Prostate specific membrane antigen (PSMA) ligands

Abstract

The present invention relates generally to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states of PSMA-expressing cancers, in particular prostate cancers, and metastases thereof. More particularly, the present invention relates to PSMA binding ligands comprising a PSMA binding motif Q and a chelating agent residue A linked via at least one linker LAQ comprising at least one neutral amino acid X1 optionally N-alkylated, or a pharmaceutically acceptable salt or solvate thereof, and uses of said PSMA binding ligands.

Description

Technical Field

[0001] The present invention relates generally to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states of PSMA-expressing cancers, particularly 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 have prostate cancer, and it is estimated that one in six men aged 55 to 85 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 this disease is second only to lung cancer. Currently, imaging methods with high anatomical resolution, such as computed tomography (CT), magnetic resonance (MR) imaging, and ultrasound, dominate clinical imaging of prostate cancer. It is estimated that $2 billion is spent annually worldwide on surgery, radiation, drug therapy, and minimally invasive treatments for prostate cancer. For the treatment of localized prostate cancer, radical prostatectomy with lymph node dissection is an established curative strategy. However, precise localization and delineation of tumor margins and metastases remain challenging. There is currently no effective therapy 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 a greater number of normal constituent proteins than normal cells. The expression of different proteins on the surface of tumor cells provides an opportunity to diagnose and characterize diseases 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 for imaging and treating tumors under non-invasive conditions. A series of promising new low molecular weight imaging agents target 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] Various experimental low-molecular-weight PCa imaging agents are currently under clinical investigation, 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-L-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.; 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] low urinary excretion of choline, 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 nearly all PCa become androgen-independent over time. PSMA has the standard of being 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 comparable to glutamate carboxypeptidase II (GCPII) (which is called "brain PSMA") and can regulate glutamatergic transmission by cleaving N-acetylaspartate glutamate (NAAG) into N-acetylaspartate (NAA) and glutamate (Nan, F. et al. J Med Chem 2000, 43, 772-774). Up to 10 of these cells are present in each cancer cell. 6 The PSMA molecule was identified in 24 samples, further indicating that it is an ideal target for imaging and therapy using radionuclide-based techniques (Tasch, J. et al. Crit Rev Immunol 2001, 21, 249-261).

[0006] A radioimmunoconjugate of the anti-PSMA monoclonal antibody (mAb) 7E11, referred to as Scans are currently used to diagnose prostate cancer metastasis and recurrence. However, this agent often produces 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 animal PSMA-positive prostate tumor models. However, diagnosis and tumor detection using monoclonal antibodies are limited by the low penetration of monoclonal antibodies in solid tumors.

[0007] Selective targeting of cancer cells using radiopharmaceuticals is challenging, both for imaging and therapeutic purposes. A variety of radionuclides are known to be used 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] In WO 2015 / 055318, novel imaging agents with improved tumor targeting and pharmacokinetics are described. These compounds contain a motif that specifically binds to the cell membrane of cancer cells, wherein the motif includes prostate-specific membrane antigen (PSMA), i.e. the glutamic acid-urea-lysine motif mentioned above. The preferred molecules described in WO 2015 / 055318 also contain a linker that is bound to the carboxylic acid group of DOTA as a chelator via an amide bond. Some of these compounds have been shown to be promising drugs for specific targeting of prostate tumors. These compounds are used 177 Lu labeling (for therapeutic purposes) or 68 Ga labels (for diagnostic purposes) and allows visualization and targeting of prostate cancer (for radiotherapy purposes).

[0009] However, in the therapeutic application of radiolabeled PSMA inhibitors, organs with physiological expression of PSMA have been shown to be dose-limiting and thus minimize the success rate of treatment. In particular, high renal and salivary gland uptake of radiolabeled PSMA inhibitor substances is evident, which can produce 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], a compound that has been used clinically with 177Lu or 225Ac for internal radiation therapy of prostate cancer. However, reduction of uptake in the salivary glands and lacrimal glands has not yet been achieved and is still described as critical and dose-limiting in early clinical work. In a first-in-human study using 225Ac-PSMA-617, two patients with extremely advanced and terminal disease showed complete remission. In both patients, PSA values ​​were below the detectable limit. Complete response was confirmed by accompanying diagnostic records using 68Ga-PSMA-11.

[0010] As already mentioned above, the massive 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 therapy with 225Ac. For example, the resulting dry mouth represents a dose-limiting side effect. To address this problem, it was proposed, for example in WO 2020 / 165420A1, to improve the tissue specificity of the PSMA ligands.

[0011] Nonetheless, there remains a need for improved PSMA ligands that provide advantageous options for the detection, treatment and management of PSMA-expressing cancers, particularly prostate cancer, and which preferably exhibit lower side effects and / or improved specificity in labeling and / or radiotherapy. Summary of the invention

[0012] The solution to this object is achieved by providing the embodiments characterized by the claims.

[0013] The present inventors have discovered novel PSMA-binding ligands that are useful and advantageous radiopharmaceuticals and that can be used in nuclear medicine as tracers, imaging agents, and for the treatment of various disease states in PSMA-expressing cancers, particularly prostate cancer.

[0014] These PSMA-binding ligands are described in more detail below.

[0015] In particular, the present invention relates to a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising: AQ The PSMA binding motif Q and the chelator residue A are connected, and the linker L AQ The invention comprises at least one neutral amino acid X1 which is optionally N-alkylated, wherein X1 is preferably selected from the group consisting of: optionally N-alkylated, Gly, Ala, βAla, Phe, aminocaproic acid (Ahx=-NH-(CH2)5-C(=O)-) and an amino acid comprising at least one -(CH2-CH2-O)- group between the N-terminus and the C-terminus, or wherein X1 is Tyr, more preferably, wherein X1 is selected from the group consisting of: Gly, Ala, βAla, Phe and an amino acid having –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 An amino acid residue of a -C(=O)- structure, wherein x1 is an integer in the range of 0 to 15, and y1 is 1 or 2, or X1 is Tyr.

[0016] In particular, the present invention relates to a PSMA-binding ligand having structure (I)

[0017] AL AQ -Q(I)

[0018] wherein the PSMA binding motif Q and the chelator residue A are linked via at least one linker L AQ Connect the connector L AQ Includes at least one neutral amino acid X1.

[0019] Furthermore, the present invention relates to a complex comprising

[0020] (a) radionuclides, and

[0021] (b) a PSMA-binding ligand as described above or below, or a pharmaceutically acceptable salt or solvate thereof.

[0022] 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.

[0023] Furthermore, the present invention relates to 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, or a pharmaceutical composition as described above or below, for use in treating or preventing PSMA-expressing cancer, in particular prostate cancer and / or its metastasis.

[0024] As used below, the terms "having", "comprising" or "including" or any arbitrary grammatical variants thereof are used in a non-exclusive manner. Thus, these terms may refer both to situations in which, in addition to the features introduced by these terms, no other features are present in the entity described in this context, and also to situations in which one or more other features are present. As an example, the expressions "A has B", "A comprises B" and "A includes B" may refer both to situations in which, in addition to B, no other elements are present in A (i.e., situations in which A is completely and exclusively composed of B), and also to situations in which, in addition to B, one or more other elements (such as element C, elements C and D or even other elements) are present in entity A. In addition, as understood by the skilled person, the expressions "comprising a" and "comprising one" preferably mean "comprising one (individual) or more (individuals)", i.e., equivalent to "comprising at least one (individual)".

[0025] In addition, as used below, the terms "preferably", "more preferably", "most preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features without limiting other 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. As the skilled person will recognize, the present invention can be implemented by using alternative features. Similarly, the features introduced by "in one embodiment" or similar expressions are intended to be optional features, without imposing any limitations on other embodiments of the invention, without imposing any limitations on the scope of the invention, and without imposing any limitations on the possibility of combining the features introduced in this way with other optional or non-optional features of the invention.

[0026] As used herein, if not otherwise specified, the term "standard conditions" refers to IUPAC standard ambient temperature and pressure (SATP) conditions, i.e., preferably a temperature of 25°C and an absolute pressure of 100 kPa; more preferably, standard conditions include a pH of 7. In addition, if not otherwise specified, the term "about" refers to a specified value with a technical accuracy generally accepted in the relevant field, preferably to a specified value ±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 specified result or use, i.e., the potential deviation will not cause the specified result to deviate by more than ±20%, more preferably ±10%, and most preferably ±5%. Therefore, "substantially consisting of..." means including the specified components, but excluding other ingredients (materials present as impurities, unavoidable materials present as a result of the process used to provide these components, and components added for purposes other than achieving the technical effects of the 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%, more preferably less than 3%, even more preferably less than 1%, and most preferably less than 0.1% by weight of one or more non-specified components.

[0027] PSMA binding motif

[0028] The PSMA binding motif Q preferably has the structure

[0029]

[0030] 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. More preferably, R 2 , R 3 and R 4 is CO2H. In particular, R1 is H, and R 2 , R 3 and R 4 It is CO2H. The wavy line indicates the connection to connector L AQ connection site.

[0031] Chelating agent residue A

[0032] 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)pentanediamine-N,N″-diacetic acid, 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]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N′-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-D TPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

[0033] The term "chelator residue" and typically also the term "chelator residue derived from a chelator selected from the group consisting of" is used to mean that the above mentioned chelator (thus typically a chelator defined in said "group") has been linked via a suitable functional group to the remainder of the PSMA binding ligand, preferably to a linker L. AQ .

