Precursor markers and radiotracers with three or more targeting vectors for theranostics used in nuclear medicine

Abstract

A precursor marker for radiotracers comprises a marker group MG for covalent or coordinative marking with a radioisotope, three or more targeting vectors TV1, TV2, TV3 for targeting cellular receptors, and three or more linkers L1, L2, L3, wherein each of the three or more linkers L1, L2, L3 is covalently conjugated with the marker group MG and one of the three or more targeting vectors TV1, TV2, TV3, or each of the three or more linkers L1, L2, L3 is covalently conjugated with a linking group V and one of the three or more targeting vectors TV1, TV2, TV3, and the marker group MG is covalently conjugated with the linking group V either directly or via a linker L, and the precursor marker has the following structure: (A), (B) or (C), s=20.

Description

[0001] Label precursors and radiotracers with three or more targeting vectors for nuclear medicine theranostics

[0002] The present invention relates to label precursors comprising a labeling group for covalent or coordinative labeling with a radioisotope and three or more targeting vectors for addressing cellular receptors, as well as radiotracers derived therefrom.

[0003] The labeling precursors according to the invention comprise 3, 4, 5, 6, or more targeting vectors and are also referred to below as tri-, tetra-, penta-, and hexamers, or generally as multimers. In a first configuration, the targeting vectors are conjugated to the labeling group via linkers. In a second configuration, the labeling group and the targeting vectors are conjugated to a linker via a linking group.

[0004] The labeling precursors and radiotracers according to the invention are intended for imaging nuclear medicine diagnosis using positron emission tomography (PET), single-photon emission computed tomography (SPECT), and the treatment / therapy (endoradiotherapy / radionuclide therapy) of various tumors and metastases (theranostics). In this case, labeling precursors can be used that are labeled with a metallic radioisotope such as gallium-68 ( 68 Ga) and fluorine-18 ( 18 F) for PET, Technetium-99m ( 99m Tc) for SPECT and Lutetium-177 ( 177 Lu) or actinium-225 ( 225 Ac) can be marked for therapy.

[0005] Each of the three or more targeting vectors binds selectively to membrane-bound receptors, proteins, enzymes, or other structures on the surface of tumor cells. A linker is positioned between each targeting vector and the labeling or linking group, ensuring largely unhindered binding to the receptor.

[0006] The labeling precursors according to the invention contain three or more targeting vectors that are conjugated to a labeling group (MG), such as a chelator, either directly or via a linking group. The targeting vectors can be identical or different from one another. The use of three or more targeting vectors disproportionately increases the enrichment of a radiotracer formed from the labeling precursor by complexation or covalent binding of a radioisotope at a biological tumor target compared to analogous radiotracers with one or two targeting vectors (mono- and dimeric radiotracers). Furthermore, the radiotracers according to the invention are characterized by a longer tumor retention time. The greater enrichment, combined with prolonged tumor retention, results in an increased local radiation dose and significantly improves therapeutic efficacy.At the same time, the radiological dose to healthy organs (e.g., kidneys, bladder, salivary glands), which is often limiting for therapy, is reduced. The labeling precursors according to the invention open up additional theranostic options for improving biological avidity, tumor enrichment, and tumor retention. This expands the theranostic application area for radioisotopes with longer half-lives, such as 177 Lu or 225 Ac, for which mono- and dimeric radiotracers often have an insufficient tumor retention time.

[0007] The labeling group—particularly chelators—modifies the configuration and chemical properties of a targeting vector conjugated with the labeling group, usually affecting its affinity for tumor cells. Accordingly, the labeling precursor must be re-evaluated with regard to complexation with radioisotopes and, above all, with regard to its biochemical and pharmacological in vitro and in vivo properties. The labeling group and its chemical coupling with the targeting vector are crucial for the biological and nuclear medicine potency of the associated radiotracer.

[0008] Regardless of this, a chelator is chosen that ensures stable complexation of the respective radioisotope, such as 68 Ga for PET / CT, 99m Tc for SPECT and 177 Lu for therapy is guaranteed. Linkers, targeting vectors, and, if necessary, a linking group are optimized for the respective medical application.

[0009] Various tumor-targeting vectors are conjugated in a novel and flexible manner in one molecule, resulting in label precursors or radiotracers with increased enrichment for relevant biological tumor targets. Due to synergistic effects, a significantly higher theranostic radiation dose is achieved with appropriately labeled ( 177 Lu, 225 Ac, etc.) radiotracers. Equipping the radiotracer with three or more targeting vectors prolongs tumor retention. By optimizing the linkers and targeting vectors, the radiotracers of the invention can be used in both diagnostics and endoradiotherapy. The optional linking group decouples the labeling group from the linkers and targeting vectors, facilitating their optimization. At the same time, structural flexibility is increased and the application spectrum of the radiotracers is expanded.

[0010] Depending on the type of cancer and the diagnostic or therapeutic modality, specific targeting vectors and a suitable labeling group are selected.

[0011] The following properties are crucial for a labeling precursor and a radiotracer derived from it: rapid and effective complexation or binding of the respective radioisotope to the labeling group; high affinity and selectivity for tumor cells and metastases relative to healthy tissue; in vivo stability, i.e., biochemical persistence in blood serum under physiological conditions; high accumulation in tumors and metastases for precise diagnosis and effective therapy; rapid clearance from healthy tissue and blood to minimize systemic dose and toxicity.

[0012] The targeting vectors ensure selective enrichment of the radiotracer in the target tissue, which is also referred to as the "target" in the context of the invention. Targeting vectors are used that address targets relevant for prostate cancer and bone metastases, as well as the tumor stroma in general.

[0013] Prostate cancer

[0014] For men in industrialized countries, prostate cancer is the most common type of cancer and the third most common fatal cancer. Tumor growth in this disease progresses slowly, and if diagnosed early, the 5-year survival rate is almost 100%. However, if the disease is only discovered after the tumor has metastasized, the survival rate drops dramatically. On the other hand, treating the tumor too early and too aggressively can unnecessarily impair the patient's quality of life. For example, surgical removal of the prostate can lead to incontinence and impotence. A reliable diagnosis and information about the stage of the disease are essential for successful treatment with a high quality of life for the patient. A widely used diagnostic tool, in addition to palpation of the prostate by a doctor, is the determination of tumor markers in the patient's blood.The most prominent marker for prostate cancer is the concentration of prostate-specific antigen (PSA) in the blood. However, the significance of PSA levels is controversial, as patients with slightly elevated levels often do not have prostate cancer, whereas 15% of patients with prostate cancer do not show elevated PSA levels in their blood. Another target for the diagnosis of prostate tumors is prostate-specific membrane antigen (PSMA). Unlike PSA, PSMA cannot be detected in the blood. It is a membrane-bound glycoprotein with enzymatic activity. Its function is to cleave the C-terminal glutamate from N-acetyl-aspartyl-glutamate (NAAG) and folic acid (poly)-γ-glutamate. PSMA is rarely found in normal tissue but is strongly overexpressed by prostate cancer cells, with its expression closely correlating with the stage of the tumor.Lymph node and bone metastases of prostate cancer also show PSMA expression in 40% of cases.

