Prostate-specific membrane antigen (PSMA) ligands with improved renal clearance

Abstract

The present invention generally relates to radiopharmaceuticals, and their use as tracers, imaging agents in nuclear medicine, and for the treatment of various disease states of PSMA-expressing cancers, particularly prostate cancer and its metastases. In particular, the present invention relates to at least one linker L AQ A PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising a PSMA-binding motif Q and a chelator residue A linked via at least one linker L, wherein the linker comprises at least one N-alkylated, preferably N-methylated amino acid, relates to a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof.

Description

Technical Field

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

Background Art

[0002] Prostate cancer (PCa) is a major cancer in people in the US and Europe. It is estimated that at least 1 to 2 million men in the Western Hemisphere suffer from prostate cancer, and the disease is estimated to affect 1 in 6 men between the ages of 55 and 85 years. There are over 300,000 new cases of prostate cancer diagnosed each year in the USA. The mortality rate from the disease is second only to lung cancer. Currently, imaging methods using high-resolution anatomy, such as computed tomography (CT), magnetic resonance (MR) imaging, and ultrasound, are superior for the clinical imaging of prostate cancer. Currently, an estimated $2 billion per year is spent worldwide on surgical, radiation, drug, and minimally invasive treatments for prostate cancer. For the treatment of localized prostate cancer, radical prostatectomy with lymph node dissection is an established curative strategy. However, accurate localization and delineation of the margins and metastases of the tumor remain difficult. Currently, there is no effective treatment for recurrent, metastatic, androgen-independent prostate cancer.

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

[0004] Radiolabeled choline analogs 18 F]Fluorodihydrotestosterone( 18 F]FDHT), anti-1-amino-3- 18 F]Fluorocyclobutyl-1-carboxylic acid (anti 18 F]F-FACBC, 11 C]Acetate and 1-(2-deoxy-2- 18 F]Fluoro-L-arabinofuranosyl)-5-methyluracil(- 18A variety of experimental low molecular weight PCa imaging agents containing [[F]FMAU] are currently being clinically pursued (Scher, B. et al., Eur J Nucl Med Mol Imaging 2007, 34, 45 - 53; Rinnab, L et al., BJU Int 2007, 100, 786, 793; Reske, S.N. et al., J Nucl Med 2006, 47, 1249 - 1254; Zophel, K., Kotzerke, J. Eur J Nucl Med Mol Imaging 2004, 31, 756 - 759; Vees, H. et al., BJU Int 2007, 99, 1415 - 1420; Larson, S. M. et al., J Nucl Med 2004, 45, 366 - 373; Schuster, D.M. et al., J Nucl Med 2007, 48, 56 - 63; Tehrani, O.S. et al., J Nucl Med 2007, 48, 1436 - 1441). Each acts by a different mechanism and has certain advantages, such as 11 low urinary excretion for [[C]choline and disadvantages, such as a short physical half - life of the positron - emitting radionuclide.

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

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

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

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

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

[0010] As already described above, the strong accumulation of PSMA ligands in non-target tissues, especially the salivary and lacrimal glands, as described in numerous scientific publications, results in significant side effects. The salivary and lacrimal glands can be severely and partially irreversibly damaged, especially during alpha therapy using 225Ac. The resulting xerostomia symptoms represent, for example, dose-limiting side effects. To solve this problem, an improvement in the tissue specificity of PSMA ligands has been proposed, for example, in WO 2020 / 165420 A1. Summary of the Invention Problems to be Solved by the Invention

[0011] Nevertheless, 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 preferably exhibit fewer side effects on the salivary and / or lacrimal glands, especially reduced uptake by the salivary and / or lacrimal glands, thereby reducing the respective side effects. Means for Solving the Problems

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

[0013] The inventors have found novel PSMA-binding ligands that are useful and advantageous radiopharmaceuticals and can be used as tracers, imaging agents in nuclear medicine, and for the treatment of various disease states of PSMA-expressing cancers, particularly prostate cancer. Surprisingly, these PSMA-binding ligands exhibit an advantageous renal excretion profile with favorable clearance acceleration.

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

[0015] In particular, the present invention relates to at least one linker L AQA PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising a PSMA-binding motif Q and a chelator residue A linked via a linker, wherein the linker comprises at least one amino acid X 1 and X 1 is preferably a neutral amino acid, or X 1 is preferably an N-alkylated amino acid, relates to a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof.

[0016] In particular, X 1 is an N-alkylated amino acid, preferably an N-methylated amino acid.

[0017] In particular, the present invention relates to a PSMA-binding ligand having the structure (I) A-L AQ -Q (I) wherein the PSMA-binding motif Q and the chelator residue A are linked via at least one linker L 1 comprising at least one amino acid X, preferably an N-alkylated, more preferably an N-methylated amino acid (N-methylamino acid). AQ Relates to a PSMA-binding ligand.

[0018] Furthermore, the present invention relates to (a) a radionuclide, and (b) a PSMA-binding ligand as described above or below, or a pharmaceutically acceptable salt or solvate thereof relates to a complex comprising the same.

[0019] 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.

[0020] Furthermore, the present invention relates to a PSMA binding ligand as described above or below, or a pharmaceutically acceptable salt or solvate thereof, or a complex as described above or below, or a pharmaceutical composition as described above or below, for use in treating or preventing PSMA-expressing cancer, particularly prostate cancer, and / or its metastasis.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5-1

Figure 5-2

Figure 5-3

Figure 5-4

Figure 5-5

Figure 6

Figure 6a

Figure 7

Figure 7a

Figure 8

Mode for Carrying Out the Invention

[0022] When used hereinafter, the terms "have", "comprise", or "include" or any grammatical variations thereof are used non-exclusively. Thus, these terms can refer to both situations where no additional features exist in the entity described in the context other than the features introduced by these terms, and situations where one or more additional features exist. By way of example, the expressions "A has B", "A comprises B", and "A includes B" can refer to both situations where no other elements exist in A other than B (i.e., the situation where A consists solely and exclusively of B), and situations where one or more additional elements such as element C, elements C and D, or further elements exist in entity A in addition to B. Moreover, as understood by those skilled in the art, the expressions "comprising a" and "comprising an" preferably refer to "comprising one or more", i.e., are equivalent to "comprising at least one".

[0023] Furthermore, when used hereinafter, the terms "preferably", "more preferably", "most preferably", "in particular", "more specifically", "specifically", "even more specifically" or similar terms are used with optional features without restricting further possibilities. Thus, the features introduced by these terms are optional features and are never intended to limit the scope of the claims. The present invention can be implemented, as will be recognized by those skilled in the art, by using alternative features. Similarly, features introduced by "in one embodiment" or similar expressions are optional features without any limitation regarding further embodiments of the present invention, without any limitation regarding the scope of the present invention, and without any limitation regarding the possibility of combining features introduced in this way with other optional or non-optional features of the present invention.

[0024] As used herein, the term "standard conditions", unless otherwise specified, refers to IUPAC standard ambient temperature and pressure (SATP) conditions, i.e., preferably a temperature of 25 °C and an absolute pressure of 100 kPa, and preferably, under standard conditions, pH 7 is included. Further, unless otherwise indicated, the term "about" relates to the value shown with the technical accuracy generally acceptable in the relevant art, preferably, ±20% of the value shown, more preferably ±10%, most preferably ±5%. Further, the term "essentially" indicates that there is no deviation having an impact on the result or use shown, i.e., the possible deviation does not cause a deviation of more than ±20%, more preferably ±10%, most preferably ±5% of the result shown. Thus, "consisting essentially of" means excluding other components, including substances present as impurities, inevitable substances present as a result of the process used to provide the specified components, and components added for purposes other than achieving the technical effects of the present invention. For example, a composition defined using the phrase "consisting essentially of" includes any known acceptable additives, excipients, diluents, carriers, etc. Preferably, a composition consisting essentially of a set of components contains less than 5% by weight, more preferably less than 3% by weight, still more preferably less than 1%, most preferably less than 0.1% by weight of unspecified components.

[0025] An amino acid preferably N-alkylated At least one linker L AQ comprises at least one amino acid X 1 wherein X 1 is - a neutral amino acid, preferably a neutral N-alkylated amino acid, more preferably a neutral N-methylated amino acid, or - an N-alkylated amino acid, preferably an N-methylated amino acid is.

[0026] The term "neutral amino acid", when used within the scope of the meaning of the present invention, includes any amino acid that has no net charge at pH 7. The term includes all naturally occurring amino acids and non-naturally occurring amino acids, for example all stereoisomers of these amino acids, such as enantiomers and diastereomers, for example glycine, alanine, valine, isoleucine, phenylalanine, beta-alanine, and non-natural amino acids containing a neutral linker between the N-terminus and the C-terminus, for example non-natural amino acids containing at least one -(CH2-CH2-O)- group between the N-terminus and the C-terminus.