[0034] More preferably, the chelating agents defined in said "group" have been linked to L via the preceding carboxylic acid group of the chelating agent. AQ N-terminal end, thus in the chelating agent and L AQ An amide bond is formed between them.

[0035] Preferably, A is a chelator residue having a structure selected from the group consisting of

[0036]

[0037] Most preferably, A has the structure

[0038]

[0039] Connector L AQ

[0040] Preferably, the connector L AQ In addition to comprising at least one optionally N-alkylated neutral amino acid X1, preferably in addition to comprising the group (X1) n1 In addition, wherein X1 is an optionally N-alkylated neutral amino acid X1 and wherein n1 is in the range of 2 to 25, at least one amino acid structural unit AS a and / or at least one amino acid structural unit AS B , preferably also comprising at least one amino acid structural unit AS a and at least one amino acid structural unit AS B .

[0041] Amino acid structural unit AS a

[0042] Amino acid structural unit AS a In particular, it has the following structure

[0043]

[0044] Where Q 1 Selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl.

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

[0046] As used in the context of the present invention, the term "alkylaryl" refers to an aryl group wherein at least one proton has been replaced by an alkyl group (alkyl-aryl-).

[0047] The term "arylalkyl" as used in the context of the present invention refers to an aryl group attached via an alkyl group (aryl-alkyl-).

[0048] As used in the context of the present invention, the term "heteroaryl" refers to optionally substituted 5- and 6-membered aromatic rings containing one or more (e.g. 1 to 4, such as 1, 2, 3 or 4) heteroatoms in the ring system, as well as substituted or unsubstituted polycyclic aromatic groups, such as tricyclic or bicyclic aromatic groups. 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 the skilled person. 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, methylenedioxyphenylyl, naphthyridinyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0049] 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-).

[0050] The term "heteroarylalkyl" as used in the context of the present invention refers to a heteroaryl group attached via an alkyl group (heteroaryl-alkyl-).

[0051] As used in the context of the present invention, the term "cycloalkyl" refers to optionally substituted cyclic alkyl residues, where they may be monocyclic or polycyclic groups. Optionally substituted cyclohexyl may be mentioned as a preferred example of a cycloalkyl residue.

[0052] As used in the context of the present invention, the term "heterocycloalkyl" refers to optionally substituted cycloalkyl residues which have at least one heteroatom such as O, N or S in the ring, whereby they may be monocyclic or polycyclic groups.

[0053] As used in the context of the present invention, the term "substituted cycloalkyl residue" or "heterocycloalkyl residue" refers to a cycloalkyl residue or heterocycloalkyl residue in which at least one H has been substituted by a suitable substituent.

[0054] 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:

[0055]

[0056] Among them, Q 1 The most preferred

[0057]

[0058] Amino acid structural unit AS b

[0059] Amino acid structural unit AS b Preferably having the following structure (b)

[0060]

[0061] Where Q 2 Selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl.

[0062] As used in the context of the present invention, the term "aryl" refers to optionally substituted 5- and 6-membered aromatic rings, as well as substituted or unsubstituted polycyclic aromatic groups (aryl groups), such as tricyclic or bicyclic aromatic groups (-Ar-). Optionally substituted phenyl groups or naphthyl groups can be mentioned as examples. Polycyclic aromatic groups can also contain non-aromatic rings, aryl groups in the context of the present invention.

[0063] As used in the context of the present invention, the term "alkylaryl" refers to an aryl group in which at least one proton has been substituted by an alkyl group (-alkyl-aryl-) and is linked via the alkyl group to a -CH2- group and via the aryl group to a carbonyl group.

[0064] As used in the context of the present invention, the term "arylalkyl" 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-).

[0065] As used in the context of the present invention, the term "heteroaryl" (-heteroaryl-) refers to optionally substituted 5- and 6-membered aromatic rings containing one or more (e.g. 1 to 4, such as 1, 2, 3 or 4) heteroatoms in the ring system, as well as substituted or unsubstituted polycyclic aromatic groups, such as tricyclic or bicyclic aryl groups. If more than one heteroatom is present in the ring system, at least two heteroatoms present may be identical or different. Suitable heteroaryl groups are known to the skilled person. 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.

[0066] As used in the context of the present invention, the term "alkylheteroaryl" refers to a heteroaryl group in which at least one proton has been replaced by an alkyl group (-alkyl-heteroaryl-) and which is linked via the alkyl group to the -CH2- group and via the heteroaryl group to the carbonyl group.

[0067] As used in the context of the present invention, the term "heteroarylalkyl" 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.

[0068] As used in the context of the present invention, the term "cycloalkyl" (-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.

[0069] As used in the context of the present invention, the term "heterocycloalkyl" refers to optionally substituted cyclic alkyl residues having at least one heteroatom such as O, N or S in the ring, whereby they may be monocyclic or polycyclic groups.

[0070] As used in the context of the present invention, the term "substituted cycloalkyl residue" or "heterocycloalkyl residue" refers to a cycloalkyl residue or heterocycloalkyl residue in which at least one H has been substituted by a suitable substituent.

[0071] Preferably, Q 2is an aryl group or a cycloalkyl group, more preferably

[0072]

[0073] The most preferred

[0074] It should be understood that Q 2 Any stereoisomers of are possible and included. 2 yes In the case of , it is to be understood that this includes cis isomers as well as trans isomers, with the trans isomers being particularly preferred.

[0075] The PSMA-binding ligand described above or below preferably has a structure selected from the group consisting of (Ia), (Ib) and (Ic)

[0076]

[0077] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 , R 4 are independently selected from the group consisting of: -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0078] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0079] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0080] and wherein q is an integer from 0 to 3, preferably 1, wherein X1 and n1 are as described above or below.

[0081] The PSMA-binding ligand described above or below more preferably has structure (Ia)

[0082]

[0083] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 , R 4 are independently selected from the group consisting of: -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0084] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0085] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0086] and wherein q is an integer from 0 to 3, preferably 1, wherein X1 and n1 are as described above or below.

[0087] More preferably, the PSMA-binding ligand described above or below has structure (Ia), wherein Q 1 comprises a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl, more preferably wherein Q 1 Select from the group consisting of:

[0088]

[0089] Preferably, Q 1 yes

[0090] And where R 3 , R 2 and R 4 Preferably –CO2H, and R 1 is H, and where Q 2 Preferably

[0091]

[0092] More preferably

[0093] In particular, the present invention relates to a PSMA-binding ligand as described above and below, which has the structure

[0094]

[0095] Where A is a chelating agent residue having the structure

[0096]

[0097] Q2 is

[0098]

[0099] More preferably

[0100]

[0101] q is 1,

[0102] Q 1 yes

[0103]

[0104] And where R 3 , R 2 and R 4 is -CO2H, and R1 is H, and wherein n1 is preferably in the range of 5 to 25, preferably 3 to 10,

[0105] X 1 and n1 are as described above or below.

[0106] Neutral amino acid X1

[0107] As mentioned above, at least one connector L AQ Contains at least one neutral amino acid. The term "neutral amino acid" as used within the meaning of the present invention includes various amino acids that have no net charge at pH 7. It is understood that the term includes all naturally occurring and non-naturally occurring amino acids, including all stereoisomers, such as enantiomers and diastereomers of the following amino acids: for example, glycine, alanine, valine, isoleucine, phenylalanine, β-alanine, and non-natural amino acids containing a neutral linker between the N-terminus and the C-terminus, such as at least one -(CH2-CH2-O)- group between the N-terminus and the C-terminus, and N-alkylated amino acids, such as N-methylated amino acids. Thus, the amino acid does not contain a proton -H, but an alkyl or methyl group attached to the amino group of the amino acid.

[0108] 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. N-methyl amino acids include, but are not limited to, N-methyl amino acids selected from the group consisting of: N-methylglycine, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methylleucine, N-methylphenylalanine.

[0109] If the amino acid is chiral, the amino acid preferably has the L-configuration.

[0110] Preferably, the neutral amino acid X1 is selected from the group consisting of: optionally N-alkylated, Gly, Ala, βAla, Phe, aminocaproic acid (Ahx=-NH-(CH2)5-C(=O)-) and an amino acid comprising at least one –(CH2-CH2-O)-group between the N-terminus and the C-terminus, more preferably, wherein X1 is selected from the group consisting of: Gly, Ala, βAla and an amino acid having –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structured amino acid residue, wherein x1 is an integer between 0 and 15, and y1 is 1 or 2.

[0111] According to a further preferred embodiment, the amino acid is, optionally N-alkylated, tyrosine (Tyr).

[0112] Optionally, the linker L AQ , comprising in addition to the optionally present at least one amino acid structural unit AS a and optionally at least one amino acid structural unit AS B In addition, and in addition to X1, further amino acids X are included, wherein preferably all additional amino acids X are neutral amino acids.

[0113] According to a preferred embodiment, the linker L AQ An amino acid sequence AA comprising 2 to 25 amino acids, and wherein the amino acid X1 is part of the sequence, and wherein preferably all amino acids present in the sequence are neutral amino acids. It should be understood that the sequence AA comprises at least one amino acid X1. Preferably, all amino acids X present in the sequence are identical and are X1.

[0114] Connector unit - (X1) n1

[0115] Preferably, the connector L AQ comprising an amino acid sequence AA, wherein the amino acid sequence AA comprises a structural unit (X1) n1 , wherein n1 ranges from 1 to 25, such as 2 to 25. Preferably, the amino acid sequence AA is composed of (X1) n1 Unit composition, in which all amino acids X1 are the same.