[0015] One strategy for molecular targeting of PSMA involves binding to the protein structure of PSMA with antibodies. Ligands are then used that target the enzymatic binding pocket of PSMA. The central enzymatic binding pocket of PSMA contains two Zn 2+ -ions that bind glutamate. An aromatic binding pocket precedes the central binding pocket. The PSMA protein is capable of expanding and adapting to various ligands, such as inhibitors or enzymatically cleavable ligands (induced fit). Thus, in addition to NAAG, PSMA also binds folic acid, with the pteroic acid group docking in the aromatic binding pocket. Addressing the PSMA binding pocket with an inhibitor or substrate usually induces cellular incorporation (endocytosis).

[0016] PSMA inhibitors are particularly suitable as targeting vectors for imaging diagnostic and theranostic radiopharmaceuticals or radiotracers. The radiolabeled inhibitors bind to the central PSMA binding pocket, which is not enzymatically converted or cleaved, and the inhibitor / targeting vector is not released from the radioactive label. Favored by endocytosis, the inhibitor and the radioactive label are taken up into the tumor cell and accumulated there.

[0017] Inhibitors with high affinity for PSMA (Scheme 1) typically contain a glutamate motif and an enzyme-resistant structure. A highly effective PSMA inhibitor is 2-phosphonomethylglutaric acid or 2-phosphonomethylpentanedioic acid (2-PMPA), in which the glutamate motif is bound to a phosphonate group that is not cleavable by PSMA. Urea-based PSMA inhibitors are also used, for example, in clinically relevant radiotracers such as PSMA-11 (Scheme 2) and PSMA-617 (Scheme 3).

[0018] It has proven advantageous to target the aromatic binding pocket of PSMA in addition to the central binding pocket. For example, in highly potent radiotracers of the PSMA-11 type, the binding motif L-lysine-urea-L-glutamate (KuE) is bound via hexyl (hexyl spacer) to an aromatic HBED chelator (N,N'-bis-[2-hydroxy-5-carboxyethyl)benzyl)ethylenediamine-N,N'-diacetate).

[0019] However, if L-lysine-urea-L-glutamate (KuE) is bound to the non-aromatic chelator DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetate), a reduced affinity and accumulation in tumor tissue can be observed. To nevertheless use the DOTA chelator for a PSMA-affine radiopharmaceutical with therapeutic radioisotopes, such as 177 Lu or 225 To use Ac, the spacer must be adapted. By targeted substitution of the hexyl spacer with various aromatic structures, the labeling precursor PSMA-617 and the derived highly effective radiotracer 177 Lu-PSMA-617, the current gold standard, was found.

[0020]

[0021] Tumor stroma

[0022] Malignant epithelial cells are a component of many tumors and tumor types and form a tumor stroma surrounding the tumor at a size of 1 - 2 mm at the latest.

[0023] The tumor stroma comprises various non-malignant cell types that are part of the tumor microenvironment surrounding tumor cells. The tumor stroma can account for up to 90% of the total tumor mass. It plays an important role in tumor development, growth, and metastasis, as well as in the supply of tumor cells.

[0024] The main cellular components of the tumor stroma are the extracellular matrix, including various cytokines, endothelial cells, pericytes, macrophages, immune regulatory cells, and activated fibroblasts. The activated fibroblasts surrounding the tumor are referred to as tumor-associated fibroblasts (CAFs).

[0025] During tumor development, CAFs alter their morphology and biological function. These changes are induced by intercellular communication between cancer cells and CAFs. CAFs create an environment that favors cancer cell growth. Therapies that target cancer cells alone have been shown to be inadequate. Effective therapies must address the tumor microenvironment, including CAFs.

[0026] In more than 90% of all human epithelial carcinomas, CAFs overexpress fibroblast activation protein (FAP). Therefore, FAP represents a promising target for nuclear medicine diagnostics and therapy. Analogous to PSMA, FAP inhibitors (FAPI or FAPi) are particularly suitable as targeting vectors for FAP labeling precursors and derived radiotracers. The role of FAP in vivo is not yet fully understood, but it is known that it is an enzyme with specific catalytic activity. It exhibits both dipeptidyl peptidase (DPP) and prolyl oligopeptidase (PREP) activity. Accordingly, inhibitors that inhibit the DPP and / or PREP activity of FAP are being considered. The decisive factor is the selectivity of the inhibitor towards other similar enzymes such as the dipeptidyl peptidases DPPII, DPPIV, DPP8 and DPP9, as well as towards prolyl oligopeptidase (PREP).However, in cancers where both FAP and PREP are overexpressed, inhibitors can also be used that do not have high selectivity between PREP and FAP, but inhibit both enzymes.

[0027] In 2013, a highly affinity and highly selective inhibitor structure was developed and published, based on a modified glycine-proline unit coupled to a quinoline (Jansen et al. ACS Med. Chem. Lett. 2013, 4, 491-496). The compound in question, (S)-N-(2-(2-cyanopyrrolidin-l-yl)-2-oxoethyl)quinoline-4-carboxamide, is depicted in Scheme 4 (left). In subsequent structure-activity studies (SAR), compounds with improved affinity and selectivity were found, including the difluorinated derivative (S)-N-(2-(2-cyano-4,4'-difluoropyrrolidin-l-yl)-2-oxoethyl)quinoline-4-carboxamide, which is depicted in Scheme 4 (right) (Jansen et al. J. Med. Chem. 2014, 57 (7), 3053-3074).

