Labeled precursors and radiotracers with three or more targeting vectors for theranostics used in nuclear medicine

Abstract

A labeling precursor of a radioactive tracer, comprising a labeling group MG for covalent or coordinate labeling of a radioisotope, three or more targeting vectors TV for targeting cell receptors. 1 , TV 2 , TV 3 and three or more linkers L 1 , L 2 , L 3 wherein the three or more linkers L 1 , L 2 , L 3 each of which comprises the labeling group MG and the three or more targeting vectors TV 1 , TV 2 , TV 3 or one of said three or more linkers L 1 , L 2 , L 3 each of which comprises a binding group V and the three or more targeting vectors TV 1 , TV 2 , TV 3 and said labeling group MG is covalently attached to a linking group V directly or via a linker L, said labeling precursor having the following structure: (A), (B) or (C) and s=20. JPEG2025507966000073.jpg36156

Description

[Technical field]

[0001] The present invention relates to labeling groups for covalent or coordinate labeling of radioisotopes and labeling precursors comprising three or more targeting vectors for targeting cellular receptors, as well as radioactive tracers derived therefrom.

[0002] The label precursor of the present invention comprises 3, 4, 5, 6 or more target vectors, hereinafter also referred to as trimers, tetramers, pentamers and hexamers, or generally multimers. In the first configuration, the target vector is linked to the label group via a linker. In the second configuration, the label group and the target vector are linked to the linking group via a linker.

[0003] The labeled precursors and radioactive tracers of the present invention are intended for imaging in nuclear medicine diagnostics by positron emission tomography (PET), single photon emission computed tomography (SPECT), and for the treatment / therapy (endoradiotherapy / radionuclide therapy) of various tumors and metastases (theranostics). Here, metallic radioisotopes, for example gallium 68 ( 68 Ga) and Fluorine-18( 18 F), and in the case of SPECT, technetium 99m ( 99m Tc), and lutetium 177 ( 177 Lu) or Actinium 225 ( 225 It is possible to use a labeled precursor labeled with Ac).

[0004] Each of the three or more targeting vectors selectively binds to a membrane-bound receptor, protein, enzyme or other structure on the surface of a tumor cell, and a linker is disposed between each targeting vector and a label or binding group, which ensures that binding to the receptor is unhindered.

[0005] The labeling precursor of the present invention includes three or more targeting vectors linked to a labeling group (MG), e.g., a chelating agent, directly through a linker or through a linking group. These targeting vectors can be the same or different. By using three or more targeting vectors, the radiotracer formed from the labeling precursor by complexation or covalent binding of the radioisotope is accumulated in the biological tumor target in a proportionately greater amount than that of a similar radiotracer with one or two targeting vectors (monomeric and dimeric radiotracers). In addition, the radiotracer of the present invention is characterized by a long tumor residence time (tumor retention). The combination of high accumulation and long tumor retention increases the local radiation dose, decisively improving the therapeutic effect. At the same time, the radiation dose to healthy organs (e.g., kidneys, bladder, salivary glands), which often have limited therapeutic effect, is reduced.

[0006] The labeled precursors of the present invention open additional theranostic options for improving biological affinity, tumor accumulation and tumor retention, allowing the use of long half-life radioisotopes, e.g., which often have insufficient tumor residence time with monomeric and dimeric radiotracers. 177 Lu or 225 The scope of theranostic applications for Ac is expanded.

[0007] Labeling groups, especially by chelators, change the composition and chemical properties of the targeting vectors bound to them, thus generally affecting their affinity for tumor cells. Therefore, labeling precursors need to be reevaluated with respect to their complexation with radioisotopes, especially in terms of their biochemical and pharmacological properties in vitro and in vivo. The chemical bond of the labeling group to its targeting vector is crucial for the biological and nuclear medicine efficacy of the corresponding radiotracer.

[0008] Nevertheless, PET / CT has 68 Ga, SPECT 99m Tc, for treatment 177A chelator is selected that ensures stable complexation of the respective radioisotope, such as Lu. The linker, targeting vector, and optionally the attachment group are optimized for the respective medical application.

[0009] Various tumor targeting vectors are combined in a single molecule in a novel and flexible manner, resulting in labeled precursors or radiotracers with enhanced accumulation in the relevant biological tumor targets. Synergistic effects result in the corresponding labeled ( 177 Lu, 225 By using radiotracers (such as Ac), a clearly higher theranostic radiation dose can be achieved. Providing three or more targeting vectors for the radiotracer results in longer tumor retention. By optimizing the linker and targeting vector, the radiotracer of the present invention can be used for both diagnosis and intraradiotherapy. The optional linking group separates the labeling group from the linker and targeting vector, facilitating their optimization. Furthermore, the structural flexibility is increased, broadening the scope of use of the radiotracer.

[0010] Depending on the type of cancer and the method of diagnosis or treatment, a particular targeting vector and an appropriate labeling group will be selected.