[0116] Preferably, X1 is selected from the group consisting of: optionally N-alkylated, Gly, Ala, βAla, Phe, aminocaproic acid (Ahx=-NH-(CH2)5-C(=O)-) and aminocaproic acid (Ahx=-NH-(CH2)5-C(=O)-) with –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1-C(=O)- structure, wherein x1 is an integer between 0 and 15 and y1 is 1 or 2. If the linker comprises more than one X1 group, the amino acids may be the same or may be different, preferably the same. Preferably, X1 is not N-alkylated.

[0117] According to an alternative, the connector L AQ , comprising, in addition to the optionally present at least one amino acid structural unit AS a , and optionally at least one amino acid structural unit AS B and contains no further amino acids except one amino acid X1. In this case, X1 is preferably: –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)-, wherein x1 is an integer between 0 and 15, y1 is 1 or 2, or aminocaproic acid (Ahx=-NH-(CH2)5-C(=O)-).

[0118] Preferably, the connector L AQ Comprising an amino acid sequence AA, wherein the amino acid sequence AA comprises a structural unit -(X1) n1 -, wherein X1 is a neutral amino acid, more preferably X1 is selected from the group consisting of: Gly, Ala, βAla, Phe, aminocaproic acid (Ahx = -NH-(CH2)5-C(=O)-) and an amino acid comprising at least one -(CH2-CH2-O)- group between the N-terminus and the C-terminus, more preferably, wherein X1 is selected from the group consisting of: Gly, Ala, βAla, Phe and an amino acid having -NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structured amino acid residue, wherein x1 is an integer between 0 and 15, and y1 is 1 or 2. The integer n1 preferably ranges from 1 to 25, and more preferably ranges from 1 to 20.

[0119] According to a first preferred embodiment, the linker L AQ Contains at least one X1 group, wherein X1 is selected from the group consisting of Gly, Ala, βAla and Phe.

[0120] More preferably, the connector L AQ Contains group (X1) n1, wherein X1 is selected from the group consisting of Gly, Ala, βAla and Phe, and n1 ranges from 2 to 20, preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, more preferably 3, 5, 10 or 15.

[0121] Therefore, according to a preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is selected from the group consisting of Gly, Ala, βAla and Phe, n1 is 3, more preferably wherein X1 is Gly or Ala and n1 is 3. Therefore, in a preferred embodiment, X1 is Gly and n1 is 3. In a further preferred embodiment, X1 is Ala and n1 is 3.

[0122] Therefore, according to a preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is selected from the group consisting of Gly, Ala, βAla and Phe, and n1 is 5, more preferably, X1 is Ala, and n1 is 5.

[0123] Therefore, according to a preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is selected from the group consisting of Gly, Ala, βAla and Phe, and n1 is 10.

[0124] Therefore, according to a preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is selected from the group consisting of Gly, Ala, βAla and Phe, and n1 is 15.

[0125] According to a further preferred embodiment, the linker L AQ Contains at least one group X1, wherein X1 is Gly, more preferably, the PSMA ligand comprises a group (X1) n1 , wherein X1 is Gly, and n1 ranges from 2 to 20, preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, more preferably 3, 5, 10 or 15, more preferably 3.

[0126] According to a further preferred embodiment, the linker L AQ Contains at least one group X1, wherein X1 is Ala, more preferably, the PSMA ligand comprises a group (X1) n1, wherein X1 is Ala, and n1 ranges from 2 to 20, preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, more preferably 3, 5, 10 or 15, more preferably 3 or 5, most preferably 5.

[0127] According to a further preferred embodiment, the linker L AQ Comprising at least one group X1, wherein X1 is βAla, more preferably, the PSMA ligand comprises a group (X1) n1 , wherein X1 is βAla, and n1 ranges from 2 to 20, preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, more preferably 3, 5, 10 or 15.

[0128] According to a further preferred embodiment, the linker L AQ Contains at least one group X1, wherein X1 is Phe, more preferably, the PSMA ligand comprises a group (X1) n1 , wherein X1 is selected from Phe, and n1 ranges from 2 to 20, preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, more preferably 3, 5, 10 or 15, more preferably 3 or 5.

[0129] According to a further preferred embodiment, the linker L AQ Contains at least one group X1, wherein X1 is Tyr, more preferably, the PSMA ligand comprises a group (X1) n1 , wherein X1 is Tyr, and n1 ranges from 2 to 20, preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, more preferably 3, 5, 10 or 15, more preferably 3 or 5, most preferably 3.

[0130] According to a second preferred embodiment, the linker L AQ Contains group (X1) n1 , where X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, wherein the integer x1 ranges from 1 to 15, y1 is 1 or 2, and n1 is 1. Preferably, the integer x1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, more preferably 1, 3, 5, 7.

[0131] According to a preferred embodiment, the linker L AQ Contains group (X1) n1, where X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, and the integer x1 ranges from 1 to 15, preferably from 1 to 7, y1 is 1 or 2, preferably y1 is 1. In a preferred embodiment, L AQ Contains group (X1) n1 , where X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, wherein integer x1 is 1 and integer y1 is 1.

[0132] According to a further preferred embodiment, the linker L AQ Contains group (X1) n1 , where X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, wherein integer x1 is 3 and integer y1 is 2.

[0133] According to a further preferred embodiment, the linker L AQ Contains group (X1) n1 , where X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, wherein integer x1 is 5 and integer y1 is 2.

[0134] According to a further preferred embodiment, the linker L AQ Contains group (X1) n1 , where X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, wherein integer x1 is 7 and integer y1 is 2.

[0135] According to a third preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is aminocaproic acid, wherein n1 is preferably 1 to 20, preferably 1 to 15, more preferably 1 to 4, such as 1, 2, 3 or 4.

[0136] According to a preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is aminocaproic acid and n1 is 1.

[0137] According to a further preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is aminocaproic acid and n1 is 2.

[0138] According to a further preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is aminocaproic acid and n1 is 3.

[0139] According to a further preferred embodiment, the linker L AQ Contains group (X1) n1 , wherein X1 is aminocaproic acid and n1 is 4.

[0140] By way of example, particularly preferred PSMA-binding ligands of the invention are shown in Table 1:

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] In particular, the PSMA-binding ligand has Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 , Figure 7 , Figure 8 , Fig. 9 , Fig.10 , Fig.11 , Fig.12 , Fig.13 , Fig.14 , Fig.15 , Fig.16 , Fig.17 , Fig.18 , Fig.19 , Fig. 20 , Fig.21 or Fig. 22 The structure shown, wherein preferably all chiral amino acids (X1) are present in the L-configuration.

[0148] In a preferred embodiment, the PSMA-binding ligand has Figure 1 , Figure 2 , Figure 5 , Figure 6 , Fig.13 , Fig.14 , Fig.15 , Fig.16 , Fig.17 , Fig.18 , Fig.19 , Fig. 20 , Fig.21 or Fig. 22 The structure shown.

[0149] In a particularly preferred embodiment, the PSMA-binding ligand has Figure 1 , Figure 5 , Figure 6 , Fig.13 , Fig.14 , Fig.15 , Fig.16 , Fig.17 , Fig.18 , Fig.19 , Fig. 20 , Fig.21 or Fig. 22 More preferably, the PSMA-binding ligand has a structure as shown in Figure 1 , Figure 5 , Figure 6 , Fig.15 , Fig.16 , Fig.17 , Fig.18 , Fig.19 , Fig. 20 , Fig.21 or Fig. 22 The structure shown.

[0150] As mentioned above, the present invention also relates to a complex comprising

[0151] (a) radionuclides, and

[0152] (b) a PSMA-binding ligand as described above or below, or a pharmaceutically acceptable salt or solvate thereof.

[0153] Typical pharmaceutically acceptable salts include those prepared by reacting the PSMA-binding ligands of the present invention with pharmaceutically acceptable inorganic or organic acids or organic or inorganic bases. Such 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, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutical acid addition salts are those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. The salt of the amine group can also include quaternary ammonium salts, in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Base addition salts include those salts derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc. Therefore, such alkalis that can be used to prepare the salt of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, etc. Potassium salt and sodium salt forms are particularly preferred. It should be appreciated that the specific counterions that form a part of any salt of the present invention do not usually have key characteristics, as long as the salt is pharmacologically acceptable as a whole, and as long as the counterions do not bring undesirable qualities to the salt as a whole.

[0154] 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, such as the corresponding hydrate, methanolate, ethanolate, DMSO solvate or acetonitrile.

[0155] Radionuclides

[0156] Depending on whether the PSMA-binding ligands of the invention are to be used as radioimaging agents or radiopharmaceuticals, different radionuclides are complexed with the chelating agent.

[0157] The complexes of the present invention may contain one or more radionuclides, preferably one radionuclide. These radionuclides are preferably suitable for use as radioimaging agents or as therapeutic agents for the treatment of proliferating cells, such as PSMA-expressing cancer cells, in particular PSMA-expressing prostate cancer cells. According to the present invention, they are referred to as "metal complexes" or "radiopharmaceuticals".

[0158] Preferred imaging methods are positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0159] Preferably, the at least one 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 (such as 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb).