[0028] The difluorinated FAP inhibitor (Scheme 4, right) serves as the target vector for various nuclear medicine FAP labeling precursors and radiotracers. Scheme 5 (top and middle) shows the labeling precursors FAPI-04 and FAPI-46 as examples (Lindner et al. J. Nucl. Med. 2018, 59 (9), 1415-1422; Altmann et al. J. Nucl. Med. 2021, 62, 160-167; Windisch et al. EJNMMI Res. 2021, 11, 18). Scheme 5 (bottom) shows another FAP labeling precursor comprising the chelator DOTA. In it, the chelator DOTA is coupled to the quinoline moiety of the pharmacophoric FAPi targeting vector via a 4-aminobutoxy, a squaric acid and an ethylenediamine group (DOTA.SA.FAPi, Moon et al. EJNMMI Radiopharmacy and Chemistry 2020, 5(1), 19).

[0029] As a further development, dimeric FAP radiotracers were synthesized, which are structurally composed of two identical targeting vectors (FAP inhibitor lead structures). One is the compound DOTA-2P(FAPI)2 (see Scheme 6 above), which contains the targeting vector and linker of FAPI-46 twice (Zhao et al. J. Nucl. Med. 2021). The other is the compound DOTAGA.(QS.FAPi)2 in Scheme 6 below (Moon et al. AJNMMI 2021, accepted). These compounds showed an extension of tumor retention time compared to the monomeric compounds (see Scheme 5).

[0030] Bone metastases

[0031] Bone metastases express farnesyl pyrophosphate synthase (FPPS), an enzyme in the HMG-CoA reductase (mevalonate) pathway. Inhibition of FPPS suppresses the production of farnesyl, a molecule important for the docking of signaling proteins to the cell membrane. As a result, apoptosis of cancerous bone cells is induced. FPPS is inhibited by bisphosphonates such as alendronate, pamidronate, and zoledronate. For example, the tracer BPAMD with the targeting vector pamidronate is regularly used in the treatment of bone metastases.

[0032] Zoledronate (ZOL), a hydroxybisphosphonate with a heteroaromatic imidazole moiety, has proven to be a particularly effective tracer for the theranostics of bone metastases. Zoledronate conjugated with the chelators NODAGA and DOTA (Scheme 7) is currently the most potent radiotheranostics for bone metastases.

[0033] In nuclear medicine, radiotracers are typically used with the "gold standard" chelator DOTA, which can be coupled with various targeting vectors and allows stable complexation with 68 Ga (for diagnostics) and 177 Lu (for endoradiotherapy). For neuroendocrine tumors (NETs), octreotide derivatives such as TOC or TATE are used as targeting vectors. The most important labeling precursors in this class of compounds are DOTA-TOC and DOTA-TATE. 177 Lu-DOTA-TATE is an important radiopharmaceutical approved for the treatment of somastatin receptor (SSTR)-positive tumors. (Fani et al. J. Nucl. Med 2017, 58(Suppl. 2), 61S-66S; Kam et al. EurJ Nucl Med Mol Imaging 2012, 39(1), 103-112; Kjaer et al. ScandJ Gastroenterol. 2015, 50(6), 740-747.)

[0034] In the diagnosis and treatment of patients with metastatic late-stage prostate cancer (PCa), PSMA inhibitors are used in nuclear medicine. These target the prostate-specific membrane antigen (PSMA) as targeting vectors. The compound PSMA-617, with DOTA as a chelator and a urea-based inhibitor moiety as a targeting vector, is currently of greatest importance. The evaluation of the 177 Lu-PSMA-617 is currently undergoing Phase III clinical trials. (Kopka et al. J. Nucl. Med. 2017, 58(Suppl. 2), 17S-26S; Benesovä et al. J Med Chem, 2016, 59, 1761-1775.) In the case of bone metastases, bisphosphonate derivatives are used. These, mediated by their high affinity for the hydroxyapatite structure of the bone matrix of bone metastases, bind very selectively to bone metastases and hardly to healthy soft tissue. (Lin et al. Bone 1996, 18, 75-85; Palma et al. Mol Biosyst 2011, 7, 2950-2966.)

[0035] DOTA-zoledronate is of particular interest in this regard. Zoledronate exhibits a high affinity for the hydroxyapatite structure, and diagnostic and therapeutic radioisotopes can be easily introduced via the DOTA chelator (Meckel et al. EJNMMI Radiopharm. Chem. 2017, 1, 1481; Pfannkuchen et al. Curr. Radiopharm 2018, 11 (3), 223-230).

[0036] Tumor-associated fibroblasts (CAFs) are becoming increasingly important as a "pan-tumor target." CAFs are found in the tumor microenvironment of various cancer types and are overexpressed in over 90% of all epithelial tumors (Garin-Chesave et al. Proc. Natl. Acad. Sci. USA 1990, 87 (18), 7235-7239). In this approach, the fibroblast activation protein (FAP), a biomarker of CAFs, is targeted via FAP inhibitors. Since FAP is overexpressed in a variety of tumor types, corresponding theranostic radiopharmaceuticals with FAP inhibitors as targeting vectors are very interesting for the universal addressing and treatment of many cancer types. The most promising and most researched compounds are currently FAPI-04 and FAPI-46, which also uses DOTA as a chelator. (Lindner et al. J. Nucl. Med. 2018, 59 (9), 1415-1422; Giesel et al. J. Nucl. Med. 2019, 60, 386-392; Kratochwil et al. J. Nucl. Med. 2019, 60 (6), 801-805.) Corresponding labeling precursors are shown in Scheme 8, with the respective targeting vector outlined and highlighted by a dashed line.

[0037] Scheme 8: Labeling precursors: DOTA-TOC, PSMA-617, DOTA-ZOL, FAPI-04. Currently clinically relevant radiotracers are "monomeric," meaning they contain only a targeting vector. Monomeric radiotracers with a targeting vector play a central role in nuclear medicine and rightfully deserve the designation "precision oncology." Monomeric FAPI radiotracers demonstrate great potential for the diagnosis of various tumor types using 68 Ga-PET / CT. A growing number of clinical patient studies worldwide demonstrate highly selective enrichment in tumors and metastases, which, compared to the clinical standard 18F-FDG enables comparable and often better imaging. Limiting factors of monomeric radiotracers include rapid renal excretion and short retention time in the tumor. Therefore, a significant proportion of clinically established monomeric radiotracers are unsuitable for theranostic use with therapeutic radioisotopes, such as 177 Lu or 225 Ac, which has a much longer half-life than 68 Ga.