[0011] The following properties are important for the labeled precursor and the radiotracer derived therefrom: - Rapid and effective complexation or binding of the respective radioisotope with the labeling group; -High affinity and selectivity for tumor cells and metastases compared to healthy tissue; - in vivo stability, i.e. biochemical stability in serum under physiological conditions; -High accumulation in tumors and metastases for accurate diagnosis and effective treatment; - Rapid clearance from healthy tissues and blood to minimize systemic dosage and toxicity.

[0012] The targeted vector ensures the selective accumulation of the radiotracer in the target tissue, also called "target" in the context of the present invention. Targeted vectors are used to target targets associated with prostate cancer and bone metastases, and generally to target the tumor stroma.

[0013] Prostate cancer For men in developed countries, prostate cancer is the most common cancer and the third most deadly. In this disease, the tumor growth is only gradual, and if diagnosed early, the 5-year survival rate is almost 100%. However, if the disease is discovered after the tumor has metastasized, the survival rate drops significantly. On the other hand, treating the tumor too early or with excessively aggressive measures can unnecessarily and significantly impair the patient's quality of life. For example, removal of the prostate by surgery can lead to incontinence and impotence. Reliable diagnosis and information on the progression of the disease are essential for successful treatment while improving the patient's quality of life. A widely used diagnostic method, along with palpation of the prostate by a physician, is the measurement of tumor markers in the patient's blood. The most prominent marker of prostate cancer is the concentration of prostate-specific antigen (PSA) in the blood. However, the significance of PSA concentration is controversial, and although patients with slightly elevated values ​​often do not have prostate cancer, 15% of patients with prostate cancer do not have elevated PSA levels in the blood. A further target structure in the diagnosis of prostate tumors is the prostate-specific membrane antigen (PSMA). Unlike PSA, PSMA is not detectable in blood. It is a membrane-bound glycoprotein with enzymatic activity. Its function is to remove C-terminal glutamic acid from N-acetylaspartylglutamate (NAAG) and folate-(poly)-gamma-glutamic acid. PSMA occurs rarely in normal tissues, but is significantly overexpressed in prostate cancer cells, and its expression correlates closely with the stage of tumor disease. PSMA is also expressed in 40% of lymph node and bone metastases of prostate cancer.

[0014] One strategy for molecular targeting of PSMA is to use an antibody to bind to the protein structure of PSMA. A ligand is then used to target the enzyme-binding pocket of PSMA. The central enzyme-binding pocket of PSMA contains two Zn2+ ligands that bind to glutamate. 2+ It contains an ion. An aromatic binding pocket is located in front of the central binding pocket. The PSMA protein can open to induce fit to various ligands, such as inhibitors or enzymatically degradable ligands. For example, PSMA binds folate as well as NAAG, with a pteroate group in the aromatic binding pocket. Targeting the PSMA binding pocket with inhibitors or substrates usually induces uptake into cells (endocytosis).

[0015] PSMA inhibitors are particularly suitable as targeting vectors for radiopharmaceuticals or radiotracers for diagnostic imaging and theranostics. The radiolabeled inhibitors bind to the central PSMA binding pocket, where they are not enzymatically converted or cleaved, and the inhibitor / targeting vector is not released from the radiolabel. Facilitated by endocytosis, the inhibitors are taken up together with the radiolabel into tumor cells and accumulate there.

[0016] Inhibitors with high affinity for PSMA (Figure 1) generally contain a glutamic acid motif and a structure that cannot be enzymatically cleaved. Highly effective PSMA inhibitors are 2-phosphonomethylglutaric acid or 2-phosphonomethylpentanedioic acid (2-PMPA), in which the glutamic acid motif is linked to a phosphonate group that cannot be cleaved by PSMA. Urea-based PSMA inhibitors are then used, for example, for the clinically relevant radiotracers of PSMA-11 type (Figure 2) and PSMA-617 type (Figure 3).

[0017] In addition to the central binding pocket, it has proven advantageous to target the aromatic binding pocket of PSMA. For example, in highly effective radiotracers of the PSMA-11 type, the binding motif L-lysine-urea-L-glutamic acid (KuE) is linked via a hexyl (hexyl spacer) to the aromatic HBED chelator (N,N'-bis[2-hydroxy-5-carboxyethyl)benzyl)ethylenediamine-N,N'-diacetate).

[0018] In contrast, it has been shown that when L-lysine-urea-L-glutamate (KuE) is conjugated with the non-aromatic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), it exhibits reduced affinity and accumulation in tumor tissue. 177 Lu and 225 To allow the use of DOTA chelators in PSMA-affinity radiopharmaceuticals containing therapeutic radioisotopes such as Ac, the spacer must be adapted. Specific replacement of the hexyl spacer with various aromatic structures allows the labeling precursor PSMA-617 and the current gold standard highly active radiotracers derived from it to be produced. 177 Lu-PSMA-617 was discovered. [ka] [ka] [ka]

[0019] Tumor stroma Malignant epithelial cells are components of many tumors and tumor types and form the tumor stroma that surrounds the tumor, measuring at least 1–2 mm in size.

[0020] The tumor stroma is composed of various types of non-malignant cells that are part of the tumor microenvironment that surrounds tumor cells. The tumor stroma can account for up to 90% of the total tumor mass. It plays an important role in tumor initiation, growth and metastasis, as well as in the supply of tumor cells.