[0160] More preferably, the at least one radionuclide is selected from the group consisting of: 90Y. 68 Ga, 177 Lu, 225 Ac and 213 Bi, more preferably, the radionuclide is 177 Lu or 225 Ac.

[0161] Preferably, the half-life of the radionuclide is at least 30 min, more preferably at least 1 h, more preferably at least 12 h, even more preferably at least 1 day, and most preferably at least 5 days; further preferably, the half-life of the radionuclide is at most 1 year, more preferably at most 6 months, still more preferably at most 1 month, and even more preferably at most 14 days. Therefore, preferably, the half-life of the radionuclide is from 30 min to 1 year, more preferably from 12 h to 6 months, more preferably from 1 day to 1 month, and most preferably from 5 days to 14 days.

[0162] Preferably, the radionuclide is an alpha-emitter and / or a beta-emitter, ie the radionuclide preferably emits alpha-particles (alpha-emitter) and / or beta-radiation (beta-emitter).

[0163] Preferably, where the radionuclide is an alpha-emitter, the energy of the alpha-particles is from 1 to 10 MeV, more preferably from 2 to 8 MeV, most preferably from 4 to 7 MeV.

[0164] Preferably, where the radionuclide is a beta-emitter, the energy of the beta radiation is from 0.1 to 10 MeV, more preferably from 0.25 to 5 MeV, most preferably from 0.4 to 2 MeV.

[0165] Preferred beta-radiation emitting radionuclides 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 Pb. A very preferred beta-radiation emitting radionuclide is 177 Lu or 90 Y, most preferably 177 Lu. Preferably, in this case, the use is diagnosis or therapy.

[0166] Preferred alpha-radiation emitting radionuclides are for example selected from the group consisting of: 213 Bi, 225 Ac,149 Tb, 230 U and 223 Ra, 213 Bi, 230 U, more preferably the radionuclide is 225 Ac and / or 213 Bi. A very preferred alpha-radiating radionuclide is, for example, 225 Ac. Preferably, in this case, the use is therapy.

[0167] According to a further embodiment, the radionuclide is a positron emitter. In this case, the radionuclide is preferably selected from the group consisting of: 89 Zr, 44 Sc, 66 Ga, 68 Ga and 64 Cu. In this case, the use is preferably PET diagnostics.

[0168] According to a further preferred embodiment, the radionuclide is a gamma emitter. In this case, the radionuclide is preferably selected from the group consisting of: 111 In, 67 Ga, 99m Tc, 155 Tb, 165 Er and 203 Pb. In this case, the use is preferably SPECT diagnostics.

[0169] According to a further preferred embodiment, the radionuclide emits Auger electrons and preferably decays by electron capture. In this case, the radionuclide is preferably selected from the group consisting of: 67 Ga, 155 Tb, 153 Gd, 165 Er and 203 Pb. In this case, the use is preferably therapy.

[0170] Pharmaceutical composition

[0171] 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 also comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0172] As used herein, the terms "drug" and "pharmaceutical composition" refer to the PSMA-binding ligand and / or complex of the present invention and optionally one or more pharmaceutically acceptable carriers, i.e., excipients. The PSMA-binding ligand of the present invention may be formulated as a pharmaceutically acceptable salt; the salts have been described herein above. The pharmaceutical composition is preferably administered locally (e.g., intratumorally), topically, or systemically. Suitable routes of administration conventionally used for drug administration are oral, intravenous or parenteral administration, and inhalation. A 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, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection or 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.

[0173] In addition, the PSMA-binding ligand can be administered in combination with other drugs in a common pharmaceutical composition or as a separate pharmaceutical composition, wherein the separate pharmaceutical composition can be provided in the form of a kit of parts. The PSMA-binding ligand is preferably administered in a conventional dosage form prepared by combining the drug with a standard pharmaceutical carrier according to conventional procedures. These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate for the desired formulation. It should be understood that the form and nature of the pharmaceutical carrier or diluent is determined by the amount of active ingredient to be combined therewith, the route of administration, and other well-known variables.

[0174] One or more excipients must be acceptable in the following sense, i.e. compatible with the other ingredients of the preparation, and within the scope of reasonable medical judgment, suitable for use in contact with patient tissues, without excessive toxicity, irritation, allergic reactions or other problems or complications, in accordance with a reasonable benefit / risk ratio. Preferably, the excipient is harmless to its recipient. The excipient adopted can be, for example, a solid, gel or liquid carrier. Examples of solid carriers include lactose, terra alba, sucrose, talcum, gelatin, agar, pectin, acacia gum (arabic gum, acacia), magnesium stearate, stearic acid, etc. Examples of liquid carriers include phosphate buffered saline solutions, syrups, oils (such as peanut oil and olive oil), water, emulsions, various types of wetting agents, sterile solutions, etc. Similarly, carriers or diluents can include time delay materials well known in the art, such as glyceryl monostearate or glyceryl distearate alone or 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 solutions, glucose solutions and Hank's solutions. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc. When solutions for infusion or injection are used, they are preferably aqueous solutions or suspensions, which can be produced before use, for example, by freeze-dried preparations containing the active substance itself or the active substance with a carrier (such as mannitol, lactose, glucose, albumin, etc.). The prepared solution is sterilized and mixed with an excipient, for example, with a preservative, stabilizer, emulsifier, solubilizer, buffer and / or a salt for adjusting the osmotic pressure. Sterilization can be achieved by sterile filtration using a filter with a small pore size (where appropriate, the composition can be lyophilized). Small amounts of antibiotics may also be added to ensure that sterility is maintained.

[0175] The therapeutically effective dose refers to the amount of the PSMA-binding ligand to be used in the pharmaceutical composition of the present invention to prevent, improve or treat the symptoms associated with the diseases or disorders mentioned 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.

[0176] The dosage regimen will be determined by the attending physician and other clinical factors; preferably determined according to any of the above methods. As is well known in the medical field, the dosage for any one patient depends on many factors, including patient 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 simultaneously. Progress can be monitored by regular assessments. Preferred dosages are specified herein below. Progress can be monitored by regular assessments. The pharmaceutical compositions and formulations mentioned herein are administered at least once to treat or prevent the diseases or conditions mentioned in this specification. However, the pharmaceutical compositions may be administered more than once, for example, from one to ten times. Preferably, the pharmaceutical compositions may be administered at a frequency of 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 mentioned herein above (in admixture or otherwise associated with a pharmaceutical carrier or diluent). To make those specific pharmaceutical compositions, one or more active compounds will typically be mixed with a carrier or diluent, or enclosed or packaged in a capsule, sachet, cachet, paper or other suitable container or vehicle. 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 by the prescribing physician or in the user's instructions so that the intended dosage can be adjusted according to the intended recipient.

[0177] As used herein, the term "patient" 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.

[0178] 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 the patient. Preferred diagnostic compound doses are 1-10 nmol / patient total dose; thus, preferably, the diagnostic compound dose is 0.02 to 0.1 nmol / kg body weight. Preferred therapeutic compound doses are 10 to 100 nmol / patient total dose; thus, preferably, the therapeutic compound dose is 0.2 to 1 nmol / kg body weight.

[0179] As will be appreciated by the skilled person, the doses of the complexes specified herein, i.e. comprising (preferably consisting of) a radionuclide and a PSMA binding ligand, are preferably specified as the compound doses specified above, with the preferred doses being the same as specified above. More preferably, the doses of the complexes are specified as active doses, i.e. as the amount of radioactivity administered to the patient. Preferably, the active dose is adjusted to avoid adverse effects as specified elsewhere herein. Preferably, the patient-specific dose, preferably the patient-specific active dose, is determined taking into account the relevant factors specified elsewhere herein, in particular taking into account the therapeutic progress and / or adverse effects observed for the respective patient. 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, still more preferably less than 10 Sv, and most preferably less than 5 Sv.

[0180] The effective amount can be administered once (single dose) at an active dose of about 2 MBq to about 30 MBq, preferably 4 to 30 MBq, more preferably 6 to 30 MBq, more preferably 8 to 30 MBq, more preferably 10 to 30 MBq, more preferably 15 to 30 MBq, preferably 20 to 30 MBq. Therefore, in such a case, a preferred therapeutic dose is 2 MBq to about 30 MBq / patient, preferably 4 to 30 MBq / patient, more preferably 6 to 30 MBq / patient, more preferably 8 to 30 MBq / patient, more preferably 10 to 30 MBq / patient, more preferably 15 to 30 MBq / patient, preferably 20 to 30 MBq / patient. Preferably, the 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 specified herein 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 phrase "effective amount" or "therapeutically effective amount" refers to an amount of a PSMA-binding ligand, material, or composition comprising a PSMA-binding ligand of the invention, or other active ingredient, that is effective to produce some desired therapeutic effect in at least one cell subpopulation 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 refers to 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 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.

[0181] 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 the use is therapy, preferably therapy of prostate cancer as described elsewhere herein; in such a case, the active dose of the complex is preferably at least 25MBq / kg body weight, more preferably at least 50MBq / kg body weight, and most preferably at least 80MBq / kg body weight. Therefore, in such a case, a preferred therapeutic dose is 2 to 10Gbq / patient, more preferably 4 to 8Gbq / patient, and most preferably about 6Gbq / patient.