[0038] The present invention provides multimeric labeling precursors with three or more identical or different targeting vectors. The targeting vectors can be conjugated with identical or different linkers. Each targeting vector is connected to the labeling group or to a linking group via a linker. The invention allows for radiolabel-independent (orthogonal) adjustment of the affinity and pharmacokinetics of the multimeric labeling precursor or radiotracer. The use of multiple targeting vectors significantly improves the enrichment of the theranostic compound at the biological tumor target, exceeding that of the corresponding monomeric radiotracers. Furthermore, multimeric radiotracers are characterized by a significantly longer tumor retention time. The improved enrichment and tumor retention time result in a significantly increased local radiation dose and enhances therapeutic efficacy.At the same time, the radiation exposure to healthy organs, such as the kidneys, bladder, and salivary glands, which often limits radionuclide therapy, is reduced. Targeting vector multiplexing improves the accumulation and tumor retention of the radiotracers according to the invention, which is advantageous for the therapeutic use of the radioisotopes. 177 Lu or 225 Ac is decisive.

[0039] The present invention aims to overcome the limitations of known radiotracers and diagnostic and therapeutic methods based thereon described above.

[0040] This object is achieved by a labeling precursor for radiotracers, comprising a labeling group MG for covalent or coordinative labeling with a radioisotope, three or more targeting vectors TV1, TV2, TV3 for addressing cellular receptors, and three or more linkers L1, L2, L3, wherein each of the three or more linkers L1, L2, L3 is covalently conjugated to the labeling group MG and one of the three or more targeting vectors TV1, TV2, TV3, or each of the three or more linkers L1, L2, L3 is covalently conjugated to a linking group V and one of the three or more targeting vectors TV1, TV2, TV3, and the labeling group MG is covalently conjugated to the linking group V directly or via a linker L.

[0041] Advantageous embodiments of the labeling precursor according to the invention are characterized by the following features in any combination, insofar as the features are not mutually exclusive, and according to which: the labeling precursor has the structure has; the three or more targeting vectors TV1, TV2, TV3 are independently selected from one of the structures [1] to

[0044] with wherein

[0042] X = H or F;

[0043] Y = H, CH3, CH(CH3)2, C(CH3)3or (CH2) n CH3where n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0044] Z is selected from the group comprising CH2, NH, alcohol, amidine, amine, amide, carboxylic acid amide, thioamide, imide, imidic acid ester, imine, urea, thiourea, guanidine, carbonate, carboxylic acid ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonic acid ester, sulfinic acid ester, sulfone, thiol, disulfide, boronic acid ester, silyl ether residues or groups and derivatives thereof; the labeling precursor comprises 3, 4, 5, 6, 7, 8, 9 or 10 targeting vectors; the labeling precursor comprises 5 to 15 or 10 to 20 targeting vectors; the labeling precursor comprises 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 targeting vectors; the linker L and the three or more linkers L1, L2, L3 independently have a structure selected from wherein A, B, C are independently selected from the group comprising amide, carboxylic acid amide, phosphinate, alkyl, triazole, thiourea, ethylene, maleimide, amino acid residues, with s = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and p, q and r are independently chosen from the set of integers {1, 2, 3, 4, 5, 6, 7, 8, 9, 10};the linker L and the three or more linkers L1, L2, L3 are independently selected from the group comprising benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, thiazine, oxazine, pyrrole, pyrrolidine, pyrazole, imidazole, tetrahydroimidazole, 1,2,4-triazole, tetrazole, thiophene, furan, 1,2-thiazole, 1,3-thiazole, thiadiazole, 1,2-oxazole, 1,3-oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, naphthalene, indene, indole, isoindole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, tetrahydroquinoline, tetrahydroisoquinoline, quinolizidine, indolizidine, 2H-chromene, 4H-chromene, 2H-thiochromene, 4H-thiochromene, coumarin and purine residues and derivatives of the above residues;the linker L and the three or more linkers L1, L2, L3 are independently selected from the group comprising alkyl or -(CH2); n -, amino acids (Ala, Arg, Asn, Asp, Cys, Gn, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA or γ-aminobutyric acid, homoserine, DOPA or 3,4-dihydroxyphenylalanine, citrulline, β-alanine, thyroxine), oligopeptides with 2 to 20 amino acids, polyethylene glycol or -(CH2CH2O) n -, polypropylene glycol or -(CH2CH(CH3)2O) n -, polyalkylene glycol ether or -((CH2) o O)-, polyamine or — ((CH2) p NH)— , polyamide or -((CH2) q CONH)-, polyester or -((CH2) r COO), polyurethane or -((CH2) s NHCOO)-, polyurea or -((CH2) tNHCONH)-, where o, p, q, r, s and t are independently selected from the set of integers {1, 2, 3, 4, 5, 6, 7, 8, 9, 10}; the linker L and the three or more linkers L1, L2, L3 independently of each other form the structure with m = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and i = 1, ... , m , where the side chains R i are independently selected from the group comprising -H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)-CH2CH3, -CH2-Phe, -CH2-Phe-OH, -CH2SH, -(CH2)2-S-CH3, -CH2OH, -(CH)(OH)(CH3), -(CH2)4NH2, -(CH2)3NH(C=NH)NH2, -CH2COOH,

[0045] -(CH2)2COOH, -CH2(C=O)NH2, -(CH2)2(C=O)NH2, alcohol, amidine, amine, amide, carboxylic acid amide, thioamide, imide, imidic acid ester, imine, urea, thiourea, guanidine, carbonate, carboxylic acid ester, carbamate, ether, Thioether, ester, ketone, phosphate, phosphonate, phospinate, sulfonic acid ester, sulfinic acid ester, sulfonic acid, thiol, disulfide, boronic acid ester, silyl ether, alkyl (CH2)—, amino acids (Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Lake, GABA or γ-aminobutyric acid, homoserine, DOPA or 3,4-dihydroxyphenylalanine, citrulline, ß-alanine, thyroxine), oligopeptides with 2 to 20 amino acids, benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine,

[0046] 1.2.4.5-Tetrazine, thiazine, oxazine, pyrrole, pyrrolidine, pyrazole, imidazole, tetrahydroimidazole, 1,2,4-triazole, tetrazole, thiophene, furan, 1,2-thiazole, 1,3-thiazole, thiadiazole, 1,2-oxazole, 1,3-oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole,