[0021] The most important cellular component of the tumor stroma is the extracellular matrix, which contains various cytokines, endothelial cells, pericytes, macrophages, immunomodulatory cells and activated fibroblasts. The activated fibroblasts that surround the tumor are called tumor-associated fibroblasts (CAFs).

[0022] During the process of tumor growth, CAFs change their morphology and biological functions. These changes are caused by intercellular communication between cancer cells and CAFs. In this context, CAFs form an environment that promotes cancer cell proliferation. Therapeutic methods that target only cancer cells have proven insufficient. Effective therapeutic methods must also include the tumor microenvironment, i.e., CAFs.

[0023] In more than 90% of human epithelial cancers, CAFs overexpress fibroblast activation protein (FAP). Thus, FAP represents a promising attack point for nuclear medicine diagnosis and therapy. Similar to PSMA, FAP inhibitors (FAPI or FAPi) in particular are suitable as targeting vectors for FAP-labeled precursors and radiotracers derived from them. Although the role of FAP in vivo has not yet been fully elucidated, it is known to be an enzyme with specific catalytic activity. FAP has both dipeptidyl peptidase activity (DPP) and prolyl oligopeptidase activity (PREP). Therefore, useful inhibitors are those that inhibit the DPP and / or PREP activity of FAP. Of importance is the selectivity of the inhibitor against other similar enzymes such as dipeptidyl peptidases DPPII, DPPIV, DPP8 and DPP9, and prolyl oligopeptidase (PREP). In the case of cancer types in which both FAP and PREP are overexpressed, inhibitors that do not have a high selectivity between PREP and FAP but inhibit both enzymes can also be used.

[0024] In 2013, a high affinity and selectivity inhibitor structure based on a modified glycine-proline unit linked to quinoline was developed and published (Jansen et al. ACS Med. Chem. Lett. 2013, 4, 491-496). The compound of interest, (S)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide, is shown in Figure 4 (left side). Subsequent structure-activity studies (SAR) have revealed compounds with improved affinity and selectivity, including the difluoro derivative (S)-N-(2-(2-cyano-4,4'-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide, shown in Figure 4 (right side) (Jansen et al. J. Med. Chem. 2014, 57 (7), 3053-3074). [ka]

[0025] Difluorinated FAP inhibitors (Figure 4, right) form the assessment vector for various nuclear medicine FAP-labeled precursors and radiotracers. As an example, Figure 5 (top and center) shows the labeled precursors FAPI-04 and FAPI-46 (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). Figure 5 (bottom) shows further FAP-labeled precursors containing the chelator DOTA. The chelator DOTA is conjugated to the quinoline unit of the pharmacophore FAPi targeting vector via 4-aminobutoxy, squaric acid and ethylenediamine groups (DOTA.SA.FAPi, Moon et al. EJNMMI Radiopharmacy and Chemistry 2020, 5(1), 19). [ka]

[0026] As a further development, dimeric FAP radiotracers structurally formed from two identical targeting vectors (FAP inhibitor lead structures) have been synthesized. One of these is compound DOTA-2P(FAPI)2 (see Figure 6 above), which contains overlapping targeting vectors and FAPI-46 linkers (Zhao et al. J. Nucl. Med. 2021). Other compounds include compound DOTAGA.(QS.FAPi)2 in Figure 6 below (Moon et al. AJNMMI 2021, accepted). [ka]

[0027] These compounds demonstrate increased tumor residence time compared to the monomeric compounds (see FIG. 5).

[0028] Bone metastases 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 binding of signaling proteins in the cell membrane. As a result, apoptosis of carcinogenic bone cells is induced. FPPS is inhibited by bisphosphonates such as alendronate, pamidronate and zoledronate. For example, the tracer BPAMD containing the targeted vector pamidronate is routinely used to treat bone metastases.

[0029] A particularly effective tracer for theranostics of bone metastases has proven to be zoledronate (ZOL), a hydroxybisphosphonate containing a heteroaromatic imidazole unit. Zoledronate conjugated with the chelators NODAGA and DOTA (Figure 7) is currently the most potent radiotherapeutic agent for bone metastases. [ka]

[0030] In nuclear medicine, radiotracers are usually used that contain the "gold standard" chelator DOTA, which can be conjugated to a variety of targeting vectors. 68 Ga (for diagnostic use) and 177 It ensures stable complexation with Lu (for intracellular radiotherapy). For neuroendocrine tumors (NETs), octreotide derivatives such as TOC and TATE are used as targeting vectors. The most important labeling precursors of this compound class are DOTA-TOC and DOTA-TATE. 177Lu-DOTA-TATE is an important radiopharmaceutical approved for the treatment of somatostatin receptor (SSTR)-positive tumors (Fani et al. J. Nucl. Med 2017, 58(Suppl. 2), 61S-66S; Kam et al. Eur J Nucl Med Mol Imaging 2012, 39(1), 103-112; Kjaer et al. Scand J Gastroenterol. 2015, 50(6), 740-747).