[0182] More preferably, the radionuclide is an alpha-emitter as described above, more preferably 225 Ac, and the use is therapy, preferably therapy of prostate cancer as described elsewhere herein; in such a case, the active dose of the complex is preferably in the range of 25 kBq / kg to about 500 kBq / kg body weight of the patient, 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, and most preferably at least 200 kBq / kg body weight. Therefore, preferably, in such a case, the active dose of the complex is 75 to 500 kBq / kg body weight, more preferably 100 to 400 kBq / kg body weight, still more preferably 150 to 350 kBq / kg body weight, and most preferably 200 to 300 kBq / kg body weight.

[0183] The present invention further relates to a PSMA-binding ligand as described above or below, a complex as described above or below or a pharmaceutical composition as described herein 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 further 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.

[0184] As used herein, the term "diagnosis" refers to assessing whether a subject suffers from a disease or condition, preferably a cell proliferative disease or condition. As will be appreciated by those skilled in the art, such an assessment (although preferably) may not be 100% correct for the subject being studied. However, the term requires that a portion (preferably a statistically significant portion) of the subject can be correctly assessed, and thus a diagnosis is made. Whether a portion is statistically significant can be determined by those skilled in the art using various well-known statistical evaluation tools (e.g., determining confidence intervals, p-value determination, Student's t-test, Mann-Whitney test, etc.) without further effort. Details can be found in Dowdy and Wearden, Statistics For Reasearch, 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 a sample from a subject, X-ray examination, and the like. The term includes individual diagnosis of a patient as well as continuous monitoring. Monitoring, i.e., diagnosing the presence or absence of a cell proliferative disease or symptoms associated with it at various 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 a patient has been successfully treated, or at least whether the symptoms of a cell proliferative disease can be improved over time by a certain treatment method. In addition, the term also includes classifying subjects according to a common classification scheme, such as T1 to T4 staging, which is known to the technician.

[0185] The terms "treating" and "treatment" refer to ameliorating to a great extent the diseases or conditions mentioned herein or the symptoms accompanying them. As used herein, the treatment also includes complete restoration of health with respect to the diseases or conditions mentioned herein. It is understood that, as the terms are 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 subjects suffering from the diseases or conditions mentioned herein can be successfully treated. Whether a portion is statistically significant can be determined by a person skilled in the art without further effort using various well-known statistical evaluation tools (as specified herein above). The terms "preventing" and "prevention" refer to maintaining health with respect to the diseases or conditions mentioned herein in a subject for a certain period of time. It is understood that the period of time may depend on the amount of the drug compound that has been administered as well as individual factors of the subject discussed elsewhere in this specification. It is understood that prevention may not be effective in all subjects treated with a PSMA-binding ligand according to the present invention. However, the term requires that, preferably, a statistically significant portion of subjects in a group or population is effectively prevented from suffering from a disease or disorder or its associated symptoms as mentioned herein. Preferably, a group or population of subjects is envisioned in this context that would normally (i.e., in the absence of preventive measures according to the present invention) develop into a disease or disorder as mentioned herein. Whether a portion is statistically significant can be determined by a person skilled in the art using various well-known statistical evaluation tools (as defined above herein) without further effort.

[0186] 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 specified above.

[0187] As used herein, the term "cell proliferative disorder" relates to a disease in animals (including humans) characterized by the uncontrolled growth of a group of somatic cells ("cancer cells"). This uncontrolled growth may be accompanied by invasion and destruction of surrounding tissues, and may allow the cancer cells to spread to other parts of the body (metastasis). Preferably, the term cancer also includes recurrence. Thus, preferably, the cancer is a solid cancer, a metastasis or a recurrence thereof. Preferably, the cell proliferative disorder is an uncontrolled proliferation of cells that include expressing PSMA.

[0188] Thus, preferably, the cell proliferative disease is a PSMA-expressing cancer. "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 cancer, 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 cancer, 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 determined by a skilled person by methods known in the art, such as in vitro by immunostaining of a cancer sample, or in vivo, such as by PSMA scintigraphy, preferably both, as described in Kratochwil et al. (2017, J Nucl Med 58(10):1624. In particularly preferred aspects of the invention, the PSMA-expressing cancer is prostate cancer or breast cancer, more preferably prostate cancer; and 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 (metastatic castration-resistant prostate cancer). Advantageously, in the studies of the present invention, it has been shown that administration of the PSMA-binding ligands and / or complexes of the present invention to patients results in improved pharmacokinetic distribution properties, in particular improved renal excretion, with substantially unchanged enrichment in target tissues, preferably cell proliferative tissues, more preferably cancer tissues, as compared to, for example, the concurrently commonly used PSMA-617. Due to the improved excretion, adverse side effects on non-target tissues (particularly salivary glands and / or lacrimal glands) can be avoided and / or reduced. This is advantageous because adverse side effects on the salivary glands are considered 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, and in particular higher doses of radioactivity, can be administered to patients, as compared to the compounds and complexes described in the art. Thus, the therapeutic window is wider than that of currently used compounds. Also advantageously, the PSMA-binding ligands of the present invention provide improved diagnosis because co-labeling of irrelevant tissues and organs (particularly salivary glands, lacrimal glands and / or kidneys) is reduced.

[0189] Thus, the PSMA-binding ligands and / or complexes of the invention allow for the treatment of PSMA-expressing cancers, in particular prostate cancer and its metastases, and / or the diagnosis of PSMA-expressing cancers, in particular prostate cancer and its metastases, wherein the PSMA-binding ligands and / or complexes exhibit a favorable renal excretion profile, preferably with a favorable acceleration of clearance. Thus, adverse side effects on the patient's kidneys are reduced. Thus, the present invention also relates to the PSMA-binding ligands and / or complexes or pharmaceutical compositions of the invention (as described above) for use in the treatment and / or prevention of PSMA-expressing cancers, in particular prostate cancer and / or its metastases, in a patient in need thereof, the subject suffering from renal failure.

[0190] As described in detail herein above and in the Examples, the compounds as specified herein provide accelerated excretion while maintaining substantially the same enrichment in target tissues as, for example, PSMA-617, thereby avoiding or reducing adverse effects on non-target tissues (preferably salivary glands and / or lacrimal glands). Thus, the treatment and / or diagnosis as specified herein has fewer or less severe adverse side effects (e.g., on salivary glands and / or lacrimal glands), or is preferably not accompanied by adverse side effects (particularly on salivary glands and / or lacrimal glands).

[0191] Preferably, the PSMA-binding ligands of the invention allow for reduction and / or avoidance of adverse side effects (e.g., on salivary glands and / or lacrimal glands) while keeping the therapeutic efficacy substantially unchanged. The skilled person will appreciate in view of the above that the PSMA-binding ligands as specified herein preferably further enable higher concentrations of the compound and / or higher doses of radioactivity to be feasible while at least not increasing adverse reactions, which may be particularly useful in diagnostic applications (for detecting, e.g., small metastases or small amounts of remaining tumor tissue) and / or in therapy.

[0192] Thus, the PSMA-binding ligands and / or complexes of the present invention allow for the treatment of PSMA-expressing cancers, particularly prostate cancer and its metastases, and / or the diagnosis of PSMA-expressing cancers, particularly prostate cancer and its metastases, wherein xerostomia can be avoided.

[0193] 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, or a radiotherapeutic agent having a radionuclide (i.e., radioiodine) as an element, or a radiometal chelate complex of the PSMA binding ligand in an amount sufficient for imaging, and a pharmaceutically acceptable radioactive vehicle. The radioactive vehicle should be suitable for injection or aspiration, such as human serum albumin; aqueous buffer solutions, such as tris (hydroxymethyl) -aminomethane (and its salts), phosphates, citrates, bicarbonates, etc.; sterile water saline; and a counterion solution containing chloride and or bicarbonate or normal plasma substances such as calcium, potassium, sodium and magnesium.

[0194] The concentration of the imaging agent or therapeutic agent in the radioactive carrier should be sufficient to provide satisfactory imaging. Appropriate dosages have been described above. The imaging agent or therapeutic agent should be administered to stay in the patient's body for about 1 hour to 10 days, but longer or shorter times are acceptable. Therefore, a convenient ampoule containing 1 to 10 ml of an aqueous solution can be prepared.

[0195] Imaging can be performed in a manner known to the skilled artisan, for example, by injecting a sufficient amount of the imaging composition to provide adequate imaging, followed by scanning with 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 conjugated to a radionuclide; (ii) exposing an 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 (which is synthesized by contacting a radionuclide and a PSMA-binding ligand, as described above).

[0196] The amount of a PSMA-binding ligand of the invention, or a formulation comprising a PSMA-binding ligand or a salt, solvate, stereoisomer or tautomer thereof, administered to a patient depends on a number of physiological factors known to the physician, including the nature of the subject being imaged, the target tissue for imaging or treatment, and the weight and medical history of the patient being imaged or treated with the radiopharmaceutical.

[0197] Thus, in another aspect, the invention provides a method of treating a patient suffering from a cell proliferative disease or disorder by administering to the patient a therapeutically effective amount of a complex as described above or below. In particular, the cell proliferative disease or disorder treated or imaged using the PSMA-binding ligand, pharmaceutical composition or radiopharmaceutical according to the invention is cancer, such as prostate cancer and / or prostate cancer metastasis (e.g., in the lung, liver, kidney, bone, brain, spinal cord, bladder).

[0198] 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 such as 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, detachment 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.