[0047] 1,2,5-Oxadiazole, naphthalene, indene, indole, isoindole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, tetrahydroquinoline, tetrahydroisoquinoline, quinolizidine, indolizidine, 2H-chromene, 4H-chromene, 2H-thiochromene, 4H-thiochromene, coumarin and purine residues, polyethylene glycol or -(CH2CH2O) n -, polypropylene glycol or -(CH2CH(CH3)2O) n -, polyalkylene glycol ether or -((CH2) o O)-, polyamine or — ((CH2) p NH)— , polyamide or -((CH2) q CONH)-, polyester or -((CH2) r COO), polyurethane or -((CH2) s NHCOO)-, polyurea or -((CH2) tNHC0NH)-, where o, p, q, r, s and t are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 and derivatives of the above residues; the labeling group MG is a chelator for the complexation of a radioisotope from the group comprising 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, m ln, 135 Sm, 140 Pr 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 He, 166 Dy, 166 Hey, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232Th; the labeling group MG is a chelator selected from the group comprising FUpypa, EDTA (ethylenediaminetetraacetate), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, NOTA (nona-1,4,7-triamine triacetate) and its derivatives, such as NODAGA (l,4,7-triazacyclononane,l-glutaric acid,4,7-acetate), TRAP (triazacyclononanephosphinic acid), NOPO (1,4,7-triazacyclononane-l,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), DOTA (dodeca-l,4,7,10-tetraamine tetraacetate), DOTAGA (2-(l,4,7,10-Tetraazacyclododecane-4,7,10)-pentanedioic acid) and other DOTA derivatives, DOTP H(l,4,7,10-Tetraazacyclododecane-l,4,7,10-tetrakis[methylene(2-carboxyethylphosphinic acid)]) and its derivatives such as DOTPI and DOTPI(azide)4, TRITA (Trideca-l,4,7,10-tetraaminetetraacetate), TETA (Tetradeca-l,4,8,11-tetraaminetetraacetate) and its derivatives, PEPA (Pentadeca-l,4,7,10,13-pentaaminepentaacetate), HEHA (Hexadeca-l,4,7,10,13,16-hexaaminehexaacetate) and its derivatives, HBED (N,N'-Bis-(2-hydroxybenzyl)ethylenediamine-N,N'-diacetate) and its derivatives such as HBED-CC (N,N'-bis-[2-hydroxy-5-carboxyethyl)benzyl)ethylenediamine-N,N'-diacetate), DEDPA and its derivatives, such as H2dedpa (l,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane) and H4octapa (l,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane-N,N'-diacetate), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives such as H3THP-Ac and H3THP-mal (YM103), TEAP (tetraacycyclodecanephosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-l,4-diazepane-N,N,N , ,N I- tetraacetate) and their derivatives, such as AAZTA 5 (5-[(6-Amino)-l,4-diazepane]pentanoic acid- N,N,N',N'-tetraacetate), DATA (6-Amino-l,4-diazepine triacetate) and DATA 5m(5-[[6-( / V-methyl)amino]-l,4-diacetate-l,4-diazepane] pentanoic acid N,N',N',-triacetate); Sarcophagin SAR (lN-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-l,8-diamine) and their derivatives, such as (NH2)2SAR (l,8-diamino-3,6,10,13,16,19-hexaazabicyclo [6.6.6]icosane), N4 (3-[(2'-aminoethyl)amino]-2-[(2"-aminoethyl) aminomethyl] propionic acid) and other N4 derivatives, PnAO (6-(4-isothiocyanatobenzyl)-3,3,9,9,-tetramethyl-4,8-diazaundecane-2,10-dione dioxime) and derivatives such as BMS181321 (3,3'-(l,4-butanediyldiamino)-bis(3-methyl-2-butanone)dioxime), MAG2 (mercaptoacetylglycylglycine) and its derivatives, MAG3 (mercaptoacetylglycylglycylglycine) and its derivatives such as N3S-adipate, MAS3 (mercaptoacetylserylserylserine) and its derivatives, MAMA (N-(2-mercaptoethyl)-2-[(2-mercaptoethyl)amino]acetamide) and its derivatives, EC (ethylenedicysteine) and its derivatives, DMSA (dimercaptosuccinic acid) and its derivatives, DADT (diaminodithiol), DADS (diaminodisulfide), N2S2 chelators and their derivatives, aminothiols and their derivatives; salts of the above chelators;.

[0048] Hydrazinnicotinamides (HYNIC) and hydrazine nicotinamide derivatives; the labeling group MG is selected from the group comprising DOTA, DATA and DATA 5m; the marking group MG is selected from the group comprising NOTA, DATA, DATA 5m and NODAGA; the marking group MG is selected from the group comprising NOTA, DATA, DATA 5m and NODAGA for the complexation of AI 18 F; the marking group MG is a structural group for the covalent bonding of 18 F, 131 l or 211 At is; the marking group MG is selected from the marking group MG has the structure with a leaving group X for substitution with 18 F, 131 l or 211At is; the labeling group MG contains a leaving group X selected from a residue of bromine (Br), chlorine (Cl) or iodine (I), tosyl (Ts), brosylate (Bs), nosylate (Nos), 2-(N-morpholino)ethanesulfonic acid (MES), triflate (Tf) and nonaflate (Non); the linking group V contains one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty trislinkers TL, TL1, TL2, ..., TL 19 which are independently selected from one of the structures

[0085] to

[0149] , with the linking group V is selected from the group comprising acrylate, vinyl, ethylene oxide, glycidol oligomers and cooligomers having 3 or more units;the linking group V is selected from the group comprising benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, thiazine, oxazine, pyrrole, pyrrolidine, pyrazole, imidazole, tetrahydroimidazole, 1,2,4-triazole, tetrazole, thiophene, furan, 1,2-thiazole, 1,3-thiazole, thiadiazole, 1,2-oxazole, 1,3-oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, naphthalene, indene, indole, isoindole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, tetrahydroquinoline, tetrahydroisoquinoline, quinolizidine, indolizidine, 2H-chromene, 4H-chromene, 2H-thiochromene, 4H-thiochromene, coumarin purine residues, and derivatives of the above residues; the linking group V structure; the linking group V has one of the structures

[0045] to

[0084] , with

[0049] with n = 1, 2, 3, 4, 5, 6, 7 or 8. the linking group V is an oligopeptide group with the structure has with t = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and j = 1, , t , where the side chains R j are independently selected from the group comprising -H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)-CH2CH3, -CH2-Phe, -CH2-Phe-OH, -CH2SH, -(CH2)2-S-CH3, -CH2OH, -(CH)(OH)(CH3), -(CH2)4NH2, -(CH2)3NH(C=NH)NH2, -CH2COOH,