[0031] In the diagnosis and treatment of patients with metastatic late-stage prostate cancer (PCa), PSMA inhibitors used in nuclear medicine target the prostate-specific membrane antigen (PSMA) as a targeting vector. Currently, the most significant is the compound PSMA-617, which contains DOTA as a chelating agent and a urea-based inhibitor unit as a targeting vector. 177 Lu-PSMA-617 is currently being evaluated in clinical Phase III trials (Kopka et al. J. Nucl. Med. 2017, 58(Suppl. 2), 17S-26S;Benesova et al. J Med Chem, 2016, 59, 1761-1775).

[0032] In the case of bone metastases, bisphosphonate derivatives are used, which bind highly selectively to bone metastases due to their high affinity for the hydroxyapatite structure of the bone matrix, with little binding to healthy soft tissues (Lin et al. Bone 1996, 18, 75-85; Palma et al. Mol Biosyst 2011, 7, 2950-2966).

[0033] In this context, DOTA-zoledronate is of particular interest, as it has a high affinity for the hydroxyapatite structure and allows for a simple introduction of diagnostic and therapeutic radioisotopes via the DOTA chelator (Meckel et al. EJNMMI Radiopharm. Chem. 2017, 1, 1481;Pfannkuchen et al. Curr. Radiopharm 2018, 11 (3), 223-230).

[0034] Cancer-associated fibroblasts (CAFs) are gaining increasing importance as a "pan-tumor target". CAFs are present in the tumor microenvironment of various types of cancer and are overexpressed in more than 90% of all epithelial tumors (Garin-Chesavet al. Proc. Natl. Acad. Sci. USA 1990, 87 (18), 7235-7239). Fibroblast activation protein (FAP), a biomarker for CAFs, is targeted here via FAP inhibitors. Since FAP is overexpressed in numerous tumor types, the corresponding theranostic radiopharmaceuticals using FAP inhibitors as targeting vectors have attracted great interest for universal targeting and treatment of various types of cancer. Currently, the most promising and most studied compounds are FAPI-04 and FAPI-46, again using DOTA as the 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). The corresponding labeled precursors are shown in Figure 8, with the respective target vectors circled and highlighted with dotted lines. [ka]

[0035] Currently, radiotracers in clinical use are "monomeric" and contain only one targeting vector. Monomeric radiotracers with one targeting vector play a central role in nuclear medicine and are referred to as "precision oncology". Monomeric FAPI radiotracers are: 68 Ga-PET / CT has great potential for the diagnosis of various tumor types. Clinical studies with an ever-increasing number of patients worldwide have shown highly selective accumulation in tumors and metastases, making it an excellent candidate for the clinical standard. 18 Measurement with F-FDG provides comparable and often superior imaging. Limiting factors for monomeric radiotracers include rapid renal excretion and short residence time in tumors. As a result, a significant portion of clinically established monomeric radiotracers are 68 Its half-life is significantly longer than that of Ga. 177 Lu and 225 It is not suitable for use in theranostics with therapeutic radioisotopes such as Ac.

[0036] The present invention provides multimeric labeled precursors with three or more different or identical targeting vectors. The targeting vectors can be linked to the same or different linkers. Each targeting vector is linked to a labeling group or a binding group via a linker. The present invention allows matching the affinity and pharmacokinetics of multimeric labeled precursors or radiotracers independent of the radiolabel (orthogonally). By using multiple targeting vectors, the accumulation of theranostic compounds in biological tumor targets is obviously improved, surpassing the corresponding monomeric radiotracers. In addition, multimeric radiotracers are notable for their obviously longer tumor retention times. The improved accumulation and tumor retention times clearly increase the local radiation dose and enhance the therapeutic effect. At the same time, the radiation burden on healthy organs such as the kidneys, bladder and salivary glands, which often limit radionuclide therapy, is reduced. The multiplexing of targeting vectors improves the accumulation and tumor retention times of the radiotracers of the present invention, which is a result of the radioisotope 177 Lu or 225 It is of vital importance for the therapeutic use of Ac.

[0037] It is an object of the present invention to overcome the above-mentioned limitations of known radiotracers and diagnostic and therapeutic methods based thereon.

[0038] The object is to obtain a labeled precursor of a radioactive tracer, a labelling group MG for covalent or coordinate labelling with a radioisotope, -Three or more targeted vectors TV1, TV2, TV3, and - three or more linkers L1, L2, L3, Including, - each of the three or more linkers L1, L2, L3 is covalently linked to the labeling group MG and to one of the three or more targeting vectors TV1, TV2, TV3; or - each of the three or more linkers L1, L2, L3 is covalently linked to a binding group V and to one of the three or more labeling vectors TV1, TV2, TV3, and the labeling group MG is covalently linked to the binding group V directly or via a linker L.

