EP4351663A1

EP4351663A1 - Trislinker-conjugated dimeric labelling precursors and radiotracers derived therefrom

Info

Publication number: EP4351663A1
Application number: EP22734235.9A
Authority: EP
Inventors: Frank RÖSCH; Marcel Martin; Tilmann Grus; Euy Sung Moon; Chandra Sekhar Bal
Original assignee: Medianezia GmbH
Current assignee: Medianezia GmbH
Priority date: 2021-06-08
Filing date: 2022-06-07
Publication date: 2024-04-17
Also published as: CA3222226A1; CN117642190A; AU2022288744A9; KR20240019301A; WO2022258637A1; BR112023023149A2; DE102021114711B4; AU2022288744A1; DE102021114711A1

Abstract

The invention relates to a radiotracer labelling precursor having the structure (I) comprising a first target vector (TV1), a second target vector (TV2), a labelling group (MG) for complexation or covalent binding of a radioisotope, a first spacer (S1), a second spacer (S2), a third spacer (S3) and a trislinker (TL).

Description

Trislinker-Conjugated Dimeric Label Precursors and Radiotracers Derived Therefrom The present invention relates to dimeric label precursors and radiotracers derived therefrom by complexation with a radioisotope for the diagnosis and treatment of cancer diseases. The tag precursor has the structure TV1-S1-TL-S2-TV2 | S3 | MG wherein TV1 is a first targeting vector, TV2 is a second targeting vector, MG is a labeling group for complexation or covalent binding of a radioisotope, S1 is a first spacer, S2 is a second spacer, S3 is a third spacer, and TL is a trislinker. The marker precursors and radiotracers according to the invention are intended for imaging nuclear medicine diagnostics, in particular positron emission tomography (PET) and single photon emission computed tomography (SPECT), and radionuclide therapy/endoradiotherapy of carcinomas and metastases of various types of cancer. In nuclear medicine diagnostics, tumor cells or metastases are marked and imaged using a radioactive isotope such as gallium-68 ( ⁶⁸ Ga), technetium-99m ( ^99m Tc) or scandium-44 ( ⁴⁴ Sc). Complex-forming chelators are used for metallic radionuclides of the above type. Non-metallic radioisotopes such as Fluorine-18 ( ¹⁸ F), Iodine-123 ( ¹²³ I), Iodine-131 ( ¹³¹ I) and Astatine-211 ( ²¹¹ At) are covalently bound, ie no chelator is needed. In contrast to diagnostics, higher doses of radiation are used in nuclear medicine therapy to destroy tumor tissue. For example, beta-minus emitting radioisotopes such as lutetium-177 ( ¹⁷⁷ Lu), yttrium-90 ( ⁹⁰ Y) and iodine-131 ( ¹³¹ I) or alpha emitters such as actinium-225 ( ²²⁵ Ac) are used. Alpha and beta minus rays have a short range in tissue. The short range enables localized irradiation of tumors and metastases with a low radiation dose and damage to the surrounding healthy tissue. In recent years, the combination of diagnostics and therapy - referred to as theranostics in specialist circles - has become increasingly important. The same marker precursor can be used for both diagnostics and therapy. In this case, the marking precursor is only marked with different radioisotopes, for example with ⁶⁸ Ga and ¹⁷⁷ Lu, so that PET diagnostics and radiotherapy can be carried out with essentially chemically identical compounds. This allows a transmission (translation) of the results of imaging nuclear medicine diagnosis in nuclear medicine treatment (theranostics) with improved dose setting. The configuration and chemical properties of a target vector conjugated with the labeling group are modified by the labeling group - in particular by chelators - and its affinity for tumor cells is usually influenced. Accordingly, the label precursor needs to be re-evaluated in terms of complexation with radioisotopes and, most importantly, in terms of its in vitro and in vivo biochemical and pharmacological properties. The labeling group and its chemical coupling with the target vector are decisive for the biological and nuclear medicine potency of the associated radiotracer. After intravenous injection into the bloodstream, the marker precursor labeled with the radioisotope—also referred to below as radiotracer—accumulates on or in tumor cells or metastases. In order to minimize the radiation dose in healthy tissue, radioisotopes with a short half-life of a few hours to a few days are used. In summary, it can be said that the label precursor and radiotracers derived from it must meet the following requirements: 1. Fast and effective complexation or binding of the respective radioisotope; 2. high selectivity for tumor cells and metastases relative to healthy tissue; 3. in vivo stability, ie biochemical stability in blood serum under physiological conditions; 4. high accumulation in the tumor and any metastases, which enables precise diagnosis and effective therapy; 5. low retention and rapid clearance from healthy tissues and the blood to minimize dose and toxicity to these organs. Prostate cancer For men in industrialized countries, prostate cancer is the most common type of cancer and the third leading cause of death from cancer. Tumor growth in this disease is slow and when diagnosed early, the 5-year survival rate is nearly 100%. However, if the disease is only discovered after the tumor has metastasized, the survival rate drops drastically. On the other hand, taking action against the tumor too early and too aggressively can unnecessarily impair the patient's quality of life. So e.g. B. 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 widespread diagnostic tool, in addition to a doctor palpating the prostate, is the determination of tumor markers in the patient's blood. The most prominent marker for prostate cancer is the level of prostate-specific antigen (PSA) in the blood. However, the validity of the PSA concentration is disputed, since patients with slightly elevated values often do not have prostate carcinoma, but 15% of patients with prostate carcinoma do not show an increased PSA concentration in the blood. Another target for the diagnosis of prostate tumors is the prostate-specific membrane antigen (PSMA). Unlike PSA, PSMA cannot be detected in the blood. It is a membrane-bound glycoprotein with enzymatic activity. Its task is to split off C-terminal glutamate from N-acetyl-aspartyl-glutamate (NAAG) and folic acid-(poly)-γ-glutamate. PSMA is rarely found in normal tissue, but is highly overexpressed by prostate carcinoma cells, with expression being closely correlated with the stage of the tumor disease. Lymph node and bone metastases from prostate carcinomas also show 40% expression of PSMA. One strategy for molecular targeting of PSMA is to bind antibodies to the protein structure of PSMA. Furthermore, ligands are used which address the enzymatic binding pocket of PSMA. The central enzymatic binding pocket of PSMA contains two Zn ²⁺ ions that bind glutamate. The central binding pocket is preceded by an aromatic binding pocket. The PSMA protein is able to expand and adapt to different ligands, such as inhibitors or enzymatically cleavable ones (induced fit). In addition to NAAG, PSMA also binds folic acid, with the pteroic acid group docking in the aromatic binding pocket. Targeting the PSMA binding pocket with an inhibitor or substrate usually induces cellular incorporation (endocytosis). PSMA inhibitors are particularly suitable as target vectors for imaging diagnostic and theranostic radiopharmaceuticals or radiotracers. The radioactively labeled inhibitors dock onto the central PSMA binding pocket, where they are not converted or cleaved enzymatically and the inhibitor/target vector is not detached from the radioactive label. Favored by endocytosis, the inhibitor with the radioactive label is absorbed into the tumor cell and accumulates there. Inhibitors with high affinity for PSMA (Scheme 1) usually contain a glutamate motif and an enzymatically non-cleavable structure. A highly effective PSMA inhibitor is 2-phosphonomethylglutaric acid or 2-phosphonomethylpentanedioic acid (2-PMPA), in which the glutamate motif is linked to a phosphonate group that cannot be cleaved by PSMA. Furthermore, urea-based PSMA inhibitors are used, such as in clinically relevant radiotracers of the type PSMA-11 (Scheme 2) and PSMA-617 (Scheme 3). It has proven advantageous to target the aromatic binding pocket of PSMA in addition to the central binding pocket. For example, in highly effective radiotracers of the PSMA-11 type, the binding motif L-lysine-urea-L-glutamate (KuE) is linked via hexyl (hexyl spacer) to an aromatic HBED chelator (N,N'-bis[2-hydroxy -5-carboxy-ethyl)benzyl)ethylene-diamine-N,N'-diacetate). However, if L-lysine-urea-L-glutamate (KuE) is bound to the non-aromatic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), there is reduced affinity and accumulation in tumor tissue. In order to still be able to use the DOTA chelator for a PSMA-affine radiopharmaceutical with therapeutic radionuclides such as ¹⁷⁷ Lu or ²²⁵ Ac, the spacer has to be adjusted. The label precursor PSMA-617 and the highly effective radiotracer ¹⁷⁷ Lu-PSMA-617 derived from it, the current gold standard, were found by means of targeted substitution of the hexyl spacer by various aromatic structures.

Tumor stroma Malignant epithelial cells are part of many tumors and tumor types and form a tumor stroma surrounding the tumor at the latest from a size of 1 – 2 mm. The tumor stroma (tumor microenvironment or TME) comprises various non-malignant types of cells and can account for up to 90% of the total tumor mass. It plays an important role in tumor progression, tumor growth and metastasis. 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 called cancer-associated fibroblasts (CAF). During tumor development, CAFs change their morphology and biological function. These changes are induced by intercellular communication between cancer cells and CAFs. Here, CAFs create an environment that favors the growth of cancer cells. It has been shown that therapies that target cancer cells alone are inadequate. Effective therapies must take into account the tumor microenvironment and thus also the CAFs. Fibroblast activation protein (FAP) is overexpressed by CAFs in more than 90% of all human epithelial carcinomas. Therefore, FAP represents a promising target for nuclear medicine diagnostics and therapy. Analogously to PSMA, FAP inhibitors (FAPI or FAPi) are particularly suitable as target vectors for FAP labeling precursors and radiotracers derived therefrom. The role of FAP in vivo is not fully understood, however, it is known to be an enzyme with specific catalytic activity. It exhibits both dipeptidyl peptidase (DPP) and prolyl oligopeptidase (PREP) activity. Accordingly, inhibitors can be considered which reduce the DPP and/or inhibit the PREP activity of FAP. The key is the selectivity of the inhibitor over other similar enzymes such as the dipeptidyl peptidases DPPII, DPPIV, DPP8 and DPP9, as well as over prolyloligopeptidase (PREP). However, in cancers in which both FAP and PREP are overexpressed, inhibitors that do not have high selectivity between PREP and FAP but inhibit both enzymes can also be used. In 2013, a high-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 relevant compound (S)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide is depicted in Scheme 4 (left). Subsequent structure activity studies (SAR) identified compounds with improved affinity and selectivity, including the difluorinated derivative (S)-N-(2-(2-Cyano-4,4'-difluoropyrrolidin-1-yl)-2 -oxoethyl)quinoline-4-carboxamide, UAMC1110 for short, which is shown in Scheme 4 (right) (JANSEN et al. J. Med. Chem.2014, 57 (7), 3053– 3074). UAMC1110 forms the basis for target vectors of various FAP label precursors and radiotracers for nuclear medicine applications. Scheme 5 (above) shows the marker precursor FAPI-04 as an example (LINDNER et al. J. Nucl. Med.2018, 59 (9), 1415-1422). Scheme 5 (below) shows another FAP-tag precursor comprising the chelator DOTA. The chelator DOTA is coupled to the quinoline unit of the pharmacophoric FAPi target vector via a 4-aminobutoxy, a squaric acid and an ethylenediamine group.