[0027] In particular, X1 is an N-alkylated amino acid (also referred to herein as an alkylated amino acid or an N-alkyl amino acid), more preferably an N-methylated amino acid (also referred to herein as a methylated amino acid or an N-methyl amino acid), that is, an amino acid containing an alkyl or methyl group bonded to the amino group of the amino acid instead of a proton-H.

[0028] As used throughout this application, the terms "alkyl", "alkyl residue", "alkyl group" and "alkyl moiety" can be understood to be straight-chain or branched saturated hydrocarbon chains. "Straight-chain" can also be referred to as "unbranched" or "linear". Preferably, the alkyl is straight-chain.

[0029] Preferably, the alkyl group is C 1~4 alkyl. "C 1~4 alkyl" means an alkyl chain having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. Preferably, the alkyl group is methyl or ethyl, preferably methyl.

[0030] It should be understood that the term includes all naturally occurring amino acids and non-naturally occurring amino acids, such as all stereoisomers of these amino acids, such as enantiomers and diastereomers, and N-alkyl, preferably N-methyl derivatives thereof. Most preferably, the amino acid is an N-alkylated, preferably N-methylated alpha amino acid. With respect to chirality, L-amino acids are preferred.

[0031] The term N-alkylated amino acid or N-alkyl amino acid includes, but is not limited to, N-alkyl-arginine, N-alkyl-histidine, N-alkyl-lysine, N-alkyl-aspartic acid, N-alkyl-glutamic acid, N-alkyl-serine, N-alkyl-threonine, N-alkyl-asparagine, N-alkyl-glutamine, N-alkyl-cysteine, selenocysteine, N-alkyl-glycine, N-alkyl-proline, N-alkyl-alanine, N-alkyl-valine, N-alkyl-isoleucine, N-alkyl-leucine, N-alkyl-methionine, N-alkyl-phenylalanine, N-alkyl-tyrosine, N-alkyl-tryptophan.

[0032] More preferably, at least one N-alkyl-amino acid is a neutral amino acid.

[0033] The term "neutral amino acid", when used within the meaning of the present invention, includes any amino acid that has no net charge at pH 7. Non-limiting examples of neutral amino acids are 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.

[0034] The term "methylated amino acid" or "N-methyl amino acid" includes, but is not limited to, N-methylarginine, N-methylhistidine, N-methyllysine, N-methylaspartic acid, N-methylglutamic acid, N-methylserine, N-methylthreonine, N-methylasparagine, N-methylglutamine, N-methylcysteine, selenocysteine, N-methylglycine, N-methylproline, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methylleucine, N-methylmethionine, N-methylphenylalanine, N-methyltyrosine, N-methyltryptophan.

[0035] More preferably, at least one N-methyl amino acid is a neutral amino acid, such as N-methylglycine, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methylleucine, N-methylmethionine, N-methylphenylalanine, N-methyltyrosine or N-methyltryptophan.

[0036] More preferably, at least one N-methyl amino acid is selected from the group consisting of N-methylglycine, N-methylalanine, N-methylvaline, N-methylisoleucine, N-methylleucine, N-methylphenylalanine.

[0037] More preferably, the methylated amino acid is N-methylalanine or N-methylglycine (sarcosine), more preferably N-methylglycine, and thus at least one amino acid preferably has the structure X1, where X 1 is -N(CH 3 )-CH 2 -C(=O)- or -N(CH 3 )-CH(CH 3 )-C(=O)-, more preferably -N(CH 3 )-CH 2 -C(=O)-.

[0038] X 1 is -N(CH 3 )-CH 2When it is -C(=O)-, the amino acid preferably has an L-conformation.

[0039] Optionally, the linker L AQ is N-alkylated X 1 and further contains an additional amino acid X.

[0040] According to one preferred embodiment, the linker L AQ contains an amino acid sequence AA of 2 to 25 amino acids, and the amino acid X1 is part of the sequence. It should be understood that the sequence AA contains at least one amino acid X1.

[0041] When the linker contains two or more N-methylated amino acids, the N-methylated amino acids may be the same as or different from each other. Thus, the linker is, for example, -N(CH 3 )-CH 2 -C(=O)- and -N(CH 3 )-CH(CH 3 )-C(=O)- groups, or only -N(CH 3 )-CH 2 -C(=O)- or -N(CH 3 )-CH(CH 3 )-C(=O)- groups or only -N(CH 3 )-CH 2 -C(=O)- groups may be included.

[0042] Preferably, the linker L AQ contains at least 3, preferably 3 to 25, amino acids which may be the same or different.

[0043] According to a preferred embodiment, the N-methylated amino acids are bonded to each other and form the sequence AA.

[0044] More preferably, the linker L AQ contains the linking unit -(X 1 )n 1 -, where X 1 is an N-alkylated amino acid, preferably X1 is -N(CH 3 )-CH 2 -C(=O)- or -N(CH 3 )-CH(CH 3 )-C(=O)-, preferably -N(CH 3 )-CH 2 -C(=O)-, and n1 is preferably an integer from 1 to 25, preferably from 2 to 25, more preferably from 3 to 25, and even more preferably from 3 to 15.

[0045] The linking unit -(X 1 )n 1 Preferably, the linker L AQ comprises the linking unit -(X 1 )n 1 -, where X 1 is --N(CH 3 )-CH 2 -C(=O)- or -N(CH 3 )-CH(CH 3 )-C(=O)-, and n1 is preferably an integer from 1 to 25, more preferably from 2 to 25, even more preferably from 3 to 25, and even more preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. Even more preferably, n1 is 3, 5, 10 or 15.

[0046] Even more preferably, the linker L AQ comprises the linking unit -(X 1 )n 1 -, where X 1 is --N(CH 3 )-CH 2 -C(=O)-, and n1 is preferably an integer from 2 to 25, more preferably from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. Even more preferably, n1 is 3, 5, 10 or 15.

[0047] In a preferred embodiment, n1 is 3 or 15, more preferably 3.

[0048] Thus, according to one preferred embodiment, L AQ comprises the linking unit -(X 1 )n 1 -, where X 1 is --N(CH 3 )-CH 2 -C(=O)-, and n1 is 3.

[0049] According to another preferred embodiment, L AQ comprises the linking unit -(X 1 )n 1 -, where X 1 is --N(CH 3 )-CH 2 -C(=O)-, and n1 is 5.

[0050] According to another preferred embodiment, L AQ comprises the linking unit -(X 1 )n 1 -, where X 1 is --N(CH 3 )-CH 2 -C(=O)-, and n1 is 10.

[0051] According to another preferred embodiment, L AQ comprises the linking unit -(X 1 )n 1 -, where X 1 is --N(CH 3 )-CH 2 -C(=O)-, and n1 is 15.

[0052] PSMA binding motif The PSMA binding motif Q preferably has the structure

[0053] [Chemical formula] (wherein R 1 is H or -CH 3 , preferably H, and R 2 , R 3 and R 4 are independently of each other -CO 2H, -SO 2 H, -SO 3 H, -OSO 3 H, -PO 2 H, -PO 3 H and -OPO 3 H 2 (selected from the group consisting of) has. More preferably, R 2 R 3 and R 4 is CO 2 H. In particular, R1 is H, and R 2 R 3 and R 4 is CO 2 H.

[0054] Chelating agent residue A A is a chelating agent residue derived from a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (=DOTA), N,N''-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N''-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), and 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA (MX-DTPA).

[0055] The term "chelating agent residue" and typically the term "chelating agent residue derived from a chelating agent selected from the group", as described above, means that the chelating agent described above, and thus typically the chelating agent defined in the "group", is linked to the remainder of the PSMA binding ligand, preferably via a suitable functional group to the linker L AQ It is shown to mean that it is linked.

[0056] More preferably, the chelating agent defined in the "group" is linked to the N-terminus of L AQ via the original carboxylic acid group of the chelating agent, thereby forming an amide bond between the chelating agent and L AQ

[0057] Preferably, A is a group consisting of the following

[0058]

Chemical formula

[0059] Most preferably, A has the structure

[0060]

Chemical formula

[0061] Linker L AQ Preferably, linker L AQ is X 1 or (X 1 ) n1 In addition, further includes at least one amino acid building block AS a and / or at least one amino acid building block AS B , preferably at least one amino acid building block AS a and at least one amino acid building block AS B

[0062] ​​​Amino acid building block AS a Amino acid building block AS a in particular has the structure

[0063] [Chemical formula] (wherein Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl) and has

[0064] The term "aryl", as used in the context of the present invention, means an optionally substituted 5- or 6-membered aromatic ring, and a substituted or unsubstituted polycyclic aromatic group (aryl group), for example, a tricyclic or bicyclic aryl group. Optionally substituted phenyl or naphthyl groups may be mentioned by way of example. The polycyclic aromatic group may also contain non-aromatic rings.

[0065] The term "alkylaryl", as used in the context of the present invention, refers to an aryl group (alkyl-aryl-) in which at least one proton has been replaced by an alkyl group.