[0050] -(CH2)2COOH, -CH2(C=O)NH2, -(CH2)2(C=O)NH2, alcohol, amidine, amine, amide, carboxylic acid amide, thioamide, imide, imidic acid ester, imine, urea, thiourea, guanidine, carbonate, carboxylic acid ester, carbamate, ether, Thioether, ester, ketone, phosphate, phosphonate, phospinate, sulfonic acid ester, sulfinic acid ester, sulfonic acid, thiol, disulfide, boronic acid ester, silyl ether, alkyl (CH2)—, amino acids (Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA or γ-aminobutyric acid, homoserine, DOPA or 3,4-dihydroxyphenylalanine, citrulline, ß-alanine, thyroxine), oligopeptides with 2 to 20 amino acids, benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine,

[0051] 1.2.4.5-Tetrazine, thiazine, oxazine, pyrrole, pyrrolidine, pyrazole, imidazole, tetrahydroimidazole, 1,2,4-triazole, tetrazole, thiophene, furan, 1,2-thiazole, 1,3-thiazole, thiadiazole, 1,2-oxazole, 1,3-oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole,

[0052] 1,2,5-Oxadiazole, naphthalene, indene, indole, isoindole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, tetrahydroquinoline, tetrahydroisoquinoline, quinolizidine, indolizidine, 2H-chromene, 4H-chromene, 2H-thiochromene, 4H-thiochromene, coumarin and purine residues, polyethylene glycol or -(CH2CH2O) n -, polypropylene glycol or -(CH2CH(CH3)2O) n -, polyalkylene glycol ether or -((CH2) o O)-, polyamine or -((CH2) p NH)-, polyamide or -((CH2) q CONH)-, polyester or -((CH2)rCOO)-, polyurethane or -((CH2) s NHCOO)-, polyurea or -((CH2) tNHCONH)-, where o, p, q, r, s and t are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 and derivatives of the above radicals.

[0053] Furthermore, the invention has the object of providing a radiotracer that overcomes the limitations of known radiotracers and diagnostic and therapeutic methods based thereon described above.

[0054] This object is achieved by a radiotracer which consists of one of the labelling precursors described above and a radioisotope complexed or covalently conjugated therewith, wherein the radioisotope is selected from the group comprising 18 F, 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, m ln, 131 l, 135 Sm, 140 Pr159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 He, 166 Dy, 166 Hey, 175 Yb, 177 Lu, 186 Re, 188 Re, 203 Pb, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th.

[0055] Scheme 9 shows exemplary configurations of inventive labeling precursors without a linking group (Schemes 9a and 9b) and with linking group V (Schemes 9c, 9d, 9e, 9f, 9g, and 9h). According to Schemes 9a and 9b, three or four targeting vectors TV1, TV2, TV3, TV4 are each linked to a labeling group MG via a linker L1, L2, L3, U. According to Schemes 9c and 9d, one labeling group MG and three or twenty targeting vectors TV1, TV2, ..., TV20 are each linked via a linker L1, L2, ..., L 20conjugated with a linking group V. In Schemes 9e, 9f, 9g, and 9h, the linking group V comprises three trislinkers TL, TL1, TL2 (Scheme 9e and 9f) and seven trislinkers TL, TL1, TL2, TL3, TU, TL5, and TL6 (Scheme 9g and 9h), respectively.

[0056] Scheme 9a to 9h: Configuration examples of labeling precursors according to the invention.

[0057] In the peptides or structural formulas [1] to [8], the following designations are used for synthetic amino acids:

[0058] Aph(Hor) = 4-[2,6-dioxo-hexahydro-pyrimidine-4-carbonylamino]-L-phenylalanine

[0059] Cpa = 4-chlorophenylalanine

[0060] D-Aph(Cbm) = D-4-amino-carbamoyl-phenylalanine

[0061] Pal = 2-, 3- or 4-pyridylalanine

[0062] The labeling group MG is designed as a chelator for the complexation of a radioisotope or as a group for the covalent binding of a radioisotope. The targeting vectors TV1, TV2, ..., TV 20 can be different, partially identical, or completely identical. Likewise, the linkers L, L1, L2, ... , L 20 different from each other, partially the same or completely the same.

[0063] The inventors have surprisingly discovered that the multimeric labeling precursors described above, or the radiotracers derived therefrom with three or more targeting vectors, exhibit significantly higher accumulation in tumor tissue (target exposure) compared to monomeric or dimeric radiotracers with one or two targeting vectors at the same systemic dose and non-specific accumulation (off-target exposure). It is assumed that this advantageous property is due to an increased docking probability and / or selectivity.

[0064] The three or more targeting vectors TV1, TV2, and TV3 used according to the invention exhibit high binding affinity to membrane-bound tumor markers, such as in particular PSMA (prostate-specific membrane antigen) and FAP (fibroblast activation protein). The labeling precursors and radiotracers according to the invention preferably also target the tumor stroma. For example, triple-negative breast cancer (TNBC) lacks specific receptors on the surface of cancerous cells that enable direct targeting. In this case, "indirect" targeting of the tumor stroma is considered. In TNBC, the tumor stroma comprises cancer-associated fibroblasts (CAFs) and altered endothelial cells (ECs) that overexpress FAP and PSMA, respectively. Accordingly, heteromeric labeling precursors with targeting vectors for FAP and PSMA are suitable for the diagnosis and treatment of TNBC.

[0065] Theranostic targeting of the tumor stroma with radioisotopes, such as 177 Lu and 225 Ac directly damages the tumor microenvironment, which is essential for progression, and causes indirect radiation damage (radiation-induced bystander effect, RIBE) in neighboring cancer cells.

[0066] The three or more linkers L1, L2, L3 of the labeling precursors according to the invention act as steric spacers and pharmacokinetic modulators that optimize the biochemical function of the targeting vectors (binding affinity to the target), the radiochemical function of the labeling group (stable complexation or conjugation of the radioisotope), and the half-life in blood serum (hydrophilicity). Preferably, the linkers contain structural elements, such as squaric acid amides or other aromatic moieties, that improve the affinity for PSMA.

[0067] In the case of a chelator-formed labeling group MG, the chelator serves for labeling with a radioisotope selected from the group comprising 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, m ln, 135 Sm, 140 Pr 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 He, 166 Dy, 166 Hey, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th.

[0068] Accordingly, the invention comprises radiotracers obtainable from the labeling precursors described above by complexing with a radioisotope, wherein the radioisotope is selected from the group comprising 43Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, m ln, 135 Sm, 140 Pr 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 He, 166 Dy, 166 Hey, 175 Yb, 177 Lu, 186 Re, 188 Re, 203 Pb, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th.