Bone Metastases Bone metastases express farnesyl pyrophosphate synthase (FPPS), an enzyme in the HMG-CoA reductase (mevalonate) pathway. Inhibiting FPPS suppresses the production of farnesyl, an important molecule for signaling proteins to dock at 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 target vector pamidronate is regularly used in the treatment of bone metastases. Zoledronate (ZOL), a hydroxy-bisphosphonate with a heteroaromatic imidazole moiety, has proven to be a particularly effective tracer for theranostics of bone metastases. Zoledronate conjugated with the chelators NODAGA and DOTA (Scheme 6) are currently the most potent radiotheranostics for bone metastases. A variety of label precursors for diagnosis and theranostics of cancers with radioactive isotopes are known in the art. Thus, WO 2015055318 A1 discloses radiotracers for the diagnosis and theranostics of prostate or epithelial carcinomas, such as, inter alia, the marker precursor PSMA-617 shown in Scheme 3. Monomeric radiotracers with a target vector (TV) play a central role in nuclear medicine and rightly deserve the designation "precision oncology". More recently, dimeric label precursors with two targeting vectors have also been explored. Here will assume that a radiotracer with two target vectors has increased affinity. "Linear" homodimeric label precursors with two identical target vectors, each coupled to a central chelator, are known in the prior art and initial studies support this hypothesis (Zia, NA et al. Angw. Chem. Int. Ed.2019, 58, 14991 - 14994). In the present invention, homo- and heterodimeric marking precursors are provided for the first time, which comprise two identical or two different target vectors, which are conjugated to a marking group via a tris linker (TL). An amino acid residue, such as in particular a lysine or glutamic acid residue, serves as a tris linker (TL). The trislinkers (TL) according to the invention decouple the chelator and the target vectors from one another with regard to steric and electronically induced interactions. The Trislinker (TL) is coupled to the chelator in such a way that it does not impair complexation with clinically relevant radioisotopes. For this purpose, couplings can be used that have proven themselves for monomeric labeling precursors. The invention enables an independent (orthogonal) optimization of the radioisotope complexation, the affinity and the pharmacokinetics and pharmacodynamics of homo- and heterodimeric radiotracers. In contrast, the known linear, homodimeric marking precursors require complex molecular engineering that is often associated with functional impairments. FAP-addressing marker precursors and radiotracers according to the invention are also characterized by: 1. A high binding affinity to FAP with IC ₅₀ values in the nanomolar and sub-nanomolar range. 2. An exceptional binding specificity with respect to the competing proteases PREP and the DPPIV family such as above all DPP4 (type II integral protein with intracellular and extracellular forms), but also DPP8 and DPP9 (intracellular proteins) (Hamson et al., Proteomics Clin. Appl 2014, 8, 454-463). Here the binding affinities of the compounds according to the invention are in the micromolar range, as a result of which the ratio of the binding to the target FAP and the competing proteases usually assumes a value of >1000. The relationship can be illustrated using a selectivity index (SI) between the IC ₅₀ values (see Table 2). This significantly reduces the accumulation of the radioactively labeled compounds of the invention in tissues outside the tumor microenvironment (healthy tissue) and guarantees exceptionally high contrast in molecular imaging. 3. A high hydrophilicity (low logD value), which leads to a short residence time of the compounds according to the invention in the blood. This guarantees an extraordinarily high contrast in the molecular imaging between the tumors and the surrounding healthy tissue with blood supply. 4. A rapid accumulation and long residence time of the compounds of the invention in the tumor microenvironment. This ensures a high radiation dose, which can be deposited in the tumor or its surroundings even when used in endoradiotherapy with relatively long-lived radioisotopes such as lutetium-177 and actinium-225. 5. A short residence time of the compounds according to the invention in healthy tissue due to rapid elimination via the kidneys and bladder. In addition to an extraordinarily high contrast in the molecular imaging between the tumors and the surrounding healthy tissue with blood supply, this also guarantees low radiation exposure for the patients. In addition, the inventive concept can be easily applied to compounds with two different target vectors. Here, for example, a bone metastasis-addressing targeting vector (bisphosphonate) can be used together with a prostate cancer-addressing targeting vector (PSMA inhibitor). This has the advantage that prostate cancer patients with bone metastases can be better addressed than with radiopharmaceuticals that only have a PSMA target vector. The reason for this lies in the great heterogeneity of PSMA expression in the bone metastases of patients, so that these can sometimes only be addressed inadequately with PSMA inhibitor structures. Overexpression of PSMA occurs in only about 90% of patients suffering from prostate cancer. Accordingly, heterodimeric marker precursors with an FAP target vector and a PSMA target vector are also provided within the scope of the invention. Such heterodimeric label precursors target both PSMA-expressing tumor tissue and tumor-associated FAP-expressing stromal cells. Thus, prostate carcinomas and metastases that do not overexpress PSMA can also be detected and visualized using PET and SPECT. It is an object of the present invention to provide label precursors and radiotracers for improved diagnosis and theranostics of cancer diseases. In particular, label precursors and radiotracers with increased selectivity and specificity, effective radioisotope complexation and conjugation as well as rapid absorption and systemic excretion are to be created. This object is achieved by a marker precursor with the structure TV1-S1-TL-S2-TV2 | S3 | MG wherein TV1 is a first target vector, TV2 is a second target vector, MG is a chelator or linker for complexation or covalent attachment of a radioisotope, S1 is a first spacer, S2 is a second spacer, S3 is a third spacer, and TL is a tris-linker. Expedient embodiments of the marking 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: - TV1 and TV2 are independently selected from one of the structures [1] to [43] with wherein - structures [1] to [8] and [43] denote peptides; - X is H or F; - Y = H, CH ₃ , CH(CH ₃ ) ₂ , C(CH ₃ ) ₃ or (CH ₂ ) _n CH ₃ with n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 is; - TV1 is equal to TV2 (TV1 = TV2); - TV1 and TV2 are different from each other (TV1 ≠ TV2); - TV1 has the structure [13]; - TV1 has the structure [14]; - TV2 has the structure [13]; - TV2 has the structure [14]; - TV1 and TV2 each have the structure [13]; - TV1 and TV2 each have the structure [14]; - TV1 has one of the structures [9] to [12] and TV2 has one of the structures [13] or [14]; - TV1 has one of the structures [9] to [12] and TV2 has one of the structures [40] or [41]; - TV2 has one of the structures [9] to [12] and TV1 has one of the structures [13] or [14]; - TV2 has one of the structures [9] to [12] and TV1 has one of the structures [40] or [41]; - S1, S2 and S3 independently of one another have a structure selected from ; and wherein A, B, C are independently selected from the group comprising amide, carboxamide, phosphinate, alkyl, triazole, thiourea, ethylene, maleimide, amino acid residues, , , and with s = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p, q and r are independently selected from the set {0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20}; - S1, S2, S3 independently of one another have the structure; - S1, S2, S3 is independently a peptide group with the structure - S1, S2, S3 is independently a dipeptide group having the structure - S1, S2, S3 is independently a tripeptide group having the structure ‒ the side chains R ¹ , R ² , R ³ peptidic spacers S1, S2, S3 are independently selected from the group consisting of ‒H , ‒CH ₃ , ‒CH(CH ₃ ) ₂ , ‒CH ₂ CH(CH ₃ ) ₂ , ‒CH(CH ₃ )‒CH ₂ CH ₃ , ‒CH ₂ ‒Phe , ‒CH ₂ ‒Phe‒OH , ‒CH ₂ SH , ‒(CH ₂ ) ₂ ‒S‒CH ₃ , ‒CH ₂ OH , ‒ (CH)(OH)(CH3) , -( _CH2 ₎ _4NH2 , -( _CH2 ₎ _3NH (C=NH)NH2, _-CH2COOH , -( _CH2 ₎ _2COOH , -CH ₂ (C=O)NH ₂ , ‒(CH ₂ ) ₂ (C=O)NH ₂ , - MG is a chelator for the complexation of a radioisotope from the group consisting of 4 ³ 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, 1 ³⁵ Nm, 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 Th; - MG is a chelator selected from the group comprising H ₄ pypa, 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- tetraazacyclododecane-4,7,10)-pentanedioic acid) and other DOTA derivatives, TRITA (trideca-1,4,7,10-tetraamine-tetraacetate), TETA (tetradeca-1,4,8,11- tetraamine-tetra-acetate) and its derivatives, PEPA (pentadeca-1,4,7,10,13-pentaaminepentaacetate), HEHA (hexadeca-1,4,7,10,13,16-hexaamine-hexaacetate) and its derivatives , HBED (N,N'-bis-(2-hydroxybenzyl)ethylene-diamine-N,N'-diacetate) and its derivatives such as HBED-CC (N,N'-bis-[2-hydroxy-5-carboxyet hyl)benzyl)ethylene-diamine-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 such as H ₃ THP -Ac and H ₃ THP-mal (YM103), TEAP (tetraacyclodecanephosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepane-N,N,N',N'- tetraacetate) and derivatives thereof, such as AAZTA ⁵ (5-[(6-amino)-1,4-diazepan]pentanoic acid-N,N,N',N'-tetraacetate) DATA ^5m (5-[[6-(N-methyl )amino]-1,4-diacetate-1,4-diazepan]pentanoic acid N,N',N'-triacetate); Sarcophagin SAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) and their derivatives such as (NH ₂ ) ₂ SAR (1,8-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 N ₄ -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 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 chelators and their derivatives, aminothiols and their derivatives; salts of the above chelators; hydrazine nicotinamides (HYNIC) and hydrazine nicotinamide derivatives; - the labeling group MG has a structure selected from the group comprising the structures [44], [45], [46] and [47] with H - the labeling group MG has a structure selected from the group comprising structures [48], [49], [50] and [51] having - MG is DOTA (dodeca-1,4,7,10-tetraamine-tetraacetate); - MG is equal to DATA ^5m (1,4-bis(carboxymethyl)-6-[methyl-carboxymethyl-amino]-6-pentanoic acid-1,4-diazepane); - MG is AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)amino]-6-pentanoic acid-1,4-diazepane); - MG is a linker for the covalent attachment of ¹⁸ F, ¹³¹ I or ²¹¹ At;