[0066] The term "arylalkyl", as used in the context of the present invention, refers to an aryl group (aryl-alkyl-) linked via an alkyl group.

[0067] As used in the context of this invention, the term "heteroaryl" means a 5- or 6-membered aromatic ring, optionally substituted, containing one or more, for example 1 to 4, for example 1, 2, 3, or 4 heteroatoms in the ring system, and a substituted or unsubstituted polycyclic aromatic group, such as a tricyclic or bicyclic aryl group. When two or more heteroatoms are present in the ring system, at least two of the heteroatoms present may be the same or different. Suitable heteroaryl groups are known to those skilled in the art. The following heteroaryl residues may be described as non-limiting examples: benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, methylenedioxyphenyl, naphthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0068] As used in the context of this invention, the term "alkylheteroaryl" refers to a heteroaryl group (alkyl-heteroaryl-) in which at least one proton has been replaced by an alkyl group.

[0069] As used in the context of this invention, the term "heteroarylalkyl" refers to a heteroaryl group (heteroaryl-alkyl-) linked via an alkyl group.

[0070] As used in the context of this invention, the term "cycloalkyl" means an optionally substituted cyclic alkyl residue, where they may be monocyclic or polycyclic groups. Optionally substituted cyclohexyl may be described as a preferred example of a cycloalkyl residue.

[0071] The term "heterocycloalkyl", as used in the context of this invention, refers to an optionally substituted cyclic alkyl residue having at least one heteroatom, such as O, N or S, in the ring, where they may be monocyclic or polycyclic groups.

[0072] The term "substituted cycloalkyl residue" or "cycloheteroalkyl", as used in the context of this invention, means a cycloalkyl residue or cycloheteroalkyl residue in which at least one H has been replaced by a suitable substituent.

[0073] Preferably, Q1 comprises a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl, and more preferably, Q 1 is from the group consisting of:

[0074]

Chemical formula

[0075]

Chemical formula

[0076] Amino acid building block AS b Amino acid building block AS b preferably has the structure (b)

[0077]

Chemical formula

[0078] The term "aryl", when used in the context of this invention, refers to optionally substituted 5- and 6-membered aromatic rings, and substituted or unsubstituted polycyclic aromatic groups (aryl groups), for example tricyclic or bicyclic aryl groups (-Ar-). Optionally substituted phenyl or naphthyl groups may be mentioned as examples. The polycyclic aromatic group may also contain a non-aromatic ring, an aryl group, in the context of this invention.

[0079]

[0079] The term "alkylaryl", when used in the context of this invention, refers to an aryl group (-alkyl-aryl-) in which at least one proton has been replaced by an alkyl group and which is linked via the alkyl group to a -CH2- group and via the aryl group to a carbonyl group.

[0080] The term "arylalkyl", when used in the context of this invention, refers to an aryl group (-aryl-alkyl-) which is linked via an alkyl group to a carbonyl group and via an aryl group to a -CH2- group.

[0081] The term "heteroaryl" (-heteroaryl-), when used in the context of the present invention, means a 5- or 6-membered aromatic ring, optionally substituted, containing one or more, for example 1 to 4, for example 1, 2, 3, or 4 heteroatoms in the ring system, and a substituted or unsubstituted polycyclic aromatic group, for example a tricyclic or bicyclic aryl group. When two or more heteroatoms are present in the ring system, at least two of the heteroatoms present may be the same or different. Suitable heteroaryl groups are known to those skilled in the art. The following heteroaryl residues may be described as non-limiting examples: benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, methylenedioxyphenyl, naphthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0082] The term "alkylheteroaryl", when used in the context of the present invention, refers to an aryl group that is linked to a -CH2- group via an alkyl group and to a carbonyl group via a heteroaryl group, with at least one proton replaced by an alkyl group (-alkyl-heteroaryl-).

[0083] The term "heteroarylalkyl", when used in the context of the present invention, refers to a heteroaryl group that is linked to a carbonyl group via an alkyl group and to a -CH2- group via a heteroaryl group (-aryl-alkyl-).

[0084] The term "cycloalkyl" (-cycloalkyl-) means, in the context of the present invention, an optionally substituted cyclic alkyl residue, where they may be monocyclic or polycyclic groups. Optionally substituted cyclohexyl may be described as a preferred example of a cycloalkyl residue.

[0085] The term "heterocycloalkyl", when used in this context of the present invention, refers to an optionally substituted cyclic alkyl residue having at least one heteroatom, such as O, N or S, in the ring, where they may be monocyclic or polycyclic groups.

[0086] The term "substituted cycloalkyl residue" or "cycloheteroalkyl", when used in this context of the present invention, means a cycloalkyl residue or cycloheteroalkyl residue in which at least one H has been replaced by a suitable substituent.

[0087] Preferably, Q 2 is an aryl group or a cycloalkyl group, more preferably

[0088]

Chemical formula

[0089]

Chemical formula

[0090] Any stereoisomers of Q 2 are possible and should be understood to be included. Q 2 when

[0091]

Chemical formula

[0092] The PSMA-binding ligand described above or below is preferably selected from the group consisting of (Ia), (Ib) and (Ic).

[0093]

Chemical formula

[0094] The PSMA-binding ligand described above or below is preferably of structure (Ia).

[0095]

Chemical formula

[0096] More preferably, the PSMA binding ligand described above or below has the structure (Ia), and Q 1 includes residues selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl. More preferably, Q 1 is from the group consisting of

[0097]

Chemical formula

[0098]

Chemical formula

[0099]

Chemical formula

[0100] [Chemical formula] is as follows.

[0101] In particular, the present invention relates to a PSMA-binding ligand as described above and below, wherein the ligand has a structure

[0102] [Chemical formula] (wherein A is a chelating agent residue having a structure

[0103] [Chemical formula] and Q2 is

[0104] [Chemical formula] and more preferably

[0105] [Chemical formula] is q is 1, Q 1 is

[0106] [Chemical formula] is R 3 , R 2 and R 4 are -CO 2 H, R 1 is H, n1 is preferably an integer of 1 to 25, preferably 2 to 25, more preferably 3 to 25, and even more preferably 3 to 15, X 1is as described above, preferably, X 1 is N-methylglycine (sarcosine) or N-methylalanine, more preferably N-methylglycine) relates to a PSMA-binding ligand having

[0107] In particular, the PSMA-binding ligand consists of the group of the following compounds:

[0108]

Chemical formula

[0109] In a preferred embodiment, the PSMA-binding ligand is

[0110]

Chemical formula

[0111]

Chemical formula

[0112]

Chemical formula

[0113] As described above, the present invention also relates to a complex comprising (a) a radionuclide, and (b) a PSMA-binding ligand as described above or below or a pharmaceutically acceptable salt or solvate thereof

[0114] ​Typical pharmaceutically acceptable salts include salts prepared by the reaction of the PSMA binding ligand of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts. Acids commonly used to form acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc., and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc. Examples of such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc. Preferred pharmaceutically acceptable acid addition salts are those formed from mineral acids such as hydrochloric acid and hydrobromic acid, and those formed from organic acids such as maleic acid and methanesulfonic acid. The salts of amine groups can also include quaternary ammonium salts in which the amino nitrogen has a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety. Base addition salts include those derived from inorganic bases such as ammonium or hydroxides, carbonates, bicarbonates of alkali metals or alkaline earth metals, etc.Such bases useful in preparing the salts of the present invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. Potassium salt and sodium salt forms are particularly preferred. The specific counterions that form part of any salt of the present invention are generally recognized as not being of critical nature provided that the salt is pharmaceutically acceptable as a whole and the counterions do not impart undesirable qualities to the salt as a whole.

[0115] The term "pharmaceutically acceptable solvate" also encompasses suitable solvates of the PSMA-binding ligand of the present invention, where the PSMA-binding ligand combines with a solvent such as water, methanol, ethanol, DMSO, acetonitrile, or a mixture thereof to form a suitable solvate such as the corresponding hydrate, methanolate, ethanolate, DMSO solvate, or acetonitrileate.

[0116] Radionuclide Depending on whether the PSMA-binding ligand of the present invention is to be used as a radioimaging agent or a radiopharmaceutical, different radionuclides are complexed to the chelating agent.

[0117] The complex of the present invention can contain one or more radionuclides, preferably one radionuclide. These radionuclides are preferably suitable for use as a radioimaging agent or as a therapeutic agent for the treatment of proliferating cells such as PSMA-expressing cancer cells, particularly PSMA-expressing prostate cancer cells. According to the present invention, they are referred to as "metal complexes" or "radiopharmaceuticals".

[0118] Preferred imaging methods are positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0119] Preferably, at least one radionuclide is 89 Zr, 44 Sc, 111 In,90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Er, 52 Fe, 59 radioactive nuclides of Fe, and Pb (e.g., 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb) selected from the group consisting of.