[0039] Suitable embodiments of the label precursor of the present invention are characterized by any combination of the following features, unless the features are mutually exclusive: -The labeled precursor has the structure [ka] having; -Three or more targeting vectors, TV1, TV2, and TV3, are independently constructed as follows: [ka] JPEG2025507966000012.jpg219145JPEG2025507966000013.jpg230145JPEG2025507966000014.jpg223143JPEG2025507966000015.jpg226145JPEG2025507966000016.jpg227145JPEG2025507966000017.jpg76147 is selected. X=H or F; Y=H, CH3, CH(CH3)2, C(CH3)3 or (CH2) n CH3, n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Z is selected from the group consisting of CH2, NH, alcohol, amidine, amine, amide, carboxamide, thioamide, imide, imidoester, imine, urea, thiourea, guanidine, carbonate, carboxylate ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonate ester, sulfinate ester, sulfone, thiol, disulfide, boronate ester and silyl ether radicals or groups, and derivatives thereof; - the labeled precursor contains 3, 4, 5, 6, 7, 8, 9 or 10 target vectors; - the labeled precursor contains 5-15 or 10-20 target vectors; - the labeled precursor contains 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 target vectors; the linker L and the three or more linkers L1, L2, L3 are independently [ka] having a structure selected from A, B, and C are independently amide, carboxamide, phosphinate, alkyl, triazole, thiourea, ethylene, maleimide, and amino acid residues; [ka] where s=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and p, q, and r 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 are independently selected from 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, thiadia the radicals of azole, 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, and derivatives of the above radicals; - the linker L and the three or more linkers L1, L2, L3 are independently alkyl or -(CH2) n -, amino acids (Ala, Arg, Asn, Asp, Cys, Gln, 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 having 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) t NHCONH)-, 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 have the structure [ka] m=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, i=1, . . . , m, and the side chain R iare independently -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, -(CH2)2COOH, -CH2(C=O)NH2, -(CH2)2(C=O)NH2, alcohol, amidine, amine, amide, carboxamide , thioamide, imide, imide ester, imine, urea, thiourea, guanidine, carbonate, carboxylate ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonate ester, sulfinate ester, sulfone, thiol, disulfide, boronic acid ester, silyl ether, alkyl-(CH2)-, amino acid (Ala, Arg, Asn, Asp, Cys, Gln, 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 having 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, Azine, 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, 1,2,5-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 radicals, 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) t NHCONH)-, and derivatives of the above radicals, where o, p, q, r, s and t are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; The labeling group MG is 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, 111 In, 135 Sm, 140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb,177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 It is a chelating agent for complexation of radioisotopes from the group consisting of Th; The labeling group MG is H4pypa, EDTA (ethylenediaminetetraacetate), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, NOTA (nona-1,4,7-triaminetriacetate) 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-tetraaminetetraacetate), DOTAGA (2-(1,4,7,10-tetraazacyclododecane-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-tetraaminetetraacetate), TETA (tetradeca-1,4,8,11-tetraaminetetraacetate) and its derivatives, PEPA (pentadeca-1,4,7,10,13-pentaaminepentaacetate), HEHA (hexadeca-1,4,7,10,13,16-hexaaminehexaacetate) and its derivatives, HBED (N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetate) and their derivatives, such as HBED-CC (N,N'-bis[2-hydro (1,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane-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 (tetraazacyclodecane phosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepane-N,N,N',N'-tetraacetate) and its derivatives, such as AAZTA 5 (5-[(6-amino)-1,4-diazepane]pentanoic acid-N,N,N',N'-tetraacetate), DATA (6-amino-1,4-diazepine triacetate) and DATA 5m(5-[[6-(N-methyl)amino]-1,4-diacetate-1,4-diazepane]pentanoic acid-N,N',N'-triacetate); sarcofagin SAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine) and its derivatives, such as (NH2)2SAR (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine); xabicyclo[6.6.6]eicosane), 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 its derivatives, such as BMS181321 (3,3'-(butane-1,4-diyldioxime) amino)bis(3-methyl-2-butanone)dioxime), MAG2 (mercaptoacetylglycylglycine) and derivatives thereof, MAG3 (mercaptoacetylglycylglycylglycine) and derivatives thereof, such as N3S adipate, MAS3 (mercaptoacetylserylserylserine) and derivatives thereof, MAMA (N-(2-mercaptoethyl)-2-[(2-mercaptoethyl)amino]acetamide) and derivatives thereof, EC (ethylenedicysteine) and derivatives thereof, dmsa (dimercaptosuccinic acid) and derivatives thereof, DADT (diaminodithiol), DADS (diaminodisulfide), N2S2 chelating agents and derivatives thereof, aminothiol and derivatives thereof; salts of said chelating agents; chelating agents selected from the group consisting of hydrazine nicotinamide (HYNIC) and hydrazine nicotinamide derivatives; The labeling group MG is DOTA, DATA, and DATA 5m selected from the group consisting of; - The labeling group MG is NOTA, DATA, DATA 5m and NODAGA; - the labeling group MG is AL 18 NOTA, DATA, DATA for F complexation 5m and NODAGA; The labeling group MG is 18 F, 131 I or 211 is the structural group for the covalent attachment of At; - the labeling group MG [ka] Selected from; The labeling group MG has the structure [ka] having 18 F, 131 I or 211 having a leaving group X for displacement by At; the labeling group MG has a leaving group X selected from the radicals 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 bonding group V is independently selected from the structures