– MG a linker of the type with a dismounting group ¹⁸ e X is for substitution with F, 1 ³¹ I or ²¹¹ At; - MG contains a leaving group X selected from a residue of bromo (Br), chloro (Cl) or iodo (I), tosyl (Ts), brosylate (Bs), nosylate (Nos), 2-(N-morpholino )ethanesulfonic acid (MES), triflate (Tf) and nonaflate (Non); - the Trislinker TL is chosen from one of the structures [52] to [64], with

- the Trislinker TL is chosen from one of the structures [65] to [116], with

The following designations are used for synthetic amino acids in the peptides and structural formulas [1] to [8]: Aph(Hor)=4-[2,6-dioxo-hexahydro-pyrimidine-4-carbonylamino]-L-phenylalanine Cpa= 4-Chloro-phenylalanine D-Aph(Cbm) = D-4-amino-carbamoyl-phenylalanine Pal = 2-, 3- or 4-pyridylalanine A labeling group MG for the covalent binding of the radioisotopes ¹⁸ F, ¹³¹ I or ²¹¹ At comprises in particular a leaving group X selected from a residue of bromine (Br), chlorine (Cl), iodine (I), tosyl (-SO ₂ -C ₆ H ₄ -CH ₃ ; abbreviated "Ts"), brosylate (- SO ₂ -C ₆ H ₄ -Br; abbreviated "Bs"), nosylate or nitrobenzenesulfonate (-OSO ₂ -C ₆ H ₄ -NO ₂ ; abbreviated "Nos"), 2-(N-morpholino)ethanesulfonic acid ( -SO ₃ -(CH ₂ ) ₂ -N(CH ₂ ) ₄ O; abbreviated "MES"), triflate or trifluoromethanesulfonyl (-SO ₂ CF ₃ ; abbreviated "Tf") or nonaflate (-OSO ₂ -C ₄ F ₉ ; abbreviated "Non"). The inventors have surprisingly found that the dimeric label precursors described above or the radiotracers derived from them with two target vectors TV1 and TV2 compared to monomeric radiotracers with a target vector at the same systemic dose and non-specific accumulation (off-target exposure) have a significantly higher accumulation in tumor tissue (target exposure). It is believed that this advantageous property is due to an increased probability of docking and/or selectivity. The target vectors TV1 and TV2 used according to the invention have a high binding affinity to membrane-bound tumor markers, such as in particular PSMA (prostate-specific membrane antigen), FAP (fibroblast activation protein) and FPPS (farnesyl pyrophosphate synthase). Various tumor tissues and metastases can be addressed with the heterodimeric label precursors and radiotracers of the invention. This is advantageous for the treatment of bone metastases induced by prostate carcinoma. For this purpose, marker precursors or radiotracers with a first target vector TV1 for PSMA (PSMA target vector) and a second osteotropic target vector TV2 for FPPS (FPPS target vector) are particularly suitable. Likewise, the label precursors and radiotracers of the present invention are useful for targeting the tumor stroma. For example, triple negative breast cancer (TNBC) lacks specific receptors on the surface of cancerous cells that allow for direct targeting. Here an "indirect" addressing of the tumor stroma comes into consideration. In TNBC, the tumor stroma comprises cancer-associated fibroblasts (CAFs) and altered endothelial cells (ECs) that overexpress FAP and PSMA, respectively. Accordingly, both homodimeric precursors with PSMAi, FAPi or bisphosphonate vectors and heterodimeric marker precursors with a first PSMA target vector and a second FAP target vector are suitable for the diagnosis and treatment of TNBC. The same applies to prostate carcinomas that are PSMA-negative, ie do not over-express PSMA, which applies to about 10% of prostate cancer cases. However, PSMA-negative tumors and metastases can be diagnosed and treated by targeting the tumor stroma using FAP targeting vectors. Accordingly, a heterodimeric tag precursor with a first PSMA target vector and a second FAP target vector is useful for the comprehensive diagnosis and treatment of PSMA-positive as well as PSMA-negative prostate cancers. Theranostic targeting of the tumor stroma with radioisotopes such as ¹⁷⁷ Lu and ²²⁵ Ac directly damages the tumor microenvironment essential for progression and induces "indirect" radiation damage (radiation induced bystander effect, RIBE) in neighboring cancer cells. Spacers S1, S2, and S3 act as steric spacers and pharmacokinetic modulators that optimize the biochemical function of the target 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). The spacers S1, S2, S3 preferably contain structural elements such as B. squaric acid amides or other aromatic moieties which improve the affinity for PSMA. The Trislinker TL creates the prerequisite for the orthogonal, sterically and pharmacokinetically optimized coupling of the marker group MG and the two target vectors TV1 and TV2 in analogy to established monomeric radiopharmaceuticals with only one target vector. Thus, the invention enables the synthesis of effective label precursors and radiotracers with high theranostic potency. The invention includes radiotracers consisting of one of the labeling precursors described above and a radioisotope complexed with the labeling precursor selected from the group consisting of 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, 9 ^9m 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 Th; or ‒ radioisotope covalently bonded to the label precursor selected from the group consisting of ¹⁸ F, ¹³¹ I and ²¹¹ At. In an expedient embodiment of the invention, the radiotracer consists of one of the labeling precursors described above with - a labeling group MG selected from the group comprising NOTA (nona-1,4,7-triamine triacetate), DATA ^5m (5-[[ 6-(N-methyl)amino]-1,4-diacetate-1,4-diazepan]pentanoic acid-N,N',N'-triacetate) and NODAGA (1,4,7-triazacyclononane,1-glutaric acid, 4,7-acetate); and - the radioactive compound aluminum[ ¹⁸ F]fluoride (or [ ¹⁸ F]AlF) complexed with the label precursor. In the case of a labeling group MG configured as a chelator, the chelator is used 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, 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 Th. Accordingly, the invention encompasses radiotracers obtainable from the label precursors described above by complexation with a radioisotope are, wherein the radioisotope is selected from the group consisting of 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 Nm, 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 Th. Chelators A variety of chelators f Known for the complexation of radioisotopes. Scheme 7 shows examples of chelators used according to the invention.