[0120] More preferably, at least one radioactive nuclide is 90 Y, 68 Ga, 177 Lu, 225 Ac, and 213 Bi selected from the group consisting of. More preferably, the radioactive nuclide is 177 Lu or 225 Ac.

[0121] Preferably, the radionuclide has a half-life of at least 30 minutes, more preferably at least 1 hour, even more preferably at least 12 hours, still more preferably at least 1 day, and most preferably at least 5 days, and preferably, the radionuclide has a half-life of at most 1 year, more preferably at most 6 months, even more preferably at most 1 month, still more preferably at most 14 days. Thus, preferably, the radionuclide has a half-life of from 30 minutes to 1 year, more preferably from 12 hours to 6 months, still more preferably from 1 day to 1 month, and most preferably from 5 days to 14 days.

[0122] Preferably, the radionuclide is an α- and / or β-emitter, i.e., the radionuclide preferably emits α-particles (α-emitter) and / or β-radiation (β-emitter).

[0123] Preferably, when the radionuclide is an α-emitter, the α-particles have an energy of from 1 to 10 MeV, more preferably from 2 to 8 MeV, and most preferably from 4 to 7 MeV.

[0124] Preferably, when the radionuclide is a β-emitter, the β-radiation has an energy of from 0.1 to 10 MeV, more preferably from 0.25 to 5 MeV, and most preferably from 0.4 to 2 MeV.

[0125] Preferred radionuclides that emit β-radiation are 90 Y, 177 Lu, 59 Fe, 66 Cu, 67 Cu, 161 Tb, 153 Sm, 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 selected from the group consisting of Pb, and highly preferred radionuclides that emit β-radiation are 177 Lu or 90 Y, most preferably 177 Lu. Preferably, in this case, the use is for diagnosis or treatment.

[0126] Preferred radionuclides that emit α-radiation are, for example, 213 Bi, 225 Ac, 149 Tb, 230 U and 223 Ra, 213 Bi, 230 U, and are selected from the group consisting of; more preferably, the radionuclide is 225 Ac and / or 213 Bi. A highly preferred radionuclide that emits α-radiation is, for example 225 Ac. Preferably, in this case, the use is for therapy.

[0127] According to a further embodiment, the radionuclide is a positron emitter. In this case, the radionuclide is preferably 89 Zr, 44 Sc, 66 Ga, 68 Ga and 64 Cu, and is selected from the group consisting of. In this case, the use is preferably for PET diagnosis.

[0128] According to a more preferred embodiment, the radionuclide is a gamma emitter. In this case, the radionuclide is preferably 111 In, 67 Ga, 99m Tc, 155 Tb, 165 Er and 203 Pb, and is selected from the group consisting of. In this case, the use is preferably for SPECT diagnosis.

[0129] According to a still more preferred embodiment, the radionuclide emits Auger electrons and preferably decays by electron capture. In this case, the radionuclide is preferably 67 Ga, 155 Tb, 153 Gd, 165 Er and 203 Pb, and is selected from the group consisting of. In this case, the use is preferably for therapy.

[0130] Pharmaceutical composition As described above, the present invention also relates to a pharmaceutical composition comprising a PSMA binding ligand as described above or below or a complex as described above or below. The pharmaceutical composition should preferably be understood to comprise a therapeutically effective amount of each of the PSMA binding ligand and / or the complex. The pharmaceutical composition may further comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0131] The terms "pharmaceutical" and "pharmaceutical composition" as used herein relate to the PSMA binding ligand and / or complex of the present invention and optionally one or more pharmaceutically acceptable carriers, i.e., excipients. The PSMA binding ligand of the present invention can be formulated as a pharmaceutically acceptable salt, and the salts are described above herein. The pharmaceutical composition is preferably administered locally (e.g., intratumorally), topically or systemically. Suitable routes of administration conventionally used for drug administration are oral, intravenous or parenteral administration, and inhalation. The preferred route of administration is parenteral administration. "Parenteral route of administration" means a mode of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, intrathecal, intramedullary and intrasternal injections and infusions. Preferably, the administration is by intravenous administration or infusion. However, depending on the nature and mode of action of the PSMA binding ligand, the pharmaceutical composition may be administered by other routes as well.

[0132] Furthermore, the PSMA binding ligand can be administered in combination with other drugs either in a common pharmaceutical composition or as separate pharmaceutical compositions, where the separate pharmaceutical compositions may be provided in the form of a 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 preparation. It is recognized that the form and characteristics of the pharmaceutically acceptable carrier or diluent are determined by the amount of active ingredient to be combined, the route of administration and other well-known variables.

[0133] An excipient must be compatible with the other ingredients of the formulation and, within the scope of sound medical judgment, must be acceptable in the sense of having an appropriate benefit / risk ratio for use in contact with the tissues of the patient without undue toxicity, irritation, allergic response, or other problems or complications. Preferably, the excipient is not harmful to its recipient. The excipient used may be, for example, a solid, gel, or liquid carrier. Exemplary solid carriers are lactose, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, etc. Exemplary liquid carriers are phosphate buffered saline aqueous solution, syrup, oil, such as peanut oil and olive oil, water, emulsion, various types of wetting agents, sterile solutions, etc. Similarly, the carrier or diluent may contain time-delay materials well known in the art, such as glyceryl monostearate or glyceryl distearate, alone or together with waxes. The suitable carriers include those described above and others well known in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic non-therapeutic non-immunogenic stabilizers, etc. When solutions for infusion or injection are used, they are preferably aqueous solutions or suspensions, which can be produced from lyophilized preparations containing, for example, the active substance as such or together with a carrier, such as mannitol, lactose, glucose, albumin, etc., prior to use. The ready-made solutions are sterilized and, where appropriate, mixed with excipients, such as preservatives, stabilizers, emulsifiers, solubilizers, buffers, and / or salts for adjusting the osmotic pressure. Sterilization can be obtained by sterile filtration using a filter with a small pore size, and, where appropriate, the composition can be lyophilized accordingly. A small amount of antibiotic can also be added to ensure the maintenance of sterility.

[0134] A therapeutically effective amount refers to the amount of a PSMA-binding ligand to be used in the pharmaceutical composition of the present invention for preventing, ameliorating, or treating symptoms associated with the diseases or conditions mentioned in this specification. The therapeutic efficacy and toxicity of such PSMA-binding ligands can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, ED50 (the therapeutically effective dose in 50% of the population) and LD50 (the lethal dose in 50% of the population). The dose ratio between the therapeutic effect and the toxic effect is the therapeutic index, which can be expressed as the ratio of LD50 / ED50.

[0135] The dosing regimen is determined, preferably according to any one of the methods described above, by the attending physician and other clinical factors. As is well known in the medical art, the dosage for any one patient depends on many factors, including the patient's size, body surface area, age, the particular PSMA-binding ligand to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Progression can be monitored by periodic assessment. Preferred dosages are specified below in this specification. Progression can be monitored by periodic assessment. The pharmaceutical compositions and formulations referred to herein are administered at least once to treat or prevent the diseases or conditions listed herein. However, said pharmaceutical compositions may be administered two or more times, for example, 1 to 10 times. Preferably, the pharmaceutical compositions may be administered at a frequency of once every 1 to 6 months, more preferably once every 2 to 4 months. The specific pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and contain at least one active PSMA-binding ligand as referred to above herein, in an additive mixture or otherwise in association with a pharmaceutically acceptable carrier or diluent. To prepare those specific pharmaceutical compositions, the active compounds are usually mixed with a carrier or diluent or enclosed or encapsulated in capsules, sachets, cachets, paper, or other suitable containers or vehicles. The resulting formulations should be adapted to the mode of administration, i.e., in the form of tablets, capsules, suppositories, solutions, suspensions, etc. Dosage recommendations are to be as indicated in the prescriber or user instructions to predict dosage adjustment depending on the recipient considered.

[0136] The term "patient" as used herein relates to vertebrates, preferably mammalian animals, more preferably humans, monkeys, female cows, horses, cats, or dogs. Preferably, the mammalian animal is a primate, more preferably a monkey, and most preferably a human.

[0137] The dosage of the PSMA-binding ligand administered to a patient is preferably defined as the compound dosage, i.e., the amount of the PSMA-binding ligand administered to the patient. A preferred diagnostic compound dosage is a total dosage of 1 to 10 nmol / patient, and thus, preferably, the diagnostic compound dosage is 0.02 to 0.1 nmol / kg body weight. A preferred therapeutic compound dosage is a total dosage of 10 to 100 nmol / patient, and thus, preferably, the therapeutic compound dosage is 0.2 to 1 nmol / kg body weight.