[0199] Summarizing the findings of the present invention, the following embodiments are preferred:

[0200] 1. A PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising: AQ The PSMA binding motif Q and the chelator residue A are connected, and the linker L AQ The invention comprises at least one, optionally N-alkylated, neutral amino acid X1, wherein X1 is preferably selected from the group consisting of: optionally N-alkylated Gly, Ala, βAla, Phe, aminocaproic acid (Ahx=-NH-(CH2)5-C(=O)-) and an amino acid comprising at least one –(CH2-CH2-O)-group between the N-terminus and the C-terminus, more preferably, wherein X1 is selected from the group consisting of: Gly, Ala, βAla, Phe and an amino acid having –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 An amino acid residue of a -C(=O)- structure, wherein x1 is an integer in the range of 0 to 15, and y1 is 1 or 2, or X1 is Tyr.

[0201] 2. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to embodiment 1, wherein the PSMA-binding ligand has structure (I):

[0202] AL AQ -Q(I)

[0203] 3. According to the PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to Embodiment 1 or 2, the PSMA-binding motif Q has the following structure

[0204]

[0205] 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.

[0206] 4. The PSMA-binding ligand according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof,

[0207] wherein A is a chelator residue derived from a chelator 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)- Glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric 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]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N′-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX- DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

[0208] 5. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 4, wherein A is a chelator residue having a structure selected from the group consisting of

[0209]

[0210]

[0211] 6. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 5, wherein A is a chelator residue having the structure

[0212]

[0213] 7. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 6, wherein the linker L AQ Comprising at least one amino acid structural unit AS a , where AS a With the following structure

[0214]

[0215] Where Q 1 Selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl.

[0216] 8. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 7, wherein the linker L AQ Comprising at least one amino acid structural unit AS b , where AS b Having the following structure (b)

[0217]

[0218] Where Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably wherein Q 2 yes

[0219]

[0220] More preferably

[0221]

[0222] 9. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 6, wherein the linker L AQComprising at least one amino acid structural unit AS a and at least one amino acid structural unit AS b , where AS a With the following structure

[0223]

[0224] Where Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, wherein AS b Having the following structure (b)

[0225]

[0226] Where Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably wherein Q 2 yes

[0227]

[0228] More preferably

[0229]

[0230] 10. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 8, wherein the PSMA-binding ligand has the following structure (Ia):

[0231]

[0232] Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 , R 4 are independently selected from the group consisting of: -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H and -OPO3H2,

[0233] Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,

[0234] Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,

[0235] And wherein q is an integer from 0 to 3, and wherein n1 is an integer in the range of 1 to 25.

[0236] 11. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to embodiment 10, wherein Q 1 Preferably, it comprises a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl, more preferably wherein Q 1 Select from the group consisting of:

[0237]

[0238] Preferably, Q 1 yes

[0239] 12. The PSMA-binding ligand according to any one of embodiments 10 or 11, wherein R 3 , R 2 and R 4 is –CO2H, and R 1 It's H.

[0240] 13. The PSMA-binding ligand of any one of embodiments 10 to 12, wherein Q 2 yes

[0241]

[0242] Preferably

[0243] 14. The PSMA-binding ligand of any one of embodiments 1 to 13, wherein the ligand has the structure

[0244]

[0245] Where A is a chelating agent residue having the structure

[0246]

[0247] Q 2 for

[0248]

[0249] More preferably

[0250]

[0251] q is 1

[0252] Q 1 for

[0253]

[0254] And where R 3 , R 2 and R 4 For -CO2H, R 1 is H, wherein n1 is an integer in the range of 1 to 25.

[0255] 15. The PSMA-binding ligand of any one of embodiments 1 to 14, wherein the X1 is selected from the group consisting of Gly, Ala, βAla, Phe, -NH-(CH2)5-C(=O)-, and an amino acid comprising at least one -(CH2-CH2-O)- group between the N-terminus and the C-terminus.

[0256] 16. The PSMA-binding ligand of any one of embodiments 1 to 14, wherein X1 is selected from the group consisting of Gly, Ala, βAla, Phe, -NH-(CH2)5-C(=O)-, and -NH-CH2-CH2-O-(CH2-CH2-O)-. x1 -(CH2) y1 An amino acid residue of a -C(=O)- structure, wherein X1 is an integer in the range of 0 to 15, and y1 is 1 or 2.

[0257] 17. The PSMA-binding ligand of any one of embodiments 1 to 16, wherein the X1 is selected from the group consisting of Gly, Ala, βAla, and Phe.

[0258] 18. The PSMA-binding ligand of any one of embodiments 1 to 14, wherein the linker L AQ Contains structural unit (X1) n1 , wherein X1 is selected from the group consisting of Gly, Ala, βAla and Phe, or wherein X1 is Tyr, and n1 ranges from 2 to 20, preferably from 3 to 15, more preferably 3, 5, 10 or 15.

[0259] 19. The PSMA-binding ligand of embodiment 18, wherein n1 is 3.

[0260] 20. The PSMA-binding ligand of embodiment 18, wherein n1 is 5.

[0261] 21. The PSMA-binding ligand of embodiment 18, wherein n1 is 10.

[0262] 22. The PSMA-binding ligand of embodiment 18, wherein n1 is 15.

[0263] 23. The PSMA-binding ligand of any one of embodiments 18 to 22, wherein X1 is Gly.

[0264] 24. The PSMA-binding ligand of any one of embodiments 18 to 22, wherein X1 is Ala.

[0265] 25. The PSMA-binding ligand of any one of embodiments 18 to 22, wherein X1 is βAla.

[0266] 26. The PSMA-binding ligand of any one of embodiments 18 to 22, wherein X1 is Phe.

[0267] 27. The PSMA-binding ligand of any one of embodiments 1 to 16, wherein the linker L AQ Contains structural unit (X1) n1 , where X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, wherein the integer x1 ranges from 0 to 15, y1 is 1 or 2, and n1 is 1.

[0268] 28. The PSMA-binding ligand of embodiment 27, wherein the integer x1 is 1, 3, 5 or 7.

[0269] 29. The PSMA-binding ligand of embodiment 27, wherein integer x1 is 1 and integer y1 is 1.

[0270] 30. The PSMA-binding ligand of embodiment 27, wherein integer x1 is 3 and integer y1 is 2.

[0271] 31. The PSMA-binding ligand of embodiment 27, wherein integer x1 is 5 and integer y1 is 2.

[0272] 32. The PSMA-binding ligand of embodiment 27, wherein integer x1 is 7 and integer y1 is 2.

[0273] 33. The PSMA-binding ligand of any one of embodiments 1 or 14, wherein the linker L AQ Contains structural unit (X1) n1 , wherein X1 is -NH-(CH2)5-C(=O)-, and n1 ranges from 2 to 20, preferably from 1 to 4.

[0274] 34. The PSMA-binding ligand of any one of Embodiments 33, wherein n1 is 1.

[0275] 35. The PSMA-binding ligand of any one of Embodiments 33, wherein n1 is 2.

[0276] 36. The PSMA-binding ligand of any one of Embodiments 33, wherein n1 is 3.

[0277] 37. The PSMA-binding ligand of any one of Embodiments 33, wherein n1 is 3.

[0278] 38. The PSMA-binding ligand of any one of embodiments 1 to 37, wherein the PSMA-binding ligand has Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 , Figure 7 , Figure 8 , Fig. 9 , Fig.10 , Fig.11 , Fig.12 , Fig.13 , Fig.14 , Fig.15 , Fig.16 , Fig.17 , Fig.18 , Fig.19 , Fig. 20 , Fig.21 or Fig. 22 The structure shown.

[0279] 39. A complex comprising

[0280] (a) radionuclides, and

[0281] (b) The PSMA-binding ligand according to any one of embodiments 1 to 37, or a pharmaceutically acceptable salt or solvate thereof.

[0282] 40. The complex according to embodiment 39, 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 (such as 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb), more preferably selected from the group consisting of: 90 Y. 68 Ga, 177 Lu, 225 Ac and 213 Bi, more preferably, the radionuclide is 177 Lu or 225 Ac.

[0283] 41. A pharmaceutical composition comprising the PSMA-binding ligand according to any one of embodiments 1 to 38 or the complex according to embodiment 39 or 40.

[0284] 42. The PSMA-binding ligand according to any one of embodiments 1 to 38 or the complex according to embodiment 39 or 40 or the pharmaceutical composition according to embodiment 41 for use in medicine, preferably for the treatment and / or prevention of PSMA-expressing cancer, in particular prostate cancer, and / or its metastases.

[0285] 43. The PSMA-binding ligand of any one of embodiments 1 to 38, or the complex of embodiment 39 or 40, or the pharmaceutical composition of embodiment 41, for use in diagnosis.

[0286] 44. The PSMA-binding ligand according to any one of embodiments 1 to 38, or the complex according to embodiment 39 or 40, or the pharmaceutical composition according to embodiment 41, for use in the diagnosis of cancer, preferably a PSMA-expressing cancer, in particular prostate cancer, and / or its metastases.

[0287] 45. The PSMA-binding ligand, complex or pharmaceutical composition for use according to embodiment 43 or 44, wherein the radionuclide is a beta-emitter, more preferably 177 Lu, and wherein 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.

[0288] 46. ​​The PSMA-binding ligand, complex or pharmaceutical composition for use according to embodiment 42, wherein the radionuclide is an alpha-emitter, more preferably 225 Ac, and wherein the active dose of the complex is preferably at least 75 kBq / kg body weight, more preferably at least 100 kBq / kg body weight.

[0289] 47. The PSMA-binding ligand of any one of embodiments 18 to 22, wherein X1 is Tyr.