[0069] Chelators:

[0070] A variety of chelators for radioisotope complexation are known in the prior art. Examples of chelators used according to the invention are shown in Scheme 10.

[0071]

[0072]

[0073] Scheme 10: Chelators used according to the invention.

[0074] Examples of compounds according to the invention are shown below in Schemes 11 to 74.

[0075] Scheme 11: Trimer

[0076] Scheme 14: Trimer

[0077] Scheme 15: Tetramer

[0078] Scheme 17: Tetramer

[0079] Scheme 18: Tetramer

[0080]

[0081] Scheme 20: Tetramer

[0082] Scheme 21: Tetramer

[0083] Scheme 22: Tetramer

[0084] Scheme 24: Tetramer

[0085] Scheme 26: Tetramer

[0086] Scheme 28: Tetramer

[0087] Scheme 30: Tetramer

[0088] Scheme 31: Tetramer

[0089] Schema 32: Tetramer

[0090] Schema 34: Tetramer

[0091] Schema 36: Tetramer

[0092] Schema 37: Tetramer

[0093] Schema 39: Tetramer

[0094] Schema 40: Tetramer

[0095] Schema 42: Tetramer

[0096] Schema 44: Tetramer

[0097] Schema 46: Tetramer

[0098] Schema 47: Tetramer

[0099] Schema 49: Tetramer

[0100] Schema 50: Tetramer

[0101] Schema 52: Tetramer

[0102] Schema 53: Multimer

[0103] Schema 65: Multimer

[0104] Schema 67: Multimer

[0105] Schema 68: Multimer

[0106] Scheme 70: Multimer

[0107] Scheme 71: Multimer Scheme 73: Multimer

[0108] Scheme 74: Multimer

[0109] In the context of the present invention, some terms are used, the meaning of which is explained below.

[0110] Theranostics: Diagnosis and therapy of cancer using nuclear medicine radiotracers.

[0111] Precursor: Chemical compound containing a first and second targeting vector and a chelator or functional group for labeling with a radioisotope.

[0112] Radiotracer: A radioisotope-labelled precursor for nuclear medicine diagnostics or theranostics, used in low concentrations without affecting a patient's metabolism.

[0113] Target: Biological target structure, in particular (membrane-bound) receptor, protein, enzyme or antibody in the living organism to which a targeting vector binds.

[0114] Targeting vector: Chemical group or residue that acts as a ligand, agonist, antagonist or inhibitor for a biological target (e.g. a protein, enzyme or receptor) and has a high binding affinity to this target.

[0115] Linking group: Structural unit with functional groups for the covalent binding of linker-targeting vector conjugates and a labeling group MG.

[0116] Linker: Structural unit, group or residue that acts as a steric and / or pharmacokinetic modulator for targeting vectors and a labeling group.

Claims

Patent claims 1. A labeling precursor for radiotracers, comprising a labeling group MG for covalent or coordinative labeling with a radioisotope; three or more targeting vectors TV1, TV2, TV3 for addressing cellular receptors; and three or more linkers L1, L2, and L3; wherein each of the three or more linkers L1, L2, L3 is covalently conjugated to the labeling group MG and one of the three or more targeting vectors TV1, TV2, TV3; or each of the three or more linkers L1, L2, L3 is covalently conjugated to a linker group V and one of the three or more targeting vectors TV1, TV2, TV3, and the labeling group MG is directly or via a linker L to the linker group V is covalently conjugated; MG is a chelator selected from the group comprising H4pypa, EDTA (ethylenediaminetetraacetate), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, NOTA (nona-1,4,7-triamine triacetate) and its derivatives, such as NODAGA (1,4,7-triazacyclononane,1-glutaric acid,4,7-acetate), TRAP (triazacyclononane-phosphinic acid), NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), DOTA (dodeca-1,4,7,10-tetraamine tetraacetate), DOTAGA (2-(1,4,7,10-tetraazacyclo- dodecane-4,7,10)-pentanedioic acid) and other DOTA derivatives, DOTP H(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethylphosphinic acid)]) and its derivatives such as DOTPI and DOTPI(azide)4, TRITA (Trideca-1,4,7,10-tetraamine tetraacetate), TETA (Tetradeca-1,4,8,1-tetraamine tetraacetate) and its derivatives, PEPA (Pentadeca-1,4,7,10,13-pentaamine pentaacetate), HEHA (Hexadeca-1,4,7,10,13,16-hexaamine hexaacetate) and its derivatives, HBED (N,N'-Bis-(2-hydroxybenzyl)ethylenediamine-N,N'-diacetate) and its derivatives such as HBED-CC (N,N'-Bis-[2-hydroxy-5-carboxyethyl)benzyl) ethylenediamine-N,N'-diacetate), DEDPA and its derivatives, such as H2dedpa (1,2-[[6-(Carboxyl)pyridin-2-yl]methylamine]ethane) and H4octapa (1,2-[[6-(Carboxyl)pyridin-2-yl]methylamine]ethane-N,N'-diacetate), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives such as H3THP-Ac and H3THP-mal (YM103), TEAP (tetraacyclodecanephosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepan-N,N,N',N'-tetraacetate) and its derivatives Derivative, like AAAAZZTTAA 55 (5-[(6-Amino)-l,4-diazepane] pentanesate-N,N,N',N'-tetraacetate), DDAATTAA (6-Amino-l,4-diazepine-triacetate) and DATA 5m (5-[[6-( / V-methyl)amino]-l,4-diacetate-l,4-diazepane]pentanesäure-N,N',N',-triacetate); Sarcophagin SAR (lN-(4-aminobenzyl)-3,6,10,13,16,19-hexaaza- bicyclo[6.6.6]-eicosan-l,8-diamine) and their derivatives, as are (NH2)2SAR (l,8-diamino-3,6,10,13,16,19-hexaazabicyclo [6.6.6]icosane), N4 (3-[(2'-Aminoethyl)amino]-2-[(2"-aminoethyl)aminomethyl]propionic acid) and other N4 derivatives, PnAO (6-(4-isothiocyanatobenzyl)-3,3,9,9,-tetramethyl-4,8-diazaundecane-2,10-dione-dioxime) and derivatives, such as BMS181321 (3,3'-(1,4-Butanediyldiamino)-bis(3-methyl-2-butanone)dioxime), MAG2 (mercaptoacetylglycylglycine) and its derivatives, MAG3 (mercaptoacetylglycylglycylglycine) and its derivatives, such as N3S-adipate, MAS3 (mercaptoacetylserylserylserine) and its derivatives, MAMA (N-(2-mercaptoethyl)-2-[(2-mercaptoethyl)amino]acetamide) and its derivatives, EC (ethylenedicysteine) and its derivatives, dmsa (dimercaptosuccinic acid) and its derivatives, DADT (diaminodithiol), DADS (diaminodisulfide), N2S2 chelators and their derivatives, aminothiols and their derivatives; salts of the foregoing chelators; hydrazine nicotinamides (HYNIC) and hydrazine nicotinamide derivatives; or MG a structural group for the covalent bonding of 18 F, 131 l or 211At is; the three or more targeting vectors TV1, TV2, TV3 are chosen independently of each other from one of the structures [1] to [44] with wherein X = H or F; Y = H, CH3, CH(CH3)2, C(CH3)3 or (CH2) n CH3 with n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and Z is chosen from the group comprising CH2, NH, alcohol-, amidine-, amine-, amide-, carboxylic acid amide-, thioamide-, imide-, imic acid ester-, imine-, urea-, thiourea-, guanidine-, carbonate-, carboxylic acid ester-, carbamate-, ether-, thioether-, ester-, ketone-, phosphate-, phosphonate-, phospinate-, sulfonic acid ester-, sulfinic acid ester-, Sulfone, thiol, disulfide, boronic ester, silyl ether residues or groups and derivatives thereof.