[0138] As will be understood by those skilled in the art, the dosage of the complex as specified herein, i.e., the complex comprising and preferably consisting of a radionuclide and a PSMA-binding ligand, is preferably indicated as the compound dosage as specified above, and the preferred dosage is the same as that specified above. More preferably, the dosage of the complex is indicated as the activity dosage, i.e., the amount of radioactivity administered to the patient. Preferably, the activity dosage is adjusted to avoid adverse effects as specified elsewhere herein. Preferably, the patient-specific dosage, preferably the patient-specific activity dosage, is determined taking into account relevant factors as specified elsewhere herein, in particular, taking into account the treatment progression and / or adverse effects observed for each patient. Thus, preferably, the activity dosage is adjusted such that the organ-specific dosage in the salivary gland is at most 30 Sv, more preferably less than 20 Sv, even more preferably less than 10 Sv, and most preferably less than 5 Sv.

[0139] The effective amount may be administered once (single dose) at an activity dose of about 2 MBq to about 30 MBq, preferably 4 to 30 MBq, more preferably 6 to 30 MBq, more preferably 8 to 30 MBq, more preferably 10 to 30 MBq, more preferably 15 to 30 MBq, preferably 20 to 30 MBq per patient. Thus, the preferred therapeutic dose in such cases is 2 MBq to about 30 MBq / patient, preferably 4 to 30 MBq / patient, more preferably 6 to 30 MBq / patient, more preferably 8 to 30 MBq / patient, more preferably 10 to 30 MBq / patient, more preferably 15 to 30 MBq / patient, preferably 20 to 30 MBq / patient. Preferably, the activity dose is about 10 to 30 MBq per administration, for example, about 10 MBq, 11 MBq, 12 MBq, 13 MBq, 14 MBq, 15 MBq, 16 MBq, 17 MBq, 18 MBq, 19 MBq, 20 MBq, 21 MBq, 22 MBq, 23 MBq, 24 MBq, 25 MBq, 26 MBq, 27 MBq, 28 MBq, 29 MBq or 30 MBq, or any range between any two of the above values, etc. However, as specified hereinafter in this specification, higher or lower doses may be expected depending on the type and / or use of the radiation emitted by the radionuclide. The phrase "effective amount" or "therapeutically effective amount", as used herein, means an amount of a PSMA-binding ligand, a material or composition comprising the PSMA-binding ligand of the present invention, or other active ingredient that is effective to produce some desired therapeutic effect in the cells of at least a subpopulation in a patient with a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutically effective amount with respect to the PSMA-binding ligand of the present invention means the amount of the therapeutic agent that provides a therapeutic benefit in the treatment or prevention of a disease, alone or in combination with other treatments. The term as used in connection with the PSMA-binding ligand of the present invention can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease, or enhances the therapeutic effectiveness or synergistic action with another therapeutic agent.

[0140] According to a preferred embodiment, the radionuclide is a β-emitter as specified above herein, more preferably177 It is Lu, and the use is for diagnosis. In such a case, the activity dosage of the complex is preferably at least 100 kBq / kg body weight, more preferably at least 500 kBq / kg body weight, and most preferably at least 1 MBq / kg body weight. More preferably, the radionuclide is a β-emitter as specified above herein, and more preferably 177 It is Lu, and the use is for treatment, preferably for the treatment of prostate carcinoma as specified elsewhere herein. In such a case, the activity dosage of the complex is preferably at least 25 MBq / kg body weight, more preferably at least 50 MBq / kg body weight, and most preferably at least 80 MBq / kg body weight. Therefore, the preferred treatment dosage in such a case is 2 - 10 Gbq / patient, more preferably 4 - 8 GBq / patient, and most preferably about 6 GBq / patient.

[0141] More preferably, the radionuclide is an α-emitter as specified above herein, and more preferably 225 It is Ac, and the use is for treatment, preferably for the treatment of prostate carcinoma as specified elsewhere herein. In such a case, the activity dosage of the complex is preferably in the range of 25 kBq / kg to about 500 kBq / kg of the patient's body weight. More preferably, the activity dosage of the complex is at least 75 kBq / kg body weight, more preferably at least 100 kBq / kg body weight, still more preferably at least 150 kBq / kg body weight, and most preferably at least 200 kBq / kg body weight. Therefore, preferably, in such a case, the activity dosage of the complex is 75 - 500 kBq / kg body weight, more preferably 100 - 400 kBq / kg body weight, still more preferably 150 - 350 kBq / kg body weight, and most preferably 200 - 300 kBq / kg body weight.

[0142] The present invention also relates to a PSMA binding ligand as described above or below, a complex as described above or below, or a pharmaceutical composition as described above herein, for use in diagnosis, preferably for diagnosing a cell proliferative disease or disorder, in particular prostate cancer and / or its metastases. Furthermore, the present invention also relates to a PSMA binding ligand as described above or below, a complex as described above or below, or a pharmaceutical composition as described above or below, for use in medicine, preferably for treating or preventing a cell proliferative disease or disorder, in particular prostate cancer and / or its metastases.

[0143] As used herein, the term "diagnosing" refers to determining whether a subject has or does not have a disease or disorder, preferably a proliferative disease or disorder. As will be understood by those skilled in the art, such determination is preferably correct for 100% of the subjects being investigated, but usually may not be correct for 100% of the subjects being investigated. However, the term requires that a statistically significant proportion of the subjects be correctly determined and thus be diagnosable. Whether a portion is statistically significant can be readily determined by those skilled in the art using various well-known statistical evaluation tools, such as determination of confidence intervals, p-value determination, Student's t-test, Mann-Whitney test, etc. Details can be found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983. Preferred confidence intervals are at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%. The p-value is preferably 0.2, 0.1, or 0.05. As will be understood by those skilled in the art, diagnosing can include further diagnostic determinations, such as visual and / or manual examination, determination of tumor biomarker concentration in a sample of the subject, X-ray examination, etc. The term includes not only the individual diagnosis of a patient, but also the continuous monitoring of a patient. Monitoring the presence or absence of a proliferative disease or associated symptoms at various time points, i.e., diagnosing, includes not only monitoring patients known to have a proliferative disease, but also monitoring subjects known to be at risk of developing a proliferative disease. Further, monitoring can also be used to determine whether a patient is being successfully treated or whether at least the symptoms of a proliferative disease can be improved over time by a particular treatment. Further, the term also includes classifying a subject according to a normal classification scheme, such as the T1-T4 staging known to those skilled in the art.

[0144] The terms "treating" and "treatment" refer to a significant degree of improvement of a disease or disorder or a symptom associated therewith mentioned herein. The treating, as used herein, also includes the restoration of overall health with respect to the disease or disorder mentioned herein. It should be understood that treating may not be effective in all subjects to be treated when the term is used herein. However, the term preferably requires that a statistically significant proportion of subjects suffering from the disease or disorder mentioned herein can be successfully treated. Whether a portion is statistically significant can be readily determined by one of ordinary skill in the art using various well-known statistical evaluation tools as specified above herein. The terms "preventing" and "prevention" refer to maintaining health in a subject for a particular period of time with respect to the disease or disorder mentioned herein. It is understood that the period of time may be dependent on the amount of the administered pharmaceutical compound and the individual factors of the subject considered elsewhere in this specification. Prevention may not be effective in all subjects treated with a PSMA-binding ligand according to the present invention. However, the term preferably requires that a statistically significant proportion of a cohort or population of subjects be effectively prevented from suffering from the disease or disorder or a symptom associated therewith mentioned herein. Preferably, a cohort or population of subjects that would develop the disease or disorder mentioned herein in the absence of the preventive measures according to the present invention is expected in this context. Whether a portion is statistically significant can be readily determined by one of ordinary skill in the art using various well-known statistical evaluation tools considered above herein.

[0145] Preferably, the treatment and / or prevention comprises administration of at least one PSMA-binding ligand and / or at least one complex as specified elsewhere herein, more preferably at an active dosage and / or a compound dosage as specified above herein.

[0146] The term "cell proliferative disorder", as used herein, relates to a disease in animals, including humans, characterized by uncontrolled growth by a group of somatic cells ("cancer cells"). This uncontrolled growth may be accompanied by invasion and destruction of the surrounding tissue by the cancer cells and possibly its spread (metastasis) to other locations in the body. Preferably, included thereon by the term cancer is recurrence. Thus, preferably, cancer is a solid tumor, metastasis, or its recurrence. Preferably, the cell proliferative disorder is an uncontrolled proliferation of cells, including cells that express PSMA.