[0290] 48. The PSMA-binding ligand of any one of embodiments 1 to 8, wherein the linker L AQ Contains structural unit (X1)n1, and wherein

[0291] - X1 is selected from the group consisting of Gly, Ala, βAla and Phe, n1 ranges from 2 to 20, preferably from 3 to 15, more preferably 3, 5, 10 or 15, or

[0292] -X1 has –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)- structure, the integer x1 ranges from 0 to 15, y1 is 1 or 2, n1 is 1, or

[0293] -X1 has a -NH-(CH2)5-C(=O)- structure, n1 ranges from 1 to 20, preferably from 1 to 4, or

[0294] -X1 is Tyr, and n1 ranges from 2 to 20, preferably from 3 to 15, more preferably 3, 5, 10 or 15.

[0295] All references cited in this specification are hereby incorporated by reference with respect to the disclosures specifically mentioned and in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS

[0296] Figure 1 :Structure of DOTA-Gly3-Chx-2-NaI-Lys-urea-Glu

[0297] Figure 2:Structure of DOTA-Gly5-Chx-2-NaI-Lys-urea-Glu

[0298] Figure 3 :DOTA-Gly 10 -Chx-2-NaI-Lys-urea-Glu structure

[0299] Figure 4 :DOTAGly 15 -Chx-2-NaI-Lys-urea-Glu structure

[0300] Figure 5 :Structure of DOTA-Ala3-Chx-2-NaI-Lys-urea-Glu

[0301] Figure 6 :Structure of DOTA-Ala5-Chx-2-NaI-Lys-urea-Glu

[0302] Figure 7 :DOTA-Ala 10 -Chx-2-NaI-Lys-urea-Glu structure

[0303] Figure 8 :DOTA-Ala 15 -Chx-2-NaI-Lys-urea-Glu structure

[0304] Fig. 9 :Structure of DOTA-βAla3-Chx-2-NaI-Lys-urea-Glu

[0305] Fig.10 :Structure of DOTA-βAla5-Chx-2-NaI-Lys-urea-Glu

[0306] Fig.11 :DOTA-βAla 10 -Chx-2-NaI-Lys-urea-Glu structure

[0307] Fig.12 :DOTA-βAla 15 -Chx-2-NaI-Lys-urea-Glu structure

[0308] Fig.13 :Structure of DOTA-Phe3-Chx-2-NaI-Lys-urea-Glu

[0309] Fig.14 :Structure of DOTA-Phe5-Chx-2-NaI-Lys-urea-Glu

[0310] Fig.15 :Structure of DOTA-PEG2-Chx-2-NaI-Lys-urea-Glu

[0311] Fig.16 :Structure of DOTA-PEG4-Chx-2-NaI-Lys-urea-Glu

[0312] Fig.17 :Structure of DOTA-PEG6-Chx-2-NaI-Lys-urea-Glu

[0313] Fig.18 :Structure of DOTA-PEG8-Chx-2-NaI-Lys-urea-Glu

[0314] Fig.19 :Structure of DOTA-Ahx1-Chx-2-NaI-Lys-urea-Glu

[0315] Fig. 20 :Structure of DOTA-Ahx2-Chx-2-NaI-Lys-urea-Glu

[0316] Fig.21 :Structure of DOTA-Ahx3-Chx-2-NaI-Lys-urea-Glu

[0317] Fig. 22 :Structure of DOTA-Ahx4-Chx-2-NaI-Lys-urea-Glu

[0318] Fig.23 :Structure of DOTA-Tyr3-Chx-2-NaI-Lys-urea-Glu

[0319] Fig.24 :Structure of DOTA-Tyr5-Chx-2-NaI-Lys-urea-Glu

[0320] Fig.25 : After 45 minutes, with or without blocking, 177 Cell surface binding and internalization of Lu-labeled compounds were expressed as a percentage of applied radioactivity (n=3). Example

[0321] All commercially available chemicals were of analytical grade and used without further purification. 68 Ga (half-life 68 minutes) from 68 Ge / 68 Ga generator ( Ge-68 / Ga-68 generator, obtained from Eckert & Ziegler,177 Lu (half-life 6.6 days) was purchased from ITG. These compounds were purified using semi-preparative reversed-phase high-performance liquid chromatography (RP-HPLC; Chromolith Semi Prep RP-18e, 100×10 mm; Merck, Darmstadt, Germany). Compound analysis was performed using analytical RP-HPLC (RP-HPLC; Chromolith RP-18e, 100×4.6 mm; Merck, Darmstadt, Germany). HPLC analytical runs were performed using a linear gradient (5% A (0.1% TFA in water) to 100% B (0.1% TFA in CH3CN) at 2 ml / min in 10 min. System Agilent Technologies 1200 series equipped with variable UV and gamma detectors (Ramona*, Elysia). UV absorbance was measured at 220 nm and 280 nm, respectively. For mass spectrometry analysis, MALDI-MS (Daltonics Microflex, Bruker Daltonics, Bremen, Germany) was used.

[0322] DOTA-Gly x -Chx-2-NaI-PSMA, DOTA-Ala x -Chx-2-NaI-PSMA, DOTA-βAla x -Synthesis of Chx-2-NaI-PSMA (x=3, 5, 10, 15)

[0323] ("PSMA" = "Lys-Urea-Glu")

[0324] The synthesis of the pharmacophore Glu-urea-Lys was carried out as described previously (1). In brief, the synthesis started with the isocyanate forming the glutamyl moiety using triphosgene. Lysine immobilized on resin (2-chloro-trityl resin, Merck, Darmstadt) ε-allyloxycarbonyl protected 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).

[0325] Subsequently, the linker between the PSMA pharmacophore and the chelator was introduced by a standard Fmoc solid phase protocol. In the first step, Fmoc-2-NaI-OH and N-Fmoc-tranexamic acid (5 eq. each) were coupled with HATU (5 eq.) and DIPEA (10 eq.) in DMF. Each coupling step was repeated once. Depending on the amino acid sequence, Fmoc-Gly-OH / Fmoc-Ala-OH or Fmoc-β-Ala-OH (5 eq. / coupling) was coupled with HATU (5 eq.) and DIPEA (10 eq.) in DMF three, five, ten, and fifteen times, respectively. Each coupling step was repeated once.

[0326] Then, tris(tBu)DOTA (tris(tBu)-ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 eq.) was coupled with HATU (4 eq.) and DIPEA (10 eq.) in DMF. The product was cleaved from the resin with TFA / TIPS / H2O (95 / 2.5 / 2.5, v / v / v) at RT for 3 hours and identified by mass spectrometry.

[0327] Table 2. Data analysis of final compounds. Metal-free species were determined by mass spectrometry (MALDI-MS).

[0328]

[0329]

[0330] DOTA-Phe y -Chx-2-NaI-Lys-urea-Glu (y=3, 5) and DOTA-Tyr y -Synthesis of Chx-2-NaI-Lys-urea-Glu (y=3, 5)

[0331] The synthesis of the pharmacophore Glu-urea-Lys was carried out as described previously (1). In brief, the synthesis started with the isocyanate forming the glutamyl moiety using triphosgene. Lysine immobilized on resin (2-chloro-trityl resin, Merck, Darmstadt) ε-allyloxycarbonyl protected 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).

[0332] Subsequently, the linker between the PSMA pharmacophore and the chelator was introduced by a standard Fmoc solid phase protocol. In the first step, Fmoc-2-NaI-OH and N-Fmoc-tranexamic acid (5 eq. each) were coupled with HATU (5 eq.) and DIPEA (10 eq.) in DMF. Each coupling step was repeated once. Depending on the amino acid sequence, Fmoc-Phe-OH (5 eq. / coupling) or Fmoc-Tyr(tBu)-OH was coupled with HATU (5 eq.) and DIPEA (10 eq.) in DMF three or five times, respectively. Each coupling step was repeated once.

[0333] Then, tris(tBu)DOTA (tris(tBu)-ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 eq.) was coupled with HATU (4 eq.) and DIPEA (10 eq.) in DMF. The product was cleaved from the resin with TFA / TIPS / H2O (95 / 2.5 / 2.5, v / v / v) at RT for 3 hours and identified by mass spectrometry.

[0334] Table 3. Data analysis of final compounds. Metal-free species were determined by mass spectrometry (MALDI-MS).

[0335]

[0336] PSMA-NaI-Chx-Ahx z -Synthesis of DOTA (z = 1, 2, 3, 4)

[0337] The synthesis of the pharmacophore Glu-urea-Lys was carried out as described previously (1). In brief, the synthesis started with the isocyanate forming the glutamyl moiety using triphosgene. Lysine immobilized on resin (2-chloro-trityl resin, Merck, Darmstadt) ε-allyloxycarbonyl protected 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).

[0338] Subsequently, the linker between the PSMA pharmacophore and the chelator was introduced by a standard Fmoc solid phase protocol. In the first step, Fmoc-2-NaI-OH and N-Fmoc-tranexamic acid (5 eq. each) were coupled with HATU (5 eq.) and DIPEA (10 eq.) in DMF. Each coupling step was repeated once. Depending on the amino acid sequence, 6-(Fmoc-amino)-hexanoic acid (5 eq. / coupling) was coupled with HATU (5 eq.) and DIPEA (10 eq.) in DMF once, twice, three times or four times, respectively. Each coupling step was repeated once.