[85] to

[0149] : [ka] JPEG2025507966000024.jpg237147JPEG2025507966000025.jpg196142, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 tris linkers TL, TL1, TL2, ..., TL 19 Contains; - the linking group V is selected from the group consisting of acrylate, vinyl, ethylene oxide and glycidol oligomers and cooligomers having 3 or more units; - the linking group V is 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-oxazo the radicals of 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, and derivatives of the above radicals; The bonding group V has the structure [ka] having; - The bonding group V is a structure

[45] to

[84] [ka] JPEG2025507966000028.jpg86144, where n=1, 2, 3, 4, 5, 6, 7 or 8; The bonding group V has the structure [ka] and t=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, j=1, . . . , t, and the side chain R jare independently -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, -(CH2)2COOH, -CH2(C=O)NH2, -(CH2)2(C=O)NH2, alcohol, amidine, amine, amide, carboxamide amide, thioamide, imide, imide ester, imine, urea, thiourea, guanidine, carbonate, carboxylate ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonate ester, sulfinate ester, sulfone, thiol, disulfide, boronate ester, silyl ether, alkyl-(CH2)-, amino acid (Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Ly s, 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 having 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 Azine, 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, 1,2,5-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 radicals, 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) t NHCONH)-, and derivatives of the above radicals, and o, p, q, r, s and t are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0040] It is a further object of the present invention to provide a radiotracer which overcomes the above-mentioned limitations of known radiotracers and the diagnostic and therapeutic methods based thereon.

[0041] This object is achieved by a radioactive tracer consisting of one of the label precursors described above and a radioisotope complexed or covalently bound thereto, the radioisotope being 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, 111 In, 131 I, 135 Sm, 140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 203 Pb, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th.

[0042] Figure 9 shows exemplary configurations of the label precursor of the present invention without a binding group (Figures 9a and 9b) and with a binding group V (Figures 9c, 9d, 9e, 9f, 9g and 9h). According to Figures 9a and 9b, three and four target vectors TV1, TV2, TV3, TV4 are linked to the label group MG via linkers L1, L2, L3, L4, respectively. In Figures 9c and 9d, the label group MG and three and twenty target vectors TV1, TV2, ..., TV 20 and are the linkers L, L1, L2, . . . , L 20 In Figures 9e, 9f, 9g and 9h, the linking group V comprises three Tris linkers TL, TL1, TL2 (Figures 9e and 9f) or seven Tris linkers TL, TL1, TL2, TL3, TL4, TL5 and TL6 (Figures 9g and 9h). [ka] JPEG2025507966000031.jpg136138

[0043] In the peptides or structural formulas [1]-[8], the following abbreviations are used for synthetic amino acids: Aph(Hor) = 4-[2,6-dioxohexahydropyrimidine-4-carbonylamino]-L-phenylalanine Cpa = 4-chlorophenylalanine D-Aph(Cbm) = D-4-aminocarbamoylphenylalanine Pal = 2-, 3- or 4-pyridylalanine

[0044] The labeling group MG is designed as a chelating agent for complexation of radioisotopes or as a group for covalent binding of radioisotopes. Targeting vectors TV1, TV2,..., TV 20 may be different from each other, may be partially the same, or may be completely the same. Similarly, the linkers L, L1, L2, ..., L 20 may be different from each other, may be partially the same, or may be completely the same.

[0045] The inventors have surprisingly found that the multimeric labeled precursors described above, or radiotracers derived from them with three or more targeting vectors, accumulate much more in tumor tissue (target exposure) when given the same systemic dose and non-specific accumulation (off-target exposure) compared to monomeric or dimeric radiotracers with one or two targeting vectors. This advantageous property is believed to be due to an improved probability and / or selectivity of binding.

[0046] The three or more targeting vectors TV1, TV2, TV3 used in the present invention have high binding affinity to membrane-bound tumor markers, especially PSMA (prostate-specific membrane antigen) and FAP (fibroblast activation protein). The labeled precursors and radiotracers of the present invention preferably also target the tumor stroma. For example, triple-negative breast cancer (TNBC) lacks specific receptors on the surface of tumorigenic cells that allow direct targeting. Here, "indirect" targeting of the tumor stroma is employed. In the case of TNBC, the tumor stroma contains cancer-associated fibroblasts (CAFs) and degenerated endothelial cells (ECs), which overexpress FAP and PSMA, respectively. Therefore, heteromeric labeled precursors with targeting vectors against FAP and PSMA are suitable for the diagnosis and treatment of TNBC.

[0047] 177 Lu and 225 Theranostic targeting of tumor stroma with radioisotopes such as Ac directly damages the tumor microenvironment essential for progression and induces “indirect” radiation damage (radiation-induced bystander effect, RIBE) in adjacent cancer cells.