[0147] Accordingly, preferably, the cell proliferative disorder is a PSMA-expressing cancer. The term "PSMA-expressing cancer" refers to any cancer in which cancerous cells express prostate-specific membrane antigen (PSMA). Preferably, the cancer (or cancer cells) that can be treated according to the present invention is selected from prostate cancer, conventional renal cell cancer, transitional cell cancer of the bladder, lung cancer, testicular embryonal cancer, neuroendocrine cancer, colon cancer, brain tumor, and breast cancer, more preferably selected from PSMA-positive prostate cancer, PSMA-positive renal cell cancer, PSMA-positive transitional cell cancer of the bladder, PSMA-positive lung cancer, PSMA-positive testicular embryonal cancer, PSMA-positive neuroendocrine cancer, PSMA-positive colon cancer, PSMA-positive brain tumor, and PSMA-positive breast cancer. Whether a cancer is PSMA-positive can be determined by those skilled in the art by methods known in the art, for example, in vitro by immunostaining a cancer sample, or in vivo, for example, by PSMA scintigraphy, preferably both as established as described by Kratochwil et al. (2017, J Nucl Med 58(10):1624). In a particularly preferred embodiment of the present invention, the PSMA-expressing cancer is prostate cancer or breast cancer, more preferably prostate cancer, even more preferably advanced-stage prostate cancer. Accordingly, preferably, the cell proliferative disorder is prostate cancer stage T2, more preferably stage T3, most preferably stage T4. Preferably, the cell proliferative disorder is metastatic prostate cancer, more preferably metastatic castration-resistant prostate cancer. Advantageously, administration of the PSMA-binding ligand and / or complex of the present invention to a patient results in an improved pharmacokinetic profile, particularly improved renal excretion, with essentially unchanged enrichment in the target tissue, preferably the cell proliferative tissue, more preferably the cancer tissue, as compared to, for example, PSMA-617 commonly used on the one hand, as shown in the studies underlying the present invention. The improved excretion can avoid and / or reduce adverse side effects on non-target tissues, particularly the salivary gland and / or lacrimal gland. This is advantageous because adverse side effects on the salivary gland are considered as a dose-limiting factor (see Kratochwil et al. (2017, J Nucl Med 58(10):1624)).Based on the findings of the present invention, larger amounts of the compounds and / or complexes, and in particular, higher doses of radioactivity, can be administered to a patient when compared to the compounds and complexes described in the art. Thus, the therapeutic window is wider than when using the compounds currently in use. Advantageously further, the PSMA-binding ligands of the present invention provide an improved diagnosis, since the co-labeling of non-related tissues and organs, in particular the salivary glands, lacrimal glands and / or kidneys, is reduced.

[0148] Thus, the PSMA-binding ligands and / or complexes of the present invention enable the treatment of PSMA-expressing cancers, in particular prostate cancer, and its metastases, and / or the diagnosis of PSMA-expressing cancers, in particular prostate cancer, and its metastases, and the PSMA-binding ligands and / or complexes exhibit an advantageous renal excretion profile, preferably with a favorable acceleration of clearance. Thus, the harmful side effects on the patient's kidneys are reduced. Accordingly, the present invention relates to the PSMA-binding ligands and / or complexes, or pharmaceutical compositions as described above, for treating and / or preventing PSMA-expressing cancers, in particular prostate cancer and / or its metastases, in patients in need thereof, and also to PSMA-binding ligands and / or complexes, or pharmaceutical compositions, in cases where the subject suffers from renal insufficiency.

[0149] As described above and in detail in the Examples herein, the compounds as specified herein provide accelerated excretion while maintaining essentially the same enrichment in the target tissue as, for example, PSMA-617, and thus the harmful effects on non-target tissues, preferably the salivary glands and / or lacrimal glands, are avoided or reduced. Thus, the treatments and / or diagnoses as specified herein have fewer or less severe harmful side effects on, for example, the salivary glands and / or lacrimal glands, or preferably, are free of harmful side effects, in particular on the salivary glands and / or lacrimal glands.

[0150] Preferably, the PSMA-binding ligands of the present invention enable the reduction and / or avoidance of adverse side effects, e.g., on the salivary and / or lacrimal glands, while maintaining essentially unchanged therapeutic efficacy. As will be appreciated by those skilled in the art in view of the above, the PSMA-binding ligands as specified herein preferably further enable the use of higher concentrations of the compound and / or higher doses of radioactivity without at least increasing adverse effects, which can be particularly useful, for example, in diagnostic applications for detecting e.g., minimal metastases or small amounts of residual tumor tissue, and / or in therapy.

[0151] Accordingly, the PSMA-binding ligands and / or complexes of the present invention enable the treatment of PSMA-expressing cancers, particularly prostate cancer, and its metastases, and / or the diagnosis of PSMA-expressing cancers, particularly prostate cancer, and its metastases, in which xerostomia symptoms are avoided.

[0152] Preferably, the PSMA-binding ligands as described above or below, or the complexes as described above or below, or the pharmaceutical compositions as described above or below are used for in vivo imaging and radiotherapy. Suitable pharmaceutical compositions may contain a radiopharmaceutical agent or a radiotherapy agent having a radionuclide either as an element, i.e., radioactive iodine, or as a radiolabeled metal chelate complex of a PSMA-binding ligand in an amount sufficient for imaging, together with a pharmaceutically acceptable radiological vehicle. The radiological vehicle should be suitable for injection or aspiration and may be, for example, human serum albumin; buffered aqueous solutions such as buffers of tris(hydroxymethyl)-aminomethane (and its salts), phosphate buffer, citrate buffer, bicarbonate buffer, etc.; sterile water, physiological saline; and balanced ion solutions containing chloride salts and / or dicarbonate salts, or normal plasma cations such as calcium, potassium, sodium and magnesium.

[0153] The concentration of the imaging agent or therapeutic agent in the radiological vehicle should be sufficient to provide satisfactory imaging. Appropriate dosages are described above herein. The imaging agent or therapeutic agent should be administered such that it remains in the patient for between about 1 hour and 10 days, although both longer and shorter time periods are acceptable. For this purpose, convenient ampoules containing 1 - 10 mL of an aqueous solution can be prepared.

[0154] Imaging can be performed in a manner known to those skilled in the art, for example, by injecting a sufficient amount of the imaging composition to provide appropriate imaging and then scanning with a suitable imaging or scanning machine, such as a tomograph or gamma camera. In certain embodiments, a method of imaging a region in a patient includes the steps of: (i) administering to the patient a diagnostically effective amount of a PSMA-binding ligand complexed with a radionuclide, (ii) exposing the region of the patient to a scanning device, and (ii) obtaining an image of the region of the patient. In certain embodiments, the region to be imaged is the head or thorax. In other embodiments, the PSMA-binding ligand and complex target the PSMA protein.

[0155] Accordingly, in some embodiments, provided is a method of imaging a tissue, such as spleen tissue, kidney tissue, or PSMA-expressing tumor tissue, comprising contacting the tissue with a complex synthesized by contacting a radionuclide and a PSMA-binding ligand as described above.

[0156] The amount of the PSMA-binding ligand of the present invention, or a formulation comprising a complex or a salt, solvate, stereoisomer, or tautomer thereof, of the PSMA-binding ligand, to be administered to a patient depends on several physiological factors. These factors, including the nature of the imaging to be performed, the tissue to be targeted for imaging or treatment, and the body weight and medical history of the patient to be imaged or treated using the radiopharmaceutical, are known to a physician.

[0157] Accordingly, in another aspect, the present invention provides a method of treating a patient suffering from a cell proliferative disease or disorder by administering to the patient a therapeutically effective amount of a complex as described above or below. Specifically, the cell proliferative diseases or disorders to be treated or imaged using the PSMA-binding ligand, pharmaceutical composition or radiopharmaceutical according to the present invention are, for example, cancers in the lung, liver, kidney, bone, brain, spinal cord, bladder, etc., such as prostate cancer and / or prostate cancer metastases.

[0158] The PSMA-binding ligand of the present invention can be synthesized, for example, not only in solution but also on a solid phase, using, for example, standard peptide coupling procedures, such as Fmoc solid-phase coupling procedures. Preferably, the chelating agent is coupled to the remainder of the molecule in the last coupling step, followed by a deprotection step and, in the case of solid-phase chemistry, cleavage from the resin. However, other synthetic procedures are possible and are known to those skilled in the art. The preferred synthesis of the PSMA-binding ligand of the present invention is described in detail in the Examples section.

[0159] By way of example, particularly preferred PSMA-binding ligands of the present invention are shown in Table 1:

[0160]

Table 1

[0161] Summarizing the findings of the present invention, the following embodiments are preferred: 1. At least one amino acid X 1 , preferably at least one N-alkylated amino acid X1, more preferably at least one N-methylated amino acid X1, more preferably structure X 1 At least one linker L containing at least one amino acid having AQ A PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising a PSMA-binding motif Q and a chelating agent residue A linked via 1is -N(CH 3 )-CH 2 -C(=O)-, and more preferably, the linker L AQ is the linking unit -(X 1 )n 1 - containing, X1 is --N(CH 3 )-CH 2 -C(=O)-, n1 is preferably an integer of 1 to 25, preferably 2 to 25, more preferably 3 to 25, and even more preferably an integer of 3 to 15, a PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof. 2. The PSMA-binding ligand has the structure (I) A-L AQ -Q (I) The PSMA-binding ligand according to Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof having the same.

[0162] 3. The PSMA-binding motif Q has the structure

[0163]

Chemical formula

[0164] 4. The PSMA-binding ligand according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, which is a chelating agent residue derived from a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (=DOTA), N,N''-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N''-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), Trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

[0165] 5. A is a group consisting of the following

[0166]

Chemical formula

[0167] 6. A is a chelating agent residue having the structure

[0168]

Chemical formula

[0169] 7. The linker L AQ comprises at least one amino acid building block AS a wherein AS a has the structure

[0170]

Chemical formula

[0171] 8. The linker L AQ comprises at least one amino acid building block AS b wherein AS b has the structure (b)

[0172]

Chemical formula

[0173] [Chemical formula] and more preferably

[0174] [Chemical formula] (wherein) having the PSMA binding ligand according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof.

[0175] 9. Linker L AQ is at least one amino acid building block AS a and at least one amino acid building block AS b and AS a has the structure

[0176] [Chemical formula] (wherein Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl) and AS b has the structure (b)

[0177] [Chemical formula] (wherein Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably Q 2 is

[0178]

Chem.

[0179]

Chem.

[0180] 10. The PSMA-binding ligand is of structure (Ia)

[0181]

Chem.

[0182] 11. Q 1 is preferably a residue selected from the group consisting of naphthyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphthylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl, more preferably Q 1 is a group consisting of

[0183]

Chemical formula

[0184]

Chemical formula

[0185] 12. R 3 , R 2 and R 4 is -CO 2 H, and R 1 is H. The PSMA binding ligand according to any one of embodiments 10 or 11

[0186] 13. Q 2 is

[0187]

Chemical formula

[0188]

Chemical formula

[0189] 14. The PSMA-binding ligand according to any one of Embodiments 1 to 13, wherein n1 is an integer from 3 to 15, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, more preferably, n1 is 3, 5, 10 or 15, even more preferably 3 or 15, and most preferably 3.

[0190] 15. The ligand has the structure

[0191]

Chemical formula

[0192]

Chemical formula

[0193]

Chemical formula

[0194]

Chemical formula

[0195]

Chemical formula

[0196] 16. The PSMA-binding ligand according to any one of Embodiments 1 to 14, wherein the ligand has a structure as shown in FIG. 1, FIG. 2, FIG. 3 or FIG. 4.

[0197] 17. (a) A radionuclide, and (b) The PSMA-binding ligand according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt or solvate thereof comprising a complex.

[0198] 18. The radionuclide is 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Er, 52 Fe, 59 radionuclides of Fe, and Pb (for example, 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb), and more preferably 90Y, 68 Ga, 177 Lu, 225 Ac, and 213 selected from the group consisting of Bi, and more preferably, the radionuclide is 177 Lu or 225 Ac, the complex according to embodiment 16.

[0199] 19. A pharmaceutical composition comprising the PSMA-binding ligand according to any one of embodiments 1 to 15 or the complex according to embodiment 16 or 17.

[0200] 20. The PSMA-binding ligand according to any one of embodiments 1 to 15, or the complex according to embodiment 16 or 17, or the pharmaceutical composition according to claim 18, for use in medicine, preferably for treating and / or preventing PSMA-expressing cancer, particularly prostate cancer and / or its metastases.

[0201] 21. The PSMA-binding ligand according to embodiment 19, wherein the harmful side effects are reduced and / or avoided, particularly for the salivary gland and / or lacrimal gland.

[0202] 22. The PSMA-binding ligand according to any one of embodiments 1 to 15, or the complex according to embodiment 16 or 17, or the pharmaceutical composition according to claim 18, for use in diagnostics.

[0203] 23. The PSMA-binding ligand, complex, or pharmaceutical composition according to embodiment 21, for use in the diagnosis of cancer, preferably PSMA-expressing cancer, particularly prostate cancer and / or its metastases.

[0204] 24. The radionuclide is a β-emitter, and more preferably 177 Lu, and preferably, the active dose of the complex is at least 100 kBq / kg body weight, more preferably at least 500 kBq / kg body weight, and most preferably at least 1 MBq / kg body weight, the PSMA-binding ligand, complex, or pharmaceutical composition for the use according to embodiment 22 or 23.

[0205] 25. The radionuclide is an α-emitter, more preferably 225 Ac, and preferably, the activity administered amount of the complex is preferably at least 75 kBq / kg body weight, more preferably at least 100 kBq / kg body weight, a PSMA-binding ligand, complex, or pharmaceutical composition for use according to embodiment 20 or 21.

[0206] All references cited throughout this specification are incorporated herein by reference in their entirety, not just with respect to the specifically recited disclosure.

[0207] References TIFF2025516758000049.tif60168

Examples

[0208] All commercially available chemical reagents were of analytical grade and used without further purification. 68 Ga (half-life 68 minutes) was 68 Ge / 68 obtained from a Ge / 177 Ga generator (Galliapharm® Ge-68 / Ga-68 Generator, Eckert & Ziegler), and 3It was carried out using 0.1% TFA in CN. The Agilent Technologies 1200 series system was equipped with variable UV and gamma detectors (Ramona*, Elysia). The UV absorbance was measured at 220 and 280 nm, respectively. For mass spectrometry, MALDI-MS (Daltonics Microflex, Bruker Daltonics, Bremen, Germany) was used.

[0209] DOTA-Sar 3 -Chx-2-NaI-Lys-urea-Glu, DOTA-Sar 5 -Chx-2-NaI-Lys-urea-Glu, DOTA-Sar 10 -Chx-2-NaI-Lys-urea-Glu and DOTA-Sar 15 Synthesis of -Chx-2-NaI-Lys-urea-Glu The synthesis of the pharmacophore Glu-urea-Lys was carried out as described previously (1). Briefly, the synthesis started with the formation of isocyanate of the glutamyl moiety using triphosgene. Resin-immobilized (2-chloro-trityl resin, Merck, Darmstadt) ε-allyloxycarbonyl-protected lysine was added and reacted for 16 h with gentle stirring. The resin was filtered off, and the allyloxy protecting group was removed by reacting twice with Pd(PPh 3 ) 4 (0.3 equiv) and morpholine (15 equiv).

[0210] Subsequently, a 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 (4 equivalents each) were coupled in DMF using HATU (4 equivalents) and DIPEA (10 equivalents). Depending on the amino acid sequence, Fmoc-sarcosine was coupled 3, 5, 10, and 15 times in DMF using HATU (4 equivalents) and DIPEA (10 equivalents), respectively. Subsequently, bis(tBu)DOTA (bis(tBu)-ester of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (4 equivalents) was coupled in DMF using HATU (4 equivalents) and DIPEA (10 equivalents). The product was cleaved from the resin using TFA / TIPS / H 2 O (95 / 2.5 / 2.5, v / v / v) at room temperature for 3 h, purified using RP-HPLC with a Chromolith RP-18e column (100×10 mm; Merck, Darmstadt, Germany), and identified by mass spectrometry.

[0211]

Table 2

[0212] 68 Ga labeling The precursor peptide [2 nmol in HEPES buffer (1 M, pH 4, 40 μL)] was added to 40 μL 68 Ga]Ga 3+ eluate (about 40 MBq). The pH was adjusted to 3.8 - 4.2 using 30% NaOH. The reaction mixture was incubated at 95 °C for 15 min. The radiochemical yield (RCY) was determined by RP-HPLC.

[0213] 177 Lu labeling The precursor peptide [2 nmol in HEPES buffer (0.1 M, pH 7, 50 μL)] was added to 10 μL 177 Lu]LuCl 3(Approximately 10 - 30 MBq, 0.04 M HCl) was added. The reaction mixture was incubated at 95 °C for 15 minutes. The radiochemical yield (RCY) was determined by RP-HPLC.

[0214] Serum stability 177 The Lu-labeled compound (10 μL) was incubated at 37 °C in 100 μL of human (BIOIVT (BRH1548721)) or mouse plasma (100 μL, BIOIVT (MSE298415)). At various time points of incubation (t = 6 h, 24 h, 48 h, 72 h), 10 μL aliquots were taken and the plasma proteins were precipitated in 30 μL of acetonitrile. The samples were centrifuged at 13000 rpm for 5 minutes and the supernatant was analyzed by analytical RP-HPLC.

[0215] Cell culture PSMA + LNCaP cells (CRL-1740; ATCC; PSMA positive) and PC-3 cells (CRL-1435; ATCC; PSMA negative) were cultured in RPMI medium supplemented with 10% fetal bovine serum and 2 mmol / L L-glutamine (all from PAA). The cells were grown at 37 °C in humidified air containing 5% CO 2 and were harvested using trypsin-ethylenediaminetetraacetic acid (trypsin-EDTA; 0.25% trypsin, 0.02% EDTA, Invitrogen).

[0216] Cell binding and internalization Competitive cell binding assays and internalization experiments were performed as previously described (2). For competitive cell binding, cells (10 5 per well) were 68 Ga-labeled radioligand [Glu-urea-Lys(Ahx)] 2Incubated with a 0.8 nM solution of -HBED-CC (precursor ordered from PSMA-10, ABX, Radeberg, Germany) in the presence of 12 different concentrations of DOTA compounds (0 - 5000 nM, 100 μL / well). After incubation, the mixture was removed and the wells were washed three times with PBS using a multi-screen vacuum manifold (Millipore, Billerica, MA). Cellular bound radioactivity was measured using a gamma counter (Perkin Elmer 2480, Wizard, Gamma Counter). The 50% inhibitory concentration (IC50) values were calculated by fitting the data using a non-linear regression algorithm (GraphPad Software) (see Table 2).