[0339] Then, tris(tBu)DOTA (tris(tBu)-ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 eq.) was coupled with HATU (4 eq.) and DIPEA (10 eq.) in DMF. The product was cleaved from the resin with TFA / TIPS / H2O (95 / 2.5 / 2.5, v / v / v) at RT for 3 hours and identified by mass spectrometry.

[0340] Table 4. Data analysis of final compounds. Mass spectrometry (MALDI-MS) determined the absence of metal species.

[0341]

[0342] Ahx = aminocaproic acid

[0343] Synthesis of DOTA-PEG2-Chx-2-NaI-Lys-urea-Glu, DOTA-PEG4-Chx-2-NaI-Lys-urea-Glu, DOTA-PEG6-Chx-2-NaI-Lys-urea-Glu, and DOTA-PEG8-Chx-2-NaI-Lys-urea-Glu

[0344] The synthesis of the pharmacophore Glu-urea-Lys was carried out as described previously (1). In brief, the synthesis started with the isocyanate forming the glutamyl moiety using triphosgene. Lysine immobilized on resin (2-chloro-trityl resin, Merck, Darmstadt) ε-allyloxycarbonyl protected 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).

[0345] Subsequently, the linker between the PSMA pharmacophore and the chelator was introduced by a standard Fmoc solid phase protocol. In the first step, Fmoc-2-Nal-OH and N-Fmoc-tranexamic acid (4 eq. each) were coupled with HATU (4 eq.) and DIPEA (10 eq.) in DMF.

[0346] Depending on the amino acid sequence, Fmoc-8-amino-3,6-dioxaoctanoic acid (5 eq.) or Fmoc-15-amino-4,7,10,13-tetraoxapentadecanoic acid (5 eq.) or Fmoc-21-amino-4,7,10,13,16,19-hexaoxaheneicosanoic acid (5 eq.) or Fmoc-27-amino-4,7,10,13,16,19-22-25-octaoxaheptacosanoic acid (5 eq.) were coupled with HATU (5 eq.) and DIPEA (10 eq.) in DMF, respectively. Each coupling step was repeated once for each peptide with a single PEG-reactant.

[0347] Then, tris(tBu)DOTA (tris(tBu)-ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (3 eq.) was coupled with HATU (3 eq.) and DIPEA (10 eq.) in DMF. The DOTA coupling was repeated once for each peptide. The product was detached from the resin with TFA / TIPS / H2O (95 / 2.5 / 2.5, v / v / v) at RT for 3 hours and identified by mass spectrometry.

[0348] Table 5. Data analysis of final compounds. Mass spectrometry (MALDI-MS) determined the absence of metal species.

[0349]

[0350] *PEG 2=–NH-CH2-CH2-O-(CH2-CH2-O)1-CH2-C(=O)-

[0351] *PEG 4=-NH-CH2-CH2-O-(CH2-CH2-O)3-(CH2)2-C(=O)-

[0352] *PEG 6=-NH-CH2-CH2-O-(CH2-CH2-O)5-(CH2)2-C(=O)-

[0353] *PEG 8=-NH-CH2-CH2-O-(CH2-CH2-O)7-(CH2)2-C(=O)-

[0354] In vivo characterization

[0355] 177 Lu-labeled

[0356] The precursor peptide [2 nmol, in HEPES buffer (0.1 M, pH 7, 50 μL)] was added to 10 μL [ 177 Lu]LuCl3 (~10-30 MBq, 0.04 M HCl). The reaction mixture was incubated at 95°C for 15 minutes. The radiochemical yield (RCY) was determined by RP-HPLC.

[0357] Cell culture

[0358] PSMA + LNCaP cells (CRL-1740; ATCC; PSMA-positive) were cultured in RPMI medium supplemented with 10% fetal bovine serum and 2 mmol / L L-glutamine (both from PAA). Cells were grown at 37°C in a humidified atmosphere with 5% CO2 and harvested using trypsin-ethylenediaminetetraacetic acid (trypsin-EDTA; 0.25% trypsin, 0.02% EDTA, Invitrogen).

[0359] Cell binding and internalization

[0360] Internalization experiments were performed as described previously ( 2 ).

[0361] For internalization experiments, 10 5 The cells were seeded in poly-L-lysine coated 24-well cell culture plates 24 hours before incubation. After washing, the cells were incubated with 30nM radiolabeled DOTA-compounds at 37°C for 45 minutes (labeling was performed using 5nmol of precursor peptide). Specific cellular uptake was determined by blocking with 500μM 2-PMPA (2-(phosphonomethyl)pentanedioic acid). Cell uptake was terminated by washing 3 times with 1ml of ice-cold PBS. In order to remove surface-bound radioactivity, the cells were incubated twice with 0.5mL of glycine-HCl in PBS (50mM, pH=2.8) for 5 minutes. The cells were washed with 1mL of ice-cold PBS and lysed with 0.3N NaOH (0.5mL). The surface-bound fraction and the internalized fraction were measured in a γ counter. Cellular uptake was calculated by combining the initial radioactivity added with 10 5 The percentage of cells [%ID / 10 5 cells] calculation.

[0362] Table A: 45 minutes later 177 Lu labeled compounds (per 10 5 Cell surface binding and internalization (no blocking or blocked by 2-PMPA) of 7.5 pmol precursor per cell were measured (n=3).

[0363]

[0364]

[0365] *Specific cellular uptake was determined by blocking with 500 μM 2-PMPA. Values ​​are expressed as the ratio of bound applied radioactivity (AR) to 10 5 The percentage of cells is expressed.

[0366] References

[0367] 1. Schafer M, Bauder-Wust U, Leotta K, et al. A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer. EJNMMI Res. 2012; 2: 23.

[0368] 2. Eder M, Schafer M, Bauder-Wust U et al. (68)Ga-Complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012; 23: 688-697.

[0369] 3. Benesova M, Bauder-Wust U, Schafer M et al. Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors. J Med Chem. 2016; 59: 1761-1775.

Claims

1. A PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising: AQ The PSMA binding motif Q and the chelator residue A are connected, and the linker L AQ The invention comprises at least one neutral amino acid X1, wherein the X1 is preferably selected from the group consisting of: Gly, Ala, βAla, Phe, aminocaproic acid (-NH-(CH2)5-C(=O)-) and an amino acid containing at least one -(CH2-CH2-O)- group between the N-terminus and the C-terminus, more preferably, wherein the X1 is selected from the group consisting of: Gly, Ala, βAla, Phe and an amino acid having -NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 An amino acid residue of a -C(=O)- structure, wherein x1 is an integer in the range of 0 to 15, and y1 is 1 or 2.

2. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the PSMA-binding ligand has structure (I): A-L AQ -Q(I)。 3. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to claim 1 or 2, wherein the PSMA-binding motif Q has the following structure: 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.

4. The PSMA-binding ligand according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a chelator residue derived from a chelator 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)- Glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric 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]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N′-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX- DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

5. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 4, wherein A is a chelator residue having a structure selected from the group consisting of: Preferably, A is a chelating agent residue having the following structure:

6. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 5, wherein the linker L AQ Comprising at least one amino acid structural unit AS a , where AS a With the following structure Where Q 1 Selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl.

7. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 6, wherein the linker L AQ Comprising at least one amino acid structural unit AS b , where AS b Having the following structure (b) Where Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably wherein Q 2 yes More preferably 8. The PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7, wherein the PSMA-binding ligand has the following structure (Ia): Where R 1 is H or -CH3, preferably H, wherein R 2 , R 3 , 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 0-3, and wherein n1 is an integer in the range of 1 to 25.

9. The PSMA-binding ligand of any one of claims 1 to 8, wherein the linker L AQ Contains structural unit (X1) n1 ,in, - X1 is selected from the group consisting of Gly, Ala, βAla and Phe, and n1 ranges from 2 to 20, preferably from 3 to 15, more preferably 3, 5, 10 or 15, or -X1 has the structure –NH-CH2-CH2-O-(CH2-CH2-O) x1 -(CH2) y1 -C(=O)-, wherein the integer x1 ranges from 0 to 15, y1 is 1 or 2, and n1 is 1, or -X1 has the structure -NH-(CH2)5-C(=O)-, wherein n1 ranges from 1 to 20, preferably from 1 to 4, or -X1 is Tyr, and n1 ranges from 2 to 20, preferably from 3 to 15, more preferably 3, 5, 10 or 15.

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

11. The complex according to claim 10, 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 Fe, and Pb radionuclides (such as 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb), more preferably selected from the group consisting of: 90 Y. 68 Ga, 177 Lu, 225 Ac and 213 Bi, more preferably, the radionuclide is 177 Lu or 225 Ac.

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

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

14. A PSMA-binding ligand according to any one of claims 1 to 9 or a complex according to claim 10 or 11 or a pharmaceutical composition according to claim 12 for use in diagnosis.

15. The PSMA-binding ligand or complex or pharmaceutical composition according to claim 14, for use in the diagnosis of cancer, preferably PSMA-expressing cancer, in particular prostate cancer, and / or its metastasis.

16. The PSMA-binding ligand, the complex or the pharmaceutical composition for use according to claim 14 or 15, 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.

17. The PSMA-binding ligand, the complex or the pharmaceutical composition for use according to claim 13, wherein the radionuclide is an α-emitter, more preferably 225 Ac, and wherein preferably the active dose of the complex is preferably at least 75 kBq / kg body weight, more preferably at least 100 kBq / kg body weight.

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