2. Marking precursor according to claim 1, characterized in that the marking precursor comprises 3, 4, 5, 6, 7, 8, 9 or 10 targeting vectors.

3. Marking precursor according to claim 1, characterized in that the marking precursor comprises 5 to 15 or 10 to 20 targeting vectors.

4. Marking precursor according to claim 1, 2 or 3, characterized in that the three or more targeting vectors TV1, TV2, TV3 are identical.

5. Marking precursor according to one or more of claims 1 to 4, characterized in that the three or more targeting vectors TV1, TV2, TV3 are selected from two or three groups with different structures.

6. Marking precursor according to one or more of claims 1 to 5, characterized in that the linker L and the three or more linkers L1, L2, L3 independently of one another have a structure selected from wherein A, B, C are independently chosen from the group comprising amide, carboxylic acid amide, phosphinate, alkyl, triazole, thiourea, ethylene, maleimide, and amino acid residues, and with s = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and p, q and r are chosen independently from the set of integers {1, 2, 3, 4, 5, 6, 7, 8, 9, 10}; 7 . Labeling precursor according to one or more of claims 1 to 5, characterized in that the linker L and the three or more linkers L1, L2, L3 are selected independently of one another from the group comprising benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1.2.4.5-Tetrazin-, Thiazin-, Oxazin-, Pyrrol-, Pyrrolidin-, Pyrazol-, Imidazol-, Tetrahydro- imidazol-, 1,2,4-Triazol-, Tetrazol-, Thiophen-, Furan-, 1,2-Thiazol-, 1,3-Thiazol-, Thiadiazol-, 1,2-Oxazol-, 1,3-Oxazol-, 1,2,3-Oxadiazol-, 1,2,4-Oxadiazol-, 1,2,4-Oxadiazol-, 1.2.5-Oxadiazol-, Napthalin-, Inden-, Indol-, Isoindol-, Indazol-, Chinolin-, Isochinolin-, Chinazolin-, Chinoxalin-, Cinnolin-, Phtalazin-, Tetrahhydrochinolin-, Tetrahydroiso- chinolin-, Chinolizidin-, Indolizidin-, 2H-Chromen-, 4H-Chromen-, 2H-Thiochromen-, 4H-Thiochromen-, Cumarin- und Purin-Reste sowie Derivate der vorstehenden Reste; 8. Labeling precursor according to one or more of claims 1 to 5, characterized in that the linker L and the three or more linkers L1, L2, L3 are selected independently of one another from the group comprising alkyl or -(CH2)n-, amino acids (Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA or γ-aminobutyric acid, homoserine, DOPA or 3,4-dihydroxyphenylalanine, citrulline, β-alanine, thyroxine), oligopeptides with 2 to 20 amino acids, polyethylene glycol or -(CH2CH2O) n -, Polypropylene glycol or -(CH2CH(CH3)2O) n - , polyalkylene glycol ether or -((CH2) o O)-, polyamine or -((CH2) p NH)- , polyamide or -((CH2) q CONH)-, Polyester or -((CH2) r COO)-, polyurethane or -((CH2) s NHCOO)-, polyurea or -((CH2) tNHCONH), where o, p, q, r, s and t are chosen independently from the set of integers {1, 2, 3, 4, 5, 6, 7, 8, 9, 10}; 9. Marking precursor according to one or more of claims 1 to 8, characterized in that the linking group V is selected from the group comprising acrylate, vinyl, ethylene oxide, glycidol oligomers and coololigomers with 3 or more repeating units.

10. Labeling precursor according to one or more of claims 1 to 8, characterized in that the linking group V is selected from the group comprising benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, thiazine, oxazine, pyrrole, pyrrolidine, pyrazole, imidazole, tetrahydroimidazole, 1,2,4-triazole, tetrazole, thiophene, furan, 1,2-thiazole, 1,3-thiazole, Thiadiazole, 1,2-oxazole, 1,3-oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, napthaline, indene, indole, isoindole, indazole, quinoline, isoquinoline, quinazoline, Quinoxaline, cinnolin, phthalazine, tetrahhydroquinoline, tetrahydroisoquinoline, quinolizidine, indolizidine, 2H-chromene, 4H-chromene, 2H-thiochromes, 4H-thiochromes, coumarin, purine residues, and derivatives of the aforementioned residues.

11. Marking precursor according to one or more of claims 1 to 8, characterized in that the linking group V structure exhibits.

12. Marking precursor according to one or more of claims 1 to 8, characterized in that the linking group V comprises one of the structures [45] to [84], with n = 1, 2, 3, 4, 5, 6, 7 or 8.

13. Labelling precursor according to one or more of claims 1 to 12, characterized in that the labelling group MG is equal to DOTA (dodeca-1,4,7,10-tetraamine tetraacetate) or DOTAGA (2-(1,4,7,10-tetraazacyclododecane-4,7,10)-pentanedioic acid).

14. Labeling precursor according to one or more of claims 1 to 12, characterized in that the labeling group MG is equal to DATA (6-Amino-1,4-diazepine triacetate) or DATA 5m(l,4-Bis(carboxy-methyl)-6-[methyl-carboxymethyl-amino]- 6-pentanoic acid-l,4-diazepane) is.

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