[0217] For the internalization experiment, 10 5 cells per well were seeded into poly-L-lysine-coated 24-well cell culture plates 24 hours prior to incubation. After washing, the cells were incubated with 30 nM radiolabeled DOTA compound 68 labeled with 177 Ga or 5 Lu at 37 °C for 45 minutes (labeling was performed using 5 nmol of precursor peptide). Specific cellular uptake was determined by blockade using 500 μM 2-PMPA (2-(phosphonomethyl)pentanedioic acid). Cellular uptake was terminated by washing three times with 1 mL of ice-cold PBS. To remove surface-bound radioactivity, the cells were incubated twice for 5 minutes with glycine-HCl (50 mM, pH = 2.8) in 0.5 mL of PBS. The cells were washed with 1 mL of ice-cold PBS and lysed using 0.3 N NaOH (0.5 mL). The surface-bound and internalized fractions were measured with a gamma counter. Cellular uptake was calculated as the percentage of the initially added radioactivity [%ID / 10 5 cells] bound to 10

[0218] PET / MR Imaging For the experimental tumor model, 5×10 6 cells of LNCaP (in 50% Matrigel; Becton Dickinson) were implanted subcutaneously into the right flank of 7- to 8-week-old male BALB / c nu / nu mice (Janvier). The tumors were grown until they reached approximately 1 cm 3 in size. For imaging studies, the mice were anesthetized (2% isoflurane), and 0.5 nmol of 68 Ga-labeled compound in 0.9% NaCl (pH 7) was injected via the tail vein. PET imaging was performed with a μPET / MRI scanner (BioSpec 3T, Bruker) in a 60-minute dynamic scan. The images were iteratively reconstructed (MLEM 0.5 algorithm, 12 iterations) and converted to SUV images. Quantification was performed using the ROI (region of interest) technique, and the data were represented as time-activity curves as SUV 体重 . All animal experiments were in accordance with the current laws of the Federal Republic of Germany.

[0219] Organ distribution For the experimental tumor model, 5×10 6 cells of LNCaP (in 50% Matrigel; Becton Dickinson) were implanted subcutaneously into the right flank of 7- to 8-week-old male BALB / c nu / nu mice (Janvier). The tumors were grown until they reached approximately 1 cm 3 in size. For biodistribution studies, the mice were anesthetized with isoflurane and 177 Lu-labeled compound was injected via the tail vein (1 - 2 MBq; 60 pmol in 100 μl). The mice were sacrificed 1 hour, 2 hours, 6 hours, and 24 hours after injection. The organs of the mice were measured in a γ-gamma counter (2480 Automatic Gamma Counter Wizard, PerkinElmer, Waltham, USA) together with standards.

[0220] The results are shown in Figures 6, 6a, 7, and 7a.

[0221] Statistical aspects All experiments were performed at least in triplicate and repeated at least three times. Quantitative data were expressed as mean ± SD. When applicable, means were compared using Student's t-test. A P-value < 0.05 was considered statistically significant.

[0222] Results In vitro characterization The final products were identified using reverse-phase HPLC / matrix-assisted laser desorption / ionization mass spectrometry. Complex formation of the compounds with 68 Ga and 177 Lu resulted in radiochemical yields higher than 99%. All compounds were found to be stable in human and mouse plasma for up to 72 h. Furthermore, all compounds showed high PSMA binding affinities in the same nanomolar range as the reference PSMA-617 (Table 2)(3). PSMA-specific cell surface binding and specific internalization equivalent to PSMA-617 were also detected for all 68 Ga-labeled compounds.

[0223]

Table 3

[0224]

Table 4

[0225] The results are shown in Figure 8.

[0226] In vivo characterization The pharmacokinetic properties of the novel compounds were analyzed using PET / MR imaging in LNCaP xenograft-bearing mice (Figure 5). Surprisingly, the renal excretion profile was found to be enhanced for all introduced sarcosine-spacer lengths compared to the parental reference PSMA-617, with a strong clearance acceleration for the introduction of linkers with 5 or 10 sarcosines. The chemical modifications tested also increased tumor uptake compared to PSMA-617. The enhancement of the excretion profile with high tumor uptake indicates the suitability of the modified compounds for improving the therapeutic profile, particularly by reducing tracer uptake in non-target organs to reduce dose-limiting side effects.

Claims

1. at least one linker L containing at least one N-alkylated amino acid X 1 AQ A PSMA-binding ligand or a pharmaceutically acceptable salt or solvate thereof, comprising a PSMA-binding motif Q and a chelating agent residue A linked via a .

2. The PSMA-binding ligand according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one N-alkylated amino acid has structure X1, and X1 is -N(CH3)-CH2-C(=O)-.

3. The PSMA-binding ligand according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the linker L AQ comprises a linking unit -(X 1 )n 1 -, where X 1 is -N(CH 3 )-CH 2-C(=O)-, and n1 is an integer from 1 to 25.

4. The PSMA-binding ligand has structure (I). A-L AQ -Q (I) A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

5. The PSMA-binding motif Q has a structure 【Chemistry 1】 (wherein, R 1 is H or -CH3, and R 2 , R 3 and R 4 are each independently selected from the group consisting of -CO 2 H, -SO 2 H, -SO 3 H, -OSO 3 H, -PO 2 H, -PO 3 H and -OPO 3 H 2 )) A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

6. A is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (=DOTA), N,N''-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N''-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7, 10-Tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-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-Do 3A) A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is a chelating agent residue derived from a chelating agent selected from the group consisting of 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).

7. A is a group consisting of the following 【Chemistry 2】 A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is a chelating agent residue having a structure selected from the above.

8. A is structure 【Transformation 3】 A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

9. Linker L AQ However, at least one amino acid constituent block AS a Includes AS a However, structure 【Chemistry 4】 (In the formula, Q 1 (Selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl, and heteroaryl) A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

10. Linker L AQ However, at least one amino acid constituent block AS b Includes AS b However, structure (b) 【Transformation 5】 (In the formula, Q 2 (Selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and alkylheteroaryl) A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

11. Q2 is, 【Transformation 6】 The PSMA-binding ligand according to claim 10, or a pharmaceutically acceptable salt or solvate thereof.

12. The PSMA-binding ligand has structure (Ia). 【Transformation 7】 (In the formula, R 1 is H or -CH3, and R 2 , R 3 and R 4 They are, independently of each other, -CO 2 H, -SO 2 H, -SO 3 H, -OSO 3 H, -PO 2 H, -PO 3 H and -OPO 3 H 2 Selected from the group consisting of, Q 1 This is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl, and heteroaryl. Q 2 This is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and alkylheteroaryl. (q is an integer between 0 and 3) A PSMA-binding ligand according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

13. The ligand has a structure 【Transformation 8】 (In the formula, A is structure 【Chemistry 9】 It is a chelating agent residue having, Q2 is, 【Chemistry 10】 or 【Chemistry 11】 And, q is 1, Q 1 teeth, 【Chemistry 12】 And, R 3 , R 2 and R 4 is, -CO 2 H and R 1 (where H is and n1 is in the range of 1 to 25) A PSMA-binding ligand according to claim 1, having the properties of claim 1.

14. (a) radionuclides, and (b) PSMA-binding ligand according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof A complex containing [a certain component].

15. Radioactive nuclides, 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Er, 52 Fe, 59 Radioactive nuclides of Fe and Pb (for example, 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 The complex according to claim 14, selected from the group consisting of Pb).

16. A pharmaceutical composition comprising a PSMA-binding ligand according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof.

17. The pharmaceutical composition according to claim 16 for use in the treatment and / or prevention of PSMA-expressing cancer.

18. The pharmaceutical composition according to claim 16 for use in the treatment and / or prevention of prostate cancer and / or its metastasis.

19. A pharmaceutical composition according to claim 16 for use in diagnostics.

20. The pharmaceutical composition according to claim 16 for use in the diagnosis of cancer and / or its metastasis.

21. A pharmaceutical composition comprising the complex described in Claim 14.

22. The pharmaceutical composition according to claim 21 for use in diagnostics, wherein the radionuclide is a β-emitter.

23. The pharmaceutical composition according to claim 22, wherein the radionuclide is 177 Lu, and the active dose of the complex is at least 100 kBq / kg body weight.

24. A pharmaceutical composition according to claim 21 for use in the treatment and / or prevention of prostate cancer and / or its metastasis, wherein the radionuclide is an α-emitter.

25. The pharmaceutical composition according to claim 24, wherein the radionuclide is 225 Ac, and the active dose of the complex is at least 75 kBq / kg body weight.

Images