Amide coupling In the invention, functional groups such as the chelator Chel, the target vectors TV1 and TV2, the spacers S1, S2, S3, and the trislinker TL are preferably conjugated by means of an amide coupling reaction. Amide coupling, the backbone of proteins, is the most commonly used reaction in medicinal chemistry. A generic example of an amide coupling is shown in Scheme 8. Due to a virtually unlimited set of readily available carboxylic acid and amine derivatives, amide-coupling strategies provide a facile route to the synthesis of new compounds. Numerous reagents and protocols for amide couplings are known to those skilled in the art. The most common amide coupling strategy relies on the condensation of a carboxylic acid with an amine. The carboxylic acid is usually activated for this purpose. Remaining functional groups are protected prior to activation. The reaction takes place in two steps either in a reaction medium (single pot) with direct reaction of the activated carboxylic acid or in two steps with isolation of an activated “trapped” carboxylic acid and reaction with an amine. Here, the carboxylic acid reacts with a coupling agent to form a reactive intermediate that can be isolated or reacted directly with an amine. Numerous reagents are available for carboxylic acid activation, such as acid halides (chloride, fluoride), azides, anhydrides, or carbodiimides. In addition, esters such as pentafluorophenyl or hydroxysuccinimido esters can be formed as reactive intermediates. Intermediates derived from acyl chlorides or azides are highly reactive. However, harsh reaction conditions and high reactivity often prevent their use for sensitive substrates or amino acids. In contrast, amide coupling strategies that use carbodiimides such as DCC (dicyclohexylcarbodiimide) or DIC (diisopropylcarbodiimide) open up a wide range of applications. Often, especially in solid phase synthesis, additives are used to improve reaction efficiency. Aminium salts are highly efficient peptide coupling reagents with short reaction times and minimal racemization. With some additives, such as HOBt, racemization can even be completely avoided. Aminium reagents are used in equimolar amounts to the carboxylic acid to prevent excessive reaction with the free amine of the peptide. Phosphonium salts react with carboxylate, typically requiring two equivalents of a base such as DIEA. A key advantage of phosphonium salts over iminium reagents is that phosphonium does not react with the free amino group of the amine component. This enables couplings in equimolar ratios of acid and amine and helps to avoid intramolecular cyclization of linear peptides and excessive use of expensive amine components. A comprehensive compilation of reaction strategies and reagents for amide coupling can be found in the reviews: – Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?; DG Brown, J. Bostrom; J. Med. Chem. 2016, 59, 4443−4458; - Peptide Coupling Reagents, More Than a Letter Soup; A. El-Faham, F. Albericio; Chem. Rev. 2011, 111, 6557-6602; – Rethinking amide bond synthesis; VR Pattabiraman, JW Bode; Nature, Vol. 480 (2011) 22/29; - Amide bond formation: beyond the myth of coupling reagents; E Valeur, M Bradley; Chem. Soc. Rev., 2009, 38, 606-631. Numerous of the chelators used according to the invention, such as. B. DOTA and derivatives thereof, have one or more carboxy or amine groups. Accordingly, these chelators can be readily conjugated to spacer S3 using any of the amide coupling strategies known in the art. Some terms are used within the scope of the present invention, the meaning of which is explained below. Theranostics: Diagnostics and therapy of cancer diseases using nuclear medical radiotracers with analog targeting vectors. Precursor Label: A chemical compound containing a first and second targeting vector and a chelator or radioisotope labeling functional group. Radiotracer: A radioisotope-labeled tracer precursor for nuclear medicine diagnostics or theranostics that is used at low concentrations without affecting a patient's metabolism. Target: Biological target structure, in particular (membrane-bound) receptor, protein, enzyme or antibody in the living organism, to which a target vector binds. Target Vector: A chemical group or moiety that acts as a ligand, agonist, antagonist, or inhibitor for a biological target (eg, a protein, enzyme, or receptor) and has high binding affinity for that target. Trislinker: Structural unit with three functional groups for conjugation with a first, second and third spacer for a first and second target vector and a labeling group. Spacer: A structural unit, group or residue that links a first and second target vector and a labeling group to a tris-linker and functions as a steric and/or pharmacokinetic modulator. EXAMPLES The compound (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide is hereinafter referred to as FAPi _-NH2 abbreviated: Scheme 9: Structure of FAPi-NH ₂ = (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4 -carboxamide. Materials and Methods: Nuclear magnetic resonance spectroscopy (NMR): NMR spectra were recorded in deuterated solvents on an Avance II 400 (400 MHz) spectrometer with a 5 mm BBFO probe (z-gradient) from Bruker (Rheinstätten, Germany). The chemical shifts δ (in ppm) refer to the proton signal of the deuterated solvent relative to the tetramethylsilane standard (= 0.00 ppm). The calculated coupling constants were given in Hertz (Hz). Spin multiplicity has been abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet or combinations thereof. The software MestReNova 14.2.0 from Mestrelab Research (Santiago de Compostela, Spain) was used to analyze the spectra. ESI-LC/MS: ESI-LC/MS mass spectra were acquired using the Agilent Technologies 1220 Infinity LC coupled to an Agilent Technologies 6130B Single Quadruple LC/MS system with an Agilent Zorbax SB-C18 column (21x50 mm, 1.8 µm ) with linear gradients of acetonitrile (ACN) / Milli-Q ^® water (H ₂ O) + 0.05% formic acid (HFo) and a flow rate of 0.5 mL/min. ESI-HPLC/MS: HPLC-MS measurements were performed using an Agilent Technologies G6545A Q-ToF with electrospray ionization coupled to a 1260 Infinity II HPLC system (Agilent Technologies) with G7111B 1260 Quaternary Pump, G7129A 1260 Vialsampler and G7116A Multicolumn Thermostat. The separation was performed with an Agilent Poroshell 120 EC-C8 column (2.1x100 mm, 2.7 µm) with H ₂ O + 2% ACN / ACN + 2% H ₂ O + 0.05% HFo and a flow rate of 0.1 mL/min . RP-HPLC: Semipreparative reversed-phase high-pressure liquid chromatography (RP-HPLC) was performed with LaChrom-HPLC (7000 series) from Merck Hitachi with L-7100 pump, L-7400 UV detector (λ = 254 nm), a D-7000 interface and autosampler. The separation was performed using a Phenomenex Synergi Max-RP C18 column (250x10 mm, 4 µm) and a linear gradient of ACN/H ₂ O + 0.1% trifluoroacetic acid (TFA) and a flow rate of 5 mL/min. Radio DC: Radio DCs were evaluated using a CR-35 Bio Test imager and Raytest's AIDA software. Radio-HPLC: Analytical radio-HPLC was performed with an identical Merck Hitachi LaChrom-HPLC (7000 series). The separation was carried out using a Phenomenex Luna C18 column (250x4.6 mm, 5 µm) and a linear gradient of ACN/H ₂ O + 0.1% TFA and a flow rate of 1 mL/min. The radio-HPLC is additionally equipped with an analogue radio detector Ramona from Elysia Raytest, whose energy window is set to 100-1200 keV for ⁶⁸ Ga measurements and to 100-250 keV for ¹⁷⁷ Lu measurements. Stability measurements: The stability of each labeled compound in human serum (HS) and phosphate-buffered saline (PBS) was investigated (n=3 each) by placing about 10 MBq of the labeling solution in 0.5 mL HS or PBS for about 2 half-lives ( ⁶⁸ Ga: 2 h, ¹⁷⁷ Lu: 14 d) were incubated at 37 °C. Determination of the logD value (lipophilicity measurement): The logD value of the respective labeled compound was determined by diluting the labeling solution 4 times, each with approx. 10 MBq, to 700 µL with PBS. 700 µL of 1-octanol were added and shaken vigorously for 2 min and then centrifuged for 1 min. The organic and aqueous phases were separated and 400 µL each was isolated. Samples of 3 µL (PBS) and 6 µL (1-octanol) were spotted onto a TLC plate. Most of the activity was in the aqueous phase. This was then diluted to 700 µL and extracted twice more with 1-octanol and spotted again. The TLC was exposed for about 5 min and the integral of each spot (octanol phase: _IO , aqueous PBS phase: I _W ) was determined. When calculating the logD value using Equation (1), the different volumes V _O = 6 µL and V _W = 3 µL were taken into account: For the evaluation, the values of the 2nd and 3rd extraction of the 4 batches were averaged. In vitro assays: The enzymes rhFAP (fibroblast activation protein), PREP (prolyl endopeptidase), DPP4 (dipeptidyl peptidase IV), DPP8 (dipeptidyl peptidase VIII) and DPP 9 (dipeptidyl peptidase IX) were expressed prior to use in the in vitro assays and then cleaned up. The IC ₅₀ measurements were carried out using the Infinite 200 device (Tecan Group Ltd.) and evaluated using the Magellan software. The data were evaluated using GraFit 7 using a non-linear fit according to the following equation, where y is the remaining enzyme activity compared to the uninhibited sample, x is the final inhibitor concentration used in the assay, s is the slope factor and IC ₅₀ is the mean inhibitory concentration. Example 1: FAPi-NH ₂ Scheme 10 shows the synthesis of FAPi-NH ₂ . 