl, adamantyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl or 7- to 11-membered heterobicyclyl, wherein T 1 Optionally substituted with one or more substituents selected from the group consisting of halogen, CN, C(O)R 8z 、COOR 8z , OR 8z 、C(O)N(R 8z R 8az )、S(O)2N(R 8z R 8az )、S(O)N(R 8z R 8az )、S(O)2R 8z 、N(R 8z )S(O)2N(R 8az R 8bz ), SR 8z 、N(R 8z R 8az ), NO2; OC(O)R 8z 、N(R 8z )C(O)R 8az 、N(R 8z )S(O)2R 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 (=0), wherein the ring is at least partially saturated, or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different; 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)2OR 8 , S(O)2O - , S(O)2N(R 8z R 8az ), S(O)N(R 8z R 8az ), S(O)2R 8z , S(O)R 8z , N(R z )S(O)2N(R 8az R 8bz ), SR 8z , N(R 8z R 8az ), NO2; P(O)(OR 8z )2, P(O)(OR 8z )O - , OC(O)R 8z , N(R 8z )C(O)R 8az , N(R 8z )S(O)2R 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 ); R 8z , R 8az , R 8bz Independently selected from H or C 1-6 The group consisting of alkyl groups, where C 1-6 The alkyl group is optionally substituted with one or more halogens, which may be the same or different; Z 0 is to connect the dye Z to the group –(L BZ ) bz -B's chemical bond, The premise is R 1z , R 2z , R 3z , R 4z , R 5z , R 6z , R 7z , R 9z One of them is (L z -) c Z 0 or Y z Contains (L-) c Z 0 .

8. The PSMA-binding ligand of claim 1, wherein the ligand has structure (IIIa) wherein R1 is H or -CH3, preferably H, wherein R2, R3 and R4 are independently selected from the group consisting of -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2, Q1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, Q2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, and wherein q is an integer from 0 to 3, wherein X1 is a methylated amino acid, preferably wherein X1 is -N(CH3)-CH2-C(=O)-, and n1 is an integer from 1 to 25, preferably 5 to 10, more preferably 10, And among them Z is the dye group, L BZ is a connector, where n bz is 0 or 1, And wherein R5 is an alkyl group, preferably a -(CH2)2-4 group.

9. A complex comprising (a) radionuclides, and (b) The PSMA-binding ligand according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof.

10. The complex according to claim 9, wherein The radionuclide is selected from the group consisting of: 89 Zr, 44 Sc, 111 ln, 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 2. 52 Fe, 59 Radionuclides of Fe and Pb (e.g. 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb), more preferably selected from 90 Y. 68 Ga, 177 Lu, 225 Ac and 213 More preferably, the radionuclide is 177 Lu or 225 Ac.

11. A pharmaceutical composition comprising a PSMA-binding ligand according to any one of claims 1 to 8 or a complex according to claim 9 or 10.

12. A PSMA-binding ligand according to any one of claims 1 to 8, a complex according to claim 9 or 10 or a pharmaceutical composition according to claim 11 for use in medicine, preferably for the treatment and / or prevention of PSMA-expressing cancers, in particular prostate cancer and / or metastases thereof.

13. The PSMA-binding ligand, complex or pharmaceutical composition for use according to claim 12, wherein adverse side effects on the kidney are reduced and / or avoided.

14. A PSMA-binding ligand according to any one of claims 1 to 8, a complex according to claim 9 or 10 or a pharmaceutical composition according to claim 11 for use in diagnosis.

15. A PSMA-binding ligand according to any one of claims 1 to 8, a complex according to claim 9 or 10 or a pharmaceutical composition according to claim 11 for use in the diagnosis of cancer, preferably the diagnosis of PSMA-expressing cancer, in particular the diagnosis of prostate cancer and / or metastases thereof.

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