[0048] The three or more linkers L1, L2, L3 in the label precursor of the present invention function as steric spacers and pharmacokinetic regulators to optimize the biochemical function (binding affinity to the target), the radiochemical function (stable complexation or binding of the radioisotope) and the serum half-life (hydrophilicity) of the targeting vector. The linkers preferably contain structural factors, such as squaramide or other aromatic units that improve affinity to PSMA.

[0049] In the case of the labelling group MG in the form of a chelating agent, the chelating agent is 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Sm, 140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 It is used to label with a radioisotope selected from the group consisting of Th.

[0050] The present invention therefore includes radioactive tracers obtained from the above-mentioned label precursors by complexation with a radioisotope, the radioisotope being 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, 111 In, 135 Sm, 140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 203 Pb,211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th.

[0051] Chelating Agents: The prior art discloses a number of chelating agents for complexation of radioisotopes. Figure 10 shows examples of chelating agents that may be used in the present invention. [ka] JPEG2025507966000033.jpg192155JPEG2025507966000034.jpg212150JPEG202 5507966000035.jpg236158JPEG2025507966000036.jpg191147JPEG2025507966 000037.jpg220152JPEG2025507966000038.jpg201153JPEG2025507966000039. jpg203146JPEG2025507966000040.jpg252170JPEG2025507966000041.jpg60140

[0052] Examples of compounds of the present invention are shown in Figures 11-74 below. [ka] JPEG2025507966000043.jpg203149JPEG2025507966000044.jpg191149JPEG202 5507966000045.jpg185148JPEG2025507966000046.jpg177146JPEG20255079660 00047.jpg188148JPEG2025507966000048.jpg218149JPEG2025507966000049.j pg231148JPEG2025507966000050.jpg207149JPEG2025507966000051.jpg200146 JPEG2025507966000052.jpg174147JPEG2025507966000053.jpg230147JPEG202 5507966000054.jpg194147JPEG2025507966000055.jpg200147JPEG20255079660 00056.jpg220145JPEG2025507966000057.jpg219145JPEG2025507966000058.j pg218144JPEG2025507966000059.jpg216144JPEG2025507966000060.jpg234145

[0053] The meaning of some terms used in the context of the present invention is explained below. Theranostics: The diagnosis and treatment of cancer using nuclear medicine radioactive tracers. Labeled Precursor (Precursor): A compound that contains a first and second targeting vector and a chelator or functional group for labeling with a radioisotope. Radiotracer: A radioisotope-labeled precursor for nuclear medicine diagnostics or theranostics that is used in low concentrations without affecting the patient's metabolism. Target: A biological target structure in an organism to which a targeting vector binds, in particular a (membrane-bound) receptor, protein, enzyme or antibody. Targeting Vector: A chemical group or radical that functions as a ligand, agonist, antagonist or inhibitor for a biological target (eg, a protein, enzyme or receptor) and has high binding affinity for the target. Linking group: A structural unit having a functional group for covalently binding a linker-target vector complex to a labeling group MG. Linker: A structural unit, group or radical of a targeting vector in which the labeling group functions as a steric and / or pharmacokinetic modifier.

Claims

1. A labeled precursor of a radioactive tracer, - a labelling group MG for covalent or coordinate labelling with a radioisotope; -Three or more targeting vectors TV targeting cell receptors １ , TV ２ , TV ３ and - 3 or more linkers L １ , L ２ and L ３ Including, said three or more linkers L １ , L ２ , L ３ each of which comprises the labeling group MG and the three or more target vectors TV １ , TV ２ , TV ３ or said three or more linkers L １ , L ２ , L ３ each of which comprises a binding group V and the three or more targeting vectors TV １ , TV ２ , TV ３ and said labelling group MG is covalently linked to said linking group V directly or via a linker L; -MG is H ４ pypa, EDTA (ethylenediaminetetraacetate), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, NOTA (nona-1,4,7-triaminetriacetate) and its derivatives, such as NODAGA (1,4,7-triazacyclononane, 1-glutaric acid, 4,7-acetate), TRAP (triazacyclononane NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), DOTA (dodeca-1,4,7,10-tetraaminetetraacetate), DOTAGA (2-(1,4,7,10-tetraazacyclododecane)-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-tetraaminetetraacetate), TETA (tetradeca-1,4,8,11-tetraaminetetraacetate) and its derivatives, PEPA (pentadeca-1,4,7,10,13-pentaaminepentaacetate), HEHA (hexadeca-1,4,7,10,13,16-hexaaminehexaacetate) and its derivatives, HBED (N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetate) and their derivatives, such as HBED-CC (N,N'-bis[2-hydroxy-5-carboxyethyl)benzyl)ethylenediamine-N,N'-diacetate), DEDPA and its derivatives, such as H ２ Dedpa (1,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane) and H ４ octapa (1,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane-N,N'-diacetate), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives, e.g. ３ THP-Ac and H ３ THP-mal (YM103), TEAP (tetraazacyclodecane phosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepane-N,N,N',N'-tetraacetate) and its derivatives, e.g. AAZTA ５ (5-[(6-amino)-1,4-diazepane]pentanoic acid-N,N,N',N'-tetraacetate), DATA (6-amino-1,4-diazepine triacetate) and DATA ５ｍ (5-[[6-(N-methyl)amino]-1,4-diacetate-1,4-diazepane]pentanoic acid-N,N',N'-triacetate); sarcofagin SAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine) and its derivatives, such as (NH ２ ) ２ SAR (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane), N4 (3-[(2'-aminoethyl)amino]-2-[(2''-aminoethyl)aminomethyl]propionic acid) and other N ４ derivatives, PnAO (6-(4-isothiocyanatobenzyl)-3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime) and its derivatives, for example BMS181321 (3,3'-(butane-1,4-diyldiamino)bis(3-methyl-2-butanone) dioxime), MAG2 (mercaptoacetylglycylglycine) and its derivatives, MAG3 (mercaptoacetylglycylglycylglycine) and its derivatives, for example N ３ S 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), N ２ S ２ A chelating agent selected from the group consisting of chelating agents and derivatives thereof, aminothiols and derivatives thereof; salts of said chelating agents; hydrazine nicotinamide (HYNIC) and hydrazine nicotinamide derivatives; or M.G. １８ F. １３１ I or ２１１ is a structural group for covalent attachment of At; - the three or more target vectors TV １ , TV ２ , TV ３ is independently selected from any of structures [1] to [44]: 【Chemistry 1】 【change】 【change】 【change】 【change】 【change】 【change】 X=H or F; Y=H, CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ Or (CH ２ ) ｎ CH ３ where n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Z is CH ２ , NH, alcohol, amidine, amine, amide, carboxamide, thioamide, imide, imidoester, imine, urea, thiourea, guanidine, carbonate, carboxylate ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonate ester, sulfinate ester, sulfone, thiol, disulfide, boronate ester and silyl ether radicals or groups, and derivatives thereof.

2. The labeled precursor of claim 1 , wherein the labeled precursor comprises 3, 4, 5, 6, 7, 8, 9, or 10 target vectors.

3. The labeled precursor of claim 1, wherein the labeled precursor comprises 5 to 15 or 10 to 20 target vectors.

4. The three or more target vectors TV １ , TV ２ , TV ３ The label precursor according to any one of claims 1 to 3, wherein are identical.

5. The three or more target vectors TV １ , TV ２ , TV ３ The label precursor according to any one of claims 1 to 4, wherein is selected from two or three groups having different structures.

6. The linker L and three or more linkers L １ , L ２ , L ３ became independent, 【Chemistry 2】 having a structure selected from A, B, and C are independently amide, carboxamide, phosphinate, alkyl, triazole, thiourea, ethylene, maleimide, and amino acid residues; 【Chemistry 3】 and s=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p, q, and r are independently selected from the set of integers {1, 2, 3, 4, 5, 6, 7, 8, 9, 10}.

7. The linker L and three or more linkers L １ , L ２ , L ３ are independently selected from 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, and 1,3-oxazo.

6. The label precursor according to claim 1, wherein the label precursor is selected from the group consisting of radicals of benzoyl, 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, and derivatives of said radicals.

8. The linker L and three or more linkers L １ , L ２ , L ３ are independently alkyl or -(CH ２ ) ｎ -, amino acids (Ala, Arg, Asn, Asp, Cys, Gln, 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 having 2 to 20 amino acids, polyethylene glycol, or -(CH ２ CH ２ O) ｎ -, polypropylene glycol or -(CH ２ CH (CH ３ ) ２ O) ｎ -, polyalkylene glycol ether or -((CH ２ ) ｏ O)-, polyamine or -((CH ２ ) ｐ NH)-, polyamide or -((CH ２ ) ｑ CONH)-, polyester or -((CH ２ ) ｒ COO)-, polyurethane or -((CH ２ ) ｓ NHCOO)-, polyurea or -((CH ２ ) ｔ 6. The label precursor of any one of claims 1 to 5, wherein 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}.

9. The label precursor of any one of claims 1 to 8, wherein the linking group V is selected from the group consisting of acrylates, vinyls, ethylene oxides, and glycidol oligomers and co-oligomers having three or more repeat units.

10. The bonding group V is selected from the group consisting of 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, and 1,3-oxazo 9. The label precursor according to claim 1, wherein the label precursor is selected from the group consisting of radicals of 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, and derivatives of said radicals.

11. The bonding group V has the structure 【Chemistry 4】 The label precursor according to any one of claims 1 to 8, having the formula:

12. The bonding group V is a structure represented by any one of [45] to [84] 【Chemistry 5】 【change】 and n=1, 2, 3, 4, 5, 6, 7 or 8.

13. The label precursor according to any one of claims 1 to 12, wherein the label group MG is DOTA (dodeca-1,4,7,10-tetraaminetetraacetate) or DOTAGA (2-(1,4,7,10-tetraazacyclododecane-4,7,10)pentanedioic acid).

14. The labeling group MG is DATA (6-amino-1,4-diazepine triacetate) or DATA ５ｍ The label precursor according to any one of claims 1 to 12, which is (1,4-bis(carboxymethyl)-6-[methylcarboxymethylamino]-6-pentanoic acid-1,4-diazepane).

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