4-Bromobutylamine 4-aminobutanol (5.39 g, 60.47 mmol, 1.00 eq) was slowly treated with 70 mL of 47% hydrobromic acid and then heated under reflux for 4 h. The reaction mixture was then fully concentrated under reduced pressure. A colorless solid was obtained (13.521 g, 58.04 mmol, 96%). This was used directly in the next synthesis step without further purification. MS (ESI positive): m/z (%) = 152.0 (100, [M+H] ⁺ ), 154.0 (98, [M+H] ⁺ ), calcd for C ₄ H ₁₀ BrN: 151.00 [M] . 1H NMR (400 MHz, MeOD): δ [ppm] = 3.51 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.00 - 1.78 (m, 4H). tert-butyl-(4-bromobutyl)carbamate 4-bromobutylamine (7.01 g, 30.09 mmol, 1.0 eq.) together with di-tert-butyldicarbonate (Boc ₂ O, 7.34 g, 33.63 mmol, 1.12 eq.) under argon in dry THF (34 mL). Then TEA (4.6 mL, 36.12 mmol, 1.2 eq.) was added. MeOH (36 mL) was added to the resulting suspension until the solution became clear again and the mixture was then stirred at RT for 19 h. Then the solvent was removed in vacuo and diluted HBr was added to the residue such that pH = 2.5 was reached. The aqueous solution was extracted with Et ₂ O (5×80 mL) and the combined organic phases were each washed once with a little NaHCO 3 and brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. A colorless solid (5.08 g, 20.15 mmol, 66%) was obtained by means of column chromatography (CH/EA 5:1). MS (ESI positive): m/z (%) = 196.0 (100, [M-tBu] ⁺ ), 198.0 (100, [M-tBu] ⁺ ), calcd for C ₉ H ₁₈ BrNO ₂ : 251.05 [M ]. ¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 3.36 - 3.21 (m, 4H), 1.86 - 1.76 (m, 4H), 1.43 (s, 9H). Boc-Gly-Pro-CONH ₂ (tert-Butyl-(S)-(2-(2-carbamoyl-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate) Boc-Gly-OH (1.38 g , 7.88 mmol, 1.05 eq.) and HBTU (3.12 g, 8.20 mmol, 1.1 eq.) were dissolved in dry DCM (8 mL) and DMF (8 mL) under argon. Then DIPEA (1.53 mL, 8.97 mmol, 1.2 eq.) was added and the mixture was stirred at RT for 1 h. In another reaction vessel, 4,4-difluoro-L-prolinamide hydrochloride was dissolved in dry DCM (5 mL) and DMF (5 mL), and DIPEA (2.54 mL, 14.90 mmol, 2.0 eq.) was also added. The solutions were combined and stirred at RT for 19 h. The precipitate formed was filtered and the mother liquor was refrigerated overnight to complete the precipitation. The two precipitates were combined. A colorless solid (1.97 g, 6.41 mmol, 86%) was obtained. MS (ESI positive): m/z (%) = 207.8 (62, [M-Boc+H] ⁺ ), 251.8 (100, [M- ^t Bu+H] ⁺ ), 307.9 (39, [M+ H] ⁺ ), _329.9 (24, [M+Na] ⁺ ), _calcd for C12 H19 _F2 N3 _O4 : _307.13 [M] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.40 (s, 1H), 7.16 (s, 1H), 6.87 (dt, J = 10.4, 5.8 Hz, 1H), 4.45 (dd , J = 9.0 Hz, 1H), 4.15–3.85 (m, 2H), 3.86–3.63 (m, 2H), 2.81–2.27 (m, 2H), 1.37 (s, 9H). Boc-Gly-Pro-CN (tert-Butyl-(S)-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate) Boc-Gly-Pro-CONH ₂ ( 1.97 g, 6.41 mmol, 1.0 eq.) was dissolved in dry THF (50 mL) under argon and cooled to 0°C. Pyridine (4.1 mL, 51.3 mmol, 8.0 eq.) was added. In another reaction vessel, TFAA (2.7 mL, 19.2 mmol, 3.0 eq.) was dissolved in dry DCM (35 mL) under argon and slowly added dropwise to the reaction solution with stirring. It was stirred at RT for 3 h. Thereafter, 1 M HCl (80 mL) was added and the aqueous solution was washed with DCM (5 x 80 mL). The combined organic phases were each washed once with a little Na ₂ CO ₃ and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the product was purified via column chromatography (CH/EA=3:2). A colorless solid (1.49 g, 4.81 mmol, 81%) was obtained. MS (ESI positive): m/z (%) = 190.0 (31, [M-Boc+H] ⁺ ), 233.9 (100, [M- ^t Bu+H] ⁺ ), calcd for C12H17F2N ₂ O3: 289.12 [M] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 5.34 (s, 1H), 4.97 (t, J = 6.5 Hz, 1H), 4.04 - 3.78 (m, 4H), 2.81 - 2.69 (m, 2H), 1.45 (s, 9H). Gly-Pro-CN ((S)-4,4-Difluoro-glycylpyrrolidine-2-carbonitrile) Boc-Gly-Pro-CN (1.15 g, 3.97 mmol, 1.0 eq.) was dissolved in dry MeCN (2 mL) under argon dissolved and TFA (2 mL) was slowly added dropwise. After stirring at RT for 5 h, the solvent was removed under reduced pressure and co-distilled with MeOH (5 x 25 mL). A yellowish oil was obtained, which was used in the next stage without further purification. MS (ESI positive): m/z (%) = 189.9 (100, [M+H] ⁺ ), 231.0 (20, [M+ACN+H] ⁺ ), calculated for CH C ₇ H ₉ F ₂ N _3O : 189.07 [M] ⁺ . ¹ H NMR (400 MHz, MeOD): δ [ppm] = 8.25 (s, 2H), 5.22 - 5.15 (m, 1H), 4.15 - 3.91 (m, 4H), 3.00 - 2.81 (m, 2H). 6-Hydroxyquinoline-4-carboxylic acid hydrobromide 6-Methoxyquinoline-4-carboxylic acid (2.46 g, 12.1 mmol, 1.0 eq.) was dissolved in 47% HBr (28.18 mL, 242.42 mmol, 20 eq.) and heated under reflux for 1 d . After cooling to RT, the hydrobromic acid was partially removed in vacuo and the precipitate was then filtered and washed first with cold EA (20 mL) and then with a little cold EA/MeOH (90:10). A yellow solid (3.25 g, 12.1 mmol, 100%) was obtained. MS (ESI positive): m/z (%) = 190.0 (100, [M+H] ⁺ ), 191.0 (12, [M+H] ⁺ ), calcd for C ₁₀ H ₈ BrNO ₃ : 189.04 [M ]. ¹ H NMR (400 MHz, MeOD): δ [ppm] = 9.04 (d, J = 5.6 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H ), 8.19 (d, J = 9.3 Hz, 1H), 7.77 (dd, J = 9.3, 2.6 Hz, 1H). Methyl 6-hydroxyquinoline-4-carboxylate First, dry MeOH (20 mL) was cooled to 0°C under argon and then SOCl2 (4.43 mL, 61.09 mmol, 5.0 eq.) was added dropwise. 6-Hydroxyquinoline-4-carboxylic acid hydrobromide was dissolved in dry MeOH (20 mL) and cooled to 0°C also under argon. Thereafter, the SOCl ₂ -MeOH solution was added dropwise. the Reaction solution was warmed to RT and heated under reflux for 1 d. SOCl ₂ (2.91 g, 24.44 mmol, 2 eq.) and MeOH (20 mL) were again combined at 0° C. and added to the reaction mixture at RT. The solution was refluxed for a further 24 h. The above step was repeated one more time and after refluxing for a further 4 h, the solvent was removed under reduced pressure. A yellow solid was obtained, which was used in the next step without further purification. MS (ESI positive): m/z (%) = 204.0 (100, [M+H] ⁺ ), 205.1 (12, [M+H] ⁺ ), calcd for C ₁₁ H ₉ NO ₃ : 203.06 [M ]. ¹ H NMR (400 MHz, MeOD): δ [ppm] = 9.02 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.6 Hz, 1H ), 8.17 (d, J = 9.3 Hz, 1H), 7.75 (dd, J = 9.3, 2.6 Hz, 1H), 4.09 (s, 3H). Boc-Chino-COOMe (6-(4-((tert-Butoxycarbonyl)amino)butoxy)quinoline-4-carboxylic acid methyl ester) Under argon, 6-hydroxyquinoline-4-carboxylic acid methyl ester (2.48 g, 12.1 mmol, 1.0 eq.) and Cs2CO3 (4.37 g, 13.4 mmol, 1.25 eq.) suspended in dry DMF (55 mL). The reaction solution was heated to 70°C. Then tert-butyl-(4-bromobutyl)carbamate (3.76 g, 14.91 mmol, 1.22 eq.) was dissolved in dry DMF (80 mL) and added dropwise to the hot reaction mixture. The solution was stirred at 70°C for 3 h. After checking the reaction, tert-butyl-(4-bromobutyl)carbamate (1.23 g, 4.88 mmol, 0.4 eq.) was again dissolved in dry DMF (20 mL) and added to the reaction mixture. It was stirred at 70°C overnight. After a further addition (308 mg, 1.22 mmol, 0.1 eq.) and 3 h at 70° C., the solvent was removed in vacuo and the residue was taken up in dilute HBr (150 mL, pH=2.6). It was extracted with EA (5×80 mL), the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was obtained via column chromatography (CHCl ₃ /MeOH, 100:1) as a pale yellow solid (2.68 g, 7.17 mmol, 59%). MS (ESI positive): m/z (%) = 375.2 (100, [M+H] ⁺ ), 376.2 (23, [M+H] ⁺ ), calcd for C ₂₀ H ₂₆ N ₂ O ₅ : 374.18 [M]. ¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.84 (d, J = 4.6 Hz, 1H), 8.24 (dd, J = 16.7, 2.8 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 4.6 Hz, 1H), 7.43 (dd, J = 9.2, 2.8 Hz, 1H), 4.74 - 4.60 (m, 1H), 4.15 (t, J = 6.21 Hz, 2H ), 4.03 (s, 3H), 3.27 - 3.16 (m, 2H), 1.95 - 1.86 (m, 2H), 1.78 - 1.67 (m, 2H), 1.42 (s, 9H). Boc-Quino-COOH (6-(4-((tert-Butoxycarbonyl)amino)butoxy)quinoline-4-carboxylic acid) Boc-Quino-COOMe (3.34 g, 8.92 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (40 mL) dissolved. 1 M LiOH (17.8 mL, 17.84 mmol, 2.0 eq.) was then added and the mixture was stirred at RT for 4 h. The organic LM was removed in vacuo and then washed with 1M HCl adjusted to pH = 3.5. The aqueous solution was extracted with EA (8×80 mL) and the combined organic phases dried over Na ₂ SO ₄ and the solvent removed under reduced pressure. A pale yellow solid (1.82 g, 5.05 mmol, 57%) was obtained. MS (ESI positive): m/z (%) = 261.1 (20, [M-Boc+H] ⁺ ), 361.2 (100, [M+H] ⁺ ), 362.2 (22, [M+H] ⁺ ), calculated for C ₁₉ H ₂₄ N ₂ O ₅ : 360.17 [M]. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.86 (d, J = 4.5 Hz, 1H), 8.15 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 9.3 Hz, 1H), 7.92 (d, J = 4.4 Hz, 1H), 7.49 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.87 (t, J = 5.8 Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 3.00 (q, J = 6.6 Hz, 2H), 1.78 (q, J = 11.8, 6.5 Hz, 2H), 1.62 - 1.51 (m, 2H), 1.37 (s, 9H). FAPi-NHBoc (tert-butyl-(S)-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl )oxy)butyl)carbamate) Boc-quino-COOH (1.64 g, 4.55 mmol, 1.0 eq.) and DIPEA (0.93 mL, 5.46 mmol, 1.2 eq.) were dissolved in dry DMF (16 mL) under argon. Then HOBt (0.68 g, 5.01 mmol, 1.1 eq.) and HBTU (1.90 g, 5.01 mmol, 1.1 eq.) were added and the reaction mixture was stirred at RT for 1 h. Gly-Pro-CN, also dissolved in dry DMF (10 mL) and treated with DIPEA (1.93 mL, 11.38 mmol, 2.5 eq.), was then added and the entire reaction mixture was stirred at RT for a further 1 d. Thereafter, the solvent was removed in vacuo and the residue taken up in EA. The organic phase was washed with 1M citric acid, saturated Na ₂ CO ₃ and brine. The aqueous phase was then extracted with EA (3×100 mL) and the combined organic extracts were dried over Na2SO4. The solvent was removed under reduced pressure and the product was obtained via column chromatography (CHCl ₃ /MeOH, 100:3) as a colorless solid (1.74 g, 3.27 mmol, 72%). MS (ESI positive): m/z (%) = 432.0 (33, [M-Boc+H] ⁺ ), 476.1 (46, [M- ^t Bu+H] ⁺ ), 532.4 (100, [M+ H] ⁺ ), calculated for C ₂₆ H ₃₁ F ₂ N ₅ O ₅ : 531.23 [M] ⁺ . ¹ H NMR (400 MHz, MeOD): δ [ppm] = 8.74 (d, J = 4.4 Hz, 1H), 7.96 (d, J = 9.3 Hz, 1H), 7.93 - 7.88 (m, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.46 (dd, J = 9.3, 2.7 Hz, 1H), 5.15 (dd, J = 9.4, 3.1 Hz, 1H), 4.39 – 3.98 (m, 8H), 3.19 – 3.09 (m, 2H), 3.02 - 2.70 (m, 2H), 1.94 - 1.83 (m, 2H), 1.76 - 1.65 (m, 2H), 1.43 (s, 9H). FAPi-NH ₂ ((S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) FAPi- NHBoc (531.6 mg, 1.0 mmol, 1.0 eq) was dissolved in dry acetonitrile (10 mL) at 0 °C and under argon. 4 M HCl in 1,4-dioxane (5.0 mL, 5.0 mmol, 5.0 eq) and slowly warmed to RT. After 3 h, another 4 M HCl in 1,4-dioxane (2.5 mL, 2.5 mmol, 2.5 eq) was added and, after a further 4 h at RT, the mixture was diluted with more acetonitrile (30 mL). and then fully concentrated in vacuo. A colorless solid (467 mg, 1.0 mmol, 100%) was obtained. MS (ESI positive): m/z (%) = 216.7 (100, [M+H] ²⁺ ), 237.2 (27, [M+ACN+H] ²⁺ ), 432.1 (22, [M+H ] ⁺ ), calculated for C ₂₁ H ₂₃ O ₅ F ₂ N ₅ O ₃ : 431.18 [M] ⁺ . 1H NMR (400 MHz, MeOD): δ [ppm] = 9.10 (d, J = 5.5 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 9.3 Hz, 1H) , 8.08 (d, J = 5.5 Hz, 1H), 7.86 (dd, J = 9.4, 2.6 Hz, 1H), 5.15 (dd, J = 9.4, 3.1 Hz, 1H), 4.48 – 4.33 (m, 4H), 4.32 - 4.07 (m, 2H), 3.06 (t, J = 6.5 Hz, 2H), 3.02 - 2.74 (m, 2H), 2.09 - 1.87 (m, 4H). Example 2: DOTA.Glu.(FAPi) ₂ , DOTAGA.Glu.(FAPi) ₂ , DATA ^5m .Glu.(FAPi) ₂ The following is the synthesis of the tag precursors DOTA.Glu.(FAPi) ₂ , DOTAGA.Glu. (FAPi) ₂ and DATA ^5m .Glu.(FAPi) ₂ described. The initial synthetic steps are identical for all 3 compounds and a representative synthesis is shown in Scheme 11. Boc-Glu.(FAPi) ₂ (tert-butyl-((S)-1,5-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine- 1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)carbamate) tert-butoxycarbonyl-L-glutamic acid (Boc-Glu-OH, 40 mg, 162 µmol, 1.0 eq), 1- hydroxybenzotrazole (HOBt, 55 mg, 405 µmol, 2.5 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC*HCl, 78 mg, 405 µmol, 2.5 eq) were dissolved in dry N,N-dimethylformamide (DMF, 4 mL) and treated with N,N-diisopropylethylamine (DIPEA, 68.9 µL, 405 µmol, 2.5 eq) and heated under an argon atmosphere for 90 min at room temperature (RT ) touched. Then a solution of FAPi-NH ₂ *TFA (265 mg, 486 μmol, 3 eq) and DIPEA (110 μL, 648 μmol, 4 eq) in DMF (4 mL) was added and stirring was continued at RT overnight. More HOBt (16 mg, 121 µmol, 0.75 eq) and EDC*HCl (23 mg, 121 µmol, 0.75 eq) were added and after a further 60 min a solution of FAPi-NH ₂ *TFA (88 mg, 162 µmol , 1.0 eq) and DIPEA (41.4 µL, 243 µmol, 1.5 eq) in DMF (2 mL). After further stirring at RT overnight, the solvent was removed in vacuo. After column chromatography (CHCl ₃ /MeOH (100:10-15)), 127 mg (118 μmol, 73%) of Boc-Glu.(FAPi) ₂ were obtained as a yellow oil. LC-MS (ESI positive): m/z (%) = 487.8 (100, [M−Boc+H] ²⁺ ), 537.8 (73, [M+H] ²⁺ ), 1074.4 (9, [M +H] ⁺ ), _1075.4 (6, [M+H] ⁺ ), _calcd for C52 H59 F4 _N11 _O10 : _1073.44 [M] ⁺ . Glu.(FAPi) ₂ ((S)-2-amino-N ¹ ,N ⁵ -bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)pentanediamide) To Boc-Glu.(FAPi) ₂ (127 mg, 118 µmol) was added 50 µL Milli-Q ^® water, 50 µL triisopropylsilane ( TIPS) and 1.9 mL TFA (TFA:TIPS:H ₂ O (95:2.5:2.5)) and stirred at RT for 1 h. Then 5x about 10 mL MeOH were added and the solvents were removed again in vacuo and a yellow oil was obtained. It was used in the next step without further purification. LC-MS (ESI positive): m/z (%) = 325.6 (100, [M−Boc+H] ³⁺ ), 487.8 (28, [M+H] ²⁺ ), 974.3 (5, [M +H] ⁺ ), calcd for C ₄₇ H ₅₁ F ₄ N ₁₁ O ₈ : 973.39 [M] ⁺ . The synthesis of the tag precursor DOTA.Glu.(FAPi) ₂ is shown in Scheme 12 below. DOTA(tBu) ₃ -NHS (2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10 - tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTA-tris(tert-butyl ester) (129 mg, 224 µmol, 1.0 eq) and 2-(1H-benzotriazol-1-yl)-1, 1,3,3-Tetramethyluronium hexafluorophosphate (HBTU, 87 mg, 229 µmol, 1.0 eq) was dissolved in dry ACN (5 mL). The mixture was stirred at RT under an argon atmosphere for 75 min and then N-hydroxysuccinimide (NHS, 31 mg, 267 μmol, 1.2 eq) was added. After further stirring overnight, HBTU (52.2 mg, 138 μmol, 0.6 eq) and one hour later NHS (22 mg, 191 μmol, 0.85 eq) were added again and the mixture was stirred for another day. After this all solvents were removed in vacuo, 145 mg (217 µmol, 97%) of DOTA(tBu) ₃ -NHS were obtained as a colorless solid after column chromatography (DCM:MeOH (100:15)). LC-MS (ESI positive): m/z (%) = 335.7 (100, [M+H] ²⁺ ), 670.4 (50, [M+H] ⁺ ), 671.4 (18, [M+H] ⁺ ), calculated for C ₃₂ H ₅₅ N ₅ O ₁₀ : 669.39 [M] ⁺ . DOTA(tBu) ₃ .Glu.(FAPi) ₂ (2,2',2''-(10-(2-(((S)-1,5-bis((4-((4-((2 -((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl) amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTA(tBu) ₃ -NHS (40 mg, 60 µmol, 1.2 eq). dissolved together with Glu.(FAPi) ₂ (48.7 mg, 50 µmol, 1.0 eq) in dry DMF (2 mL) and treated with DIPEA (200 µL). The mixture was stirred under an argon atmosphere at 40° C. for 1 d and then all solvents were completely removed in vacuo. A yellow oil was obtained and used directly in the next stage without further purification. HPLC-MS (ESI positive): m/z (%) = 382.95 (22, [M+H] ⁴⁺ ), 383.20 (19, [M+H] ⁴⁺ ), 491.57 (34, [M-tBu +H] ³⁺ ), 491.90 (28, [M-tBu+H] ³⁺ ), 492.24 (13, [M-tBu+H] ³⁺ ), 510.26 (100, [M+H] ³⁺ ), 510.59 (90, [M+H] ³⁺ ), 510.93 (44, [M+H] ³⁺ ), 511.26 (14, [M+H] ³⁺ ), 764.88 (42, [M+H] ²⁺ ), 765.38 (37, [M+H] ²⁺ ), 765.89 (17, [M+H] ²⁺ ), 1528.76 (25, [M+H] ⁺ ), 1529.76 (22, [M+H] ⁺ ), _1530.77 (10, [M+H] ⁺ ), _calcd for: C75 _H101 F4 N15 _O15 : _1527.75 [M] ⁺ . DOTA.Glu.(FAPi) ₂ (2,2',2''-(10-(2-(((S)-1,5-bis((4-((4-((2-((S )-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)amino)-2 - oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTA(tBu) ₃ .Glu.(FAPi) ₂ 50 µL Milli-Q ^® water, 50 µL TIPS and 1.9 mL TFA (TFA:TIPS:H ₂ O (95:2.5:2.5)) and stirred at RT for 8 h. Then 4 times about 10 mL MeOH were added and the solvents were removed again in vacuo. The crude product was purified using semi-preparative RP-HPLC (22-23% ACN in 16 min, tR = 14-15 min). 19.9 mg (14.6 μmol, 29%) of a yellow solid were obtained. LC-MS (ESI positive): m/z (%) = 340.85 (42, [M+H] ⁴⁺ ), 351.00 (57, [M+ACN+H] ⁴⁺ ), 361.35 (13, [M +2ACN+H] ⁴⁺ ), 454.15 (100, [M+H] ³⁺ ), 468.00 (20, [M+ACN+H] ³⁺ ), 680.85 (9, [M+H] ²⁺ ), _calcd for C63 _H77 F4 _N15 _O15 : _1359.57 [M] ⁺ . [ ^nat Lu]Lu-DOTA.Glu.(FAPi) ₂ DOTA.Glu.(FAPi) ₂ (2.8 mg, 2.0 µmol, 1.0 eq) was dissolved in 500 µL 1 M HEPES buffer (pH = 5.5) with 40 µL of a 0.1 M LuCl ₃ solution (4 µmol, 2.0 eq) and shaken for 4 h at 90 °C. Subsequent semipreparative RP-HPLC (20-25% ACN in 20 min, t _R = 14-15 min) gave 0.7 mg (0.46 µmol, 23%) of [ ^nat Lu]Lu-DOTA.Glu.(FAPi) ₂ as a yellow solid . LC-MS (ESI positive): m/z (%) = 511.55 (100, [M+H] ³⁺ ), 766.75 (14, [M+H] ²⁺ ), calculated for C ₆₃ H ₇₄ F ₄ _LuN15 _O15 : 1531.48 [M] ⁺ . [ ⁶⁸ Ga]Ga-DOTA.Glu.(FAPi) ₂ 100 MBq [ ⁶⁸ Ga]GaCl ₃ were placed and a solution of 400 µL 1 M HEPES buffer (pH = 4.5 or 5.5) and 5- 20 nmol DOTA.Glu.(FAPi) ₂ (5-20 µL of a 1 µmol/mL stock solution with Trace-Select H ₂ O) is added and then shaken for 30 min. The labeling was carried out at least three times (n=3) for each amount of substance (5, 10 and 20 nmol) and in each case via radio-TLC with 0.1 M Na ₃ citrate buffer (pH = 4.0) as the mobile phase (see Fig. 1) examined. In addition, the consistency was examined in comparison to radio-DCs with 1 M AmOAc (pH = 4)/MeOH (1:1) and analytical radio-HPLC (Fig. 2). A high radiochemical conversion of >98% could be achieved. The stability is more than 98% after 2 hours in HS and PBS (see FIG. 3). The logD value was determined to be -2.08 ± 0.07. [ ¹⁷⁷ Lu]Lu-DOTA.Glu.(FAPi) ₂ 50-100 MBq [ ¹⁷⁷ Lu]LuCl ₃ in 20-40 µL 0.04 M HCl were introduced and a solution of 400 µL 1 M HEPES buffer was prepared at 95 °C (pH = 5.5) and 2-5 nmol DOTA.Glu.(FAPi) ₂ (2-5 µL of a 1 µmol/mL stock solution with Trace-Select H ₂ O) and then shake for 60 min. The labeling was carried out several times (n=3 (50 MBq), n=2 (100 MBq)) and examined by in each case radio-DCs with 0.1 M Na ₃ citrate buffer (pH = 4.0) as mobile phase (s. Fig.4) were developed and evaluated. In addition, the consistency was examined in comparison to radio-DCs with 1 M AmOAc (pH = 4)/MeOH (1:1) and analytical radio-HPLC (Fig. 5). A high radiochemical conversion of >99% could be achieved. After 14 days, the stability is about 99% in HS and 95% in PBS (see FIG. 6). The logD value was determined to be -1.77 ± 0.10.

The synthesis of the tag precursor DOTAGA.Glu.(FAPi) ₂ is shown in Scheme 12 below. DOTAGA(tBu)4.Glu.(FAPi) ₂ (2,2',2''-(10-(5-(((S)-1,5-bis((4-((4-((2 -((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl) amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTAGA(tBu) 4 (60 mg, 85.6 µmol, 1.0 eq) and O-(7-AzaBenzotriazol-1-yl)-N,N,N´,N´- tetramethyluronium hexafluorophosphate (HATU, 36 mg, 94.2 µmol, 1.1 eq). dissolved in dry DMF (2 mL) under an argon atmosphere and treated with DIPEA (17.5 µL, 103 µmol, 1.2 eq). After 1 h at 30 °C, a solution of Glu.(FAPi) ₂ (104 mg, 107 µmol, 1.25 eq) and DIPEA (43.7 µL, 257 µmol, 3 eq) in dry DMF (3 mL) was added. It was stirred overnight at 30° C. and then HATU (16 mg, 42 μmol, 0.5 eq) was added again. After a further day of stirring at 30°C, the solvent was removed in vacuo. Column chromatographic purification (CHCl ₃ :MeOH:triethylamine(TEA) (100:10-15:1)) yielded 39 mg (23.5 µmol, 27%) DOTAGA(tBu) ₄ .Glu.(FAPi) ₂ as a yellow oil. HPLC-MS (ESI positive): m/z (%) = 414.97 (13, [M+H] ⁴⁺ ), 415.22 (12, [M+H] ⁴⁺ ), 552.95 (100, [M+H ] ³⁺ ), 553.29 (97, [M+H] ³⁺ ), 553.62 (51, [M+H] ³⁺ ), 553.96 (18, [M+H] ³⁺ ), 828.93 (82, [M +H] ²⁺ ), 829.43 (78, [M+H] ²⁺ ), 829.93 (40, [M+H] ²⁺ ), 830.43 (15, [M+H] ²⁺ ), 1656.85 (87, [M+H] ⁺ ), 1657.85 (85, [M+H] ⁺ ), 1658.85 (43, [M+H] ⁺ ), 1659.86 (15, [M+H] ⁺ ), calcd for C82H113F4N15O17: 1655.84 [ M] ⁺ . DOTAGA.Glu.(FAPi) ₂ (2,2',2''-(10-(4-(((S)-1,5-bis((4-((4-((2-((S )-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)amino)-1 - carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTAGA(tBu) ₄ .Glu.(FAPi) ₂ add 50 µL Milli-Q ^® water, 50 µL TIPS and 1.9 mL TFA (TFA:TIPS:H ₂ O (95:2.5:2.5)) and stirred at RT for 7 h. Then 5x about 10 mL MeOH were added and the solvents were removed again in vacuo. The crude product was purified by semi-preparative RP-HPLC (23% ACN isocratic, tR = 10-10.5 min). 16.4 mg (11.5 μmol, 49%) of a yellow solid were obtained. LC-MS (ESI positive): m/z (%) = 358.85 (65, [M+H] ⁴⁺ ), 369.05 (24, [M+ACN+H] ⁴⁺ ), 478.30 (100, [M +H] ³⁺ ), 717.30 (6, [M+H] ²⁺ ), 1432.40 (1, [M+H] ⁺ ), 1454.70 (1, [M+Na] ⁺ ), calculated for C ₆₆ H ₈₁ _F4 N15 _O17 : _1431.59 [M] ⁺ . [ ^nat Lu]Lu-DOTAGA.Glu.(FAPi) ₂ DOTAGA.Glu.(FAPi) ₂ (2.8 mg, 2.0 µmol, 1.0 eq) was dissolved in 550 µL 1 M HEPES buffer (pH = 5.5) and 50 µL EtOH dissolved, mixed with 40 µL of a 0.1 M LuCl ₃ solution (4 µmol, 2.0 eq) and shaken at 90 °C for 4 h. Subsequent semipreparative RP-HPLC (23% ACN isocratic, tR = 13-14 min) gave 0.5 mg (0.31 µmol, 16%) of [ ^nat Lu]Lu.DOTAGA.Glu.(FAPi) ₂ as a yellow solid. LC-MS (ESI positive): m/z (%) = 535.50 (100, [M+H] ³⁺ ), 802.95 (36, [M+H] ²⁺ ), calculated for C ₆₆ H ₇₈ F ₄ _LuN15 _O17 : 1603.50 [M] ⁺ . [ ⁶⁸ Ga]Ga-DOTAGA.Glu.(FAPi) ₂ 100 or 400 MBq [ ⁶⁸ Ga]GaCl ₃ in 0.05 M HCl (0.5 or 2 mL) were placed and a solution of 0.5 or 2 mL 1 M HEPES buffer (pH = 4.5) and 10-40 nmol DOTAGA.Glu.(FAPi) ₂ (10-40 µL of a 1 µmol/mL stock solution with Trace-Select H ₂ O) are added and then 30 min shaken. The labeling was carried out several times (n=4 (100 MBq), n=2 (400 MBq)) and the reaction kinetics each time via radio-DC with 0.1 M Na ₃ citrate buffer (pH = 4.0) as the mobile phase (s. Fig.7) examined. In addition, the consistency was examined in comparison to radio-DCs with 1 M AmOAc (pH = 4)/MeOH (1:1) and analytical radio-HPLC (Fig. 8). A high radiochemical conversion of >97% could be achieved. The stability is more than 95% after 2 hours in HS and PBS (see FIG. 9). The logD value was determined to be -2.48 ± 0.05. [ ¹⁷⁷ Lu]Lu-DOTAGA.Glu.(FAPi) ₂ 50-100 MBq [ ¹⁷⁷ Lu]LuCl ₃ in 20-40 µL 0.04 M HCl were introduced and a solution of 400 µL 1 M HEPES buffer was prepared at 95 °C (pH = 5.5) and 1-5 nmol DOTAGA.Glu.(FAPi) ₂ (1-5 µL of a 1 µmol/mL stock solution with Trace-Select H ₂ O) and then shake for 60 min. The reaction kinetics were examined (number of labels: n=3 (50 MBq), n=1-2 (100 MBq)) by using radio-DCs with 0.1 M Na ₃ citrate buffer (pH = 4.0) as mobile Phase (s. Fig.10) were developed and evaluated. In addition, the consistency was examined in comparison to radio-DCs with 1 M AmOAc (pH = 4)/MeOH (1:1) and analytical radio-HPLC (Fig. 11). A high radiochemical conversion of >99% could be achieved. After 14 days, the stability is >99% in HS and PBS (see FIG. 12). The logD value was determined to be -2.77 ± 0.10. [ ²²⁵ Ac]Ac-DOTAGA.Glu.(FAPi) ₂ 1.6-3.2 MBq [ ²²⁵ Ac]AcCl ₃ in 100 µL 0.04 M HCl were introduced and at 95 °C a solution of 1 mL 0.1 sodium ascorbate (pH = 7.0) and 30 nmol/MBq DOTAGA.Glu.(FAPi) ₂ (30 µl/MBq 1 µmol/mL stock solution with Trace-Select H ₂ O) and then shaken for 60 min. The labeling was carried out three times (n=3) and the reaction kinetics were examined. For this purpose, radio-DCs were developed with 0.1 M Na ₃ citrate buffer (pH=4.0) as the mobile phase (see FIG. 13) and exposed and evaluated at different times (1 h and 1 d). A high radiochemical conversion of > 94.3 ± 2.1% (exposure after 1 day) was observed after 15 min. Subsequent purification using a SepPak ^® Light C18 cartridge finally gave the product with high radiochemical purity (> 98%, determined via radio-DC and high-resolution gamma spectroscopy with HPGe detector). For the stability measurements of [ ²²⁵ Ac]Ac-DOTAGA.Glu.(FAPi) ₂ , 350-400 kBq of the labeling solution were added to HS and PBS (n=3 each) and incubated for 20 d at 37 °C (see Fig. 14). The synthesis of the tag precursor DATA ^5m .Glu.(FAPi) ₂ is shown in Scheme 13 below. DATA ^5m (tBu) ₃ .Glu.(FAPi) ₂ (2,2'-(6-(5-(((S)-1,5-bis((4-((4-((2-(( S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5- dioxopentan-2-yl)amino)-5-oxopentyl)-6-((2-(tert-butoxy)-2-oxoethyl)(methyl)amino)-1,4-diazepan-1,4-diyl)diacetic acid- tert-butyester) DATA ^5m (tBu) ₃ (22.8 mg, 40 µmol, 1.0 eq) and HATU (17.5 mg, 46 µmol, 1.15 eq) was dissolved in dry DMF (1 mL) and treated with DIPEA (8.5 µL, 50 µmol , 1.25 eq) offset. After 1 h at 25 °C, a solution of Glu.(FAPi) ₂ (39 mg, 40 µmol, 1.0 eq) and DIPEA (17 µL, 100 µmol, 2.5 eq) in dry DMF (2 mL ) admitted. Stirring was continued for 2 h at 25 °C. The solvent was removed in vacuo and subsequent purification by column chromatography (CHCl ₃ :MeOH:triethylamine(TEA) (100:10-15:1)) yielded 60 mg (39.2 µmol, 98%). of a yellow oil. LC-MS (ESI positive): m/z (%) = 510.0 (100, [M+H] ³⁺ ), 764.5 (24, [M+H] ²⁺ ), calculated for C ₇₆ H ₁₀₂ F ₄ N14 _O15 : _1526.76 [M] ⁺ . DATA ^5m .Glu.(FAPi) ₂ (2,2'-(6-(5-(((S)-1,5-bis((4-((4-((2-((S)-2 -cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)amino)-5-oxopentyl) -6-((carboxymethyl)(methyl)amino)-1,4-diazepan-1,4-diyl)diacetic acid) To DATA ^5m (tBu) ₃ .Glu.(FAPi) ₂ was added 25 µL Milli-Q ^® water, 25 μL TIPS and 950 μL TFA (TFA:TIPS:H ₂ O (95:2.5:2.5)) and stirred at RT for 2.5 h. Then 3x about 10 mL MeOH were added and the solvents were removed again in vacuo. The crude product was purified by semipreparative RP-HPLC (23% ACN isocratic, t _R = 13-13.5 min). 8.2 mg (6.0 μmol, 15%) of a yellow solid were obtained. LC-MS (ESI positive): m/z (%) = 340.7 (6, [M+H] ⁴⁺ ), 454.0 (100, [M+H] ³⁺ ), 680.4 (48, [M+H ] ²⁺ ), 706.8 (47, [M+Fe] ²⁺ ), 707.3 (35, [M+Fe] ²⁺ ), 1359.5 (6, [M+H] ⁺ ), 1360.5 (5, [M+ H] ⁺ ), calculated for C ₆₄ H ₇₈ F ₄ N ₁₄ O ₁₅ : 1358.57 [M] ⁺ . [ ⁶⁸ Ga]Ga-DATA ^5m .Glu.(FAPi) ₂ 50 MBq [ ⁶⁸ Ga]GaCl ₃ were placed and a solution of 400 µL 0.5 M HEPES buffer (pH = 5.5) and 10-20 nmol DOTA .Glu.(FAPi) ₂ (10-20 µL of a 1 µmol/mL stock solution with Trace-Select H ₂ O) is added and then shaken for 30 min. The markings were carried out four times (n=4) for both amounts of substance and examined via radio-TLC with 0.1 M Na3citrate buffer (pH=4.0) as the mobile phase (see FIG. 15). In addition, the consistency was examined in comparison to radio-DCs with 1 M AmOAc (pH = 4)/MeOH (1:1) and analytical radio-HPLC (Fig. 16). A high radiochemical conversion of >96% could be achieved. After 2 hours in HS and PBS, the stability is >97% (see FIG. 17). ^{The logD value was determined to be -2.03 ± 0.05.} Table 1 summarizes the experimentally determined logD values. Table 1: LogD values of the ⁶⁸ Ga and ¹⁷⁷ Lu labeled compounds DOTAGA.Glu.(FAPi) ₂ , DOTA.Glu.(FAPi) ₂ and DATA ^5m .Glu.(FAPi) ₂ . In vitro studies: FAP: IC ₅₀ measurements were performed with Z-Gly-Pro-7-amino-4-methylcumaine (AMC) as substrate at a concentration of 50 µM at pH = 8 (0.05 M Tris-HCl buffer, 1 mg/mL bovine serum albumin (BSA) and 140 mM NaCl). 8 concentrations of the investigated FAP inhibitors were examined, with the DMSO concentration always being the same. The inhibitors were pre-incubated for 15 min at 37°C before the substrate Z-Gly-Pro-AMC was added. The release kinetics of AMC were measured at an excitation wavelength λ _ex = 380 nm and emission wavelength λ _em = 465 nm for at least 10 min. PREP: IC50 measurements were performed using N-Succinyl-Gly-Pro-AMC as substrate at a concentration of 250 µM at pH = 7.4 (0.1 M K-phosphate buffer, 1 mM EDTA, 1 mM DTT and 1 mg/mL BSA ) carried out. 8 concentrations of the investigated FAP inhibitors were examined, with the DMSO concentration always being the same. The inhibitors were pre-incubated for 15 min at 37°C before the substrate N-Succinyl-Gly-Pro-AMC was added. The release kinetics of AMC were measured at an excitation wavelength λ _ex = 380 nm and emission wavelength λ _em = 465 nm for at least 10 min. DPP4, DPP8 and DPP9: IC ₅₀ measurements were made with Ala-Pro-p-nitroanilide (pNA) as substrate at a concentration of 25 µM (DPP4), 300 µM (DPP8) and 150 µM (DPP9) at pH = 7.4 (0.05 M HEPES-NaOH buffer with 0.1% Tween-20, 1 mg/mL BSA and 150 mM NaCl). At least 8 concentrations of the investigated FAP inhibitors were examined, with the DMSO concentration always being the same. The inhibitors were heated for 15 min at 37 °C preincubated before the substrate Ala-Pro-pNA was added. The release kinetics of pNA were measured at a wavelength λ _ex = 405 nm for at least 10 min. Table 2 summarizes the results of the IC ₅₀ measurements. The selectivity index (SI) results from the ratio of the IC ₅₀ value of FAP and the respective competitor enzyme (PREP, DPP4, DPP8, DPP9). Table 2: IC ₅₀ measured values of the compounds DOTAGA.Glu.(FAPi) ₂ , DOTA.Glu.(FAPi) ₂ and DATA ^5m .Glu.(FAPi) ₂ and the established FAP inhibitor UAMC1110 (see scheme 4 right) . Example 3: DOTA.NPyr.(FAPi) ₂ , DOTAGA.NPyr.(FAPi) ₂ The synthesis of the tag precursors DOTA.NPyr.(FAPi) ₂ , DOTAGA.NPyr.(FAPi) ₂ is described below. The initial synthetic steps are identical for both compounds and a representative synthesis is shown in Scheme 14.

Boc-NPyr(OBzl) ₂ ((S)-2,2'-((1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)azanediyl)-diacetic acid benzyl ester) (S)-1-Boc-3-aminopyrrolidine (1.07 g, 5.74 mmol, 1.0 eq) and DIPEA (1.5 mL) were dissolved in acetonitrile (6 mL). After 60 min, a solution of bromoacetic acid benzyl ester (1.74 g, 7.55 mmol, 1.3 eq) in acetonitrile (6 mL) was slowly added dropwise and the mixture was stirred at RT for a further 2 h. Acetonitrile was removed under reduced pressure. Subsequent column chromatography (CHCl ₃ :MeOH (30:1) + 1% TEA) afforded Boc-NPyr(OBzl) ₂ (1.31 g, 2.71 mmol, 47%) as a side product along with Boc-NPyr-OBzl (benzyl-(S)- N-(pyrrolidine-3-tert-butoxy-carbamate)glycine, 680 mg, 2.03 mmol, 35%). LC-MS (ESI positive): m/z (%) = 383.2 (45, [M−Boc+H] ⁺ ), 483.2 (100, [M+H] ⁺ ), 484.2 (30, [M+H ] ⁺ ), calculated for C ₂₇ H ₃₄ N ₂ O6: 482.24 [M] ⁺ . Boc-NPyr ((S)-2,2'-((1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)azanediyl)diacetic acid) Boc-NPyr(OBzl) ₂ (1.21 g, 2.51 mmol, 1.0 eq). treated with palladium on activated carbon (10 wt% Pd, 53 mg, 50 µmol, 0.02 eq) and dry methanol (8 mL). The mixture was stirred at RT under a hydrogen atmosphere for 2 d. It was filtered through celite and the methanol was then removed under reduced pressure. A colorless solid was obtained (643 mg, 2.13 mmol, 85%). LC-MS (ESI positive): m/z (%) = 247.0 (100, [M- ^t Bu+H] ⁺ ), 303.1 (36, [M+H] ⁺ ), 605.3 (23, [2M+ H] ⁺ ), calculated for C ₁₃ H ₂₂ N ₂ O ₆ : 302.15 [M] ⁺ . Boc-NPyr.(FAPi) ₂ (tert-butyl (S)-3-(bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine- 1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidine-1- carboxylate) Boc-NPyr (30.2 mg, 100 µmol, 1.0 eq), HOBt (36 mg, 266 µmol, 2.7 eq) and EDC*HCl (50 mg, 260 µmol, 2.6 eq) were dissolved in dry DMF (3 mL) and stirred at 30 °C under an argon atmosphere for 60 min. Then a solution of FAPi-NH ₂ *TFA (110 mg, 202 µmol, 2.0 eq) and DIPEA (51.0 µL, 300 µmol, 3.0 eq) in DMF (2 mL) was added and continued for 3.5 h stirred at 30°C. Then HOBt (8.5 mg, 63 µmol, 0.63 eq) and EDC*HCl (12 mg, 63 µmol, 0.63 eq) were added and 30 min later a solution of FAPi-NH ₂ *TFA (25 mg, 46 µmol, 0.46 eq ) and DIPEA (17.0 µL, 100 µmol, 1.0 eq) in DMF (1 mL). After stirring at 30 °C overnight, the additions were repeated by adding HOBt (8.5 mg, 63 µmol, 0.63 eq), EDC*HCl (12 mg, 63 µmol, 0.63 eq) and after a further 30 min FAPi-NH ₂ *TFA (16 mg, 29 µmol, 0.29 eq) and DIPEA (17.0 µL, 100 µmol, 1.0 eq) in DMF (1 mL) was added. The mixture was stirred at 30° C. for a further 5 h and then the solvent was removed in vacuo. After column chromatography (CHCl ₃ :MeOH:TEA (100:7.5-10:1)), 102 mg (90.3 µmol, 90%) of Boc-NPyr.(FAPi) ₂ were obtained as a yellow oil. LC-MS (ESI positive): m/z (%) = 358.6 (86, [M− ^t Bu+H] ³⁺ ), 372.2 (58, [M− ^t Bu+ACN+H] ³⁺ ), 377.3 (100, [M+H] ³⁺ ), 390.3 (68, [M+ACN+H] ³⁺ ), 515.3 (36, [M−Boc+H] ²⁺ ), 537.5 (8, [M− ^t Bu+H] ²⁺ ), 565.5 (84, [M+H] ²⁺ ), 1129.6 (28, [M+H] ⁺ ), 1130.6 (17, [M+H] ⁺ ), calculated for C ₅₅ _H64 F4 _N12 _O10 : _1128.48 [M] ⁺ . NPyr.(FAPi) ₂ (6,6'-((((2,2'-(((S)-pyrrolidin-3-yl)azanediyl)bis(acetyl))bis(azanediyl)))bis(butane-4 ,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) Zu Boc -NPyr.(FAPi) ₂ (102 mg, 90 µmol) was added to 50 µL Milli-Q ^® water, 50 µL triisopropylsilane (TIPS) and 1.9 mL TFA (TFA:TIPS:H ₂ O (95:2.5:2, 5)) and stirred for 1 h at RT. Then 5x each about 10 mL MeOH was added and the solvents were removed again in vacuo and a yellow oil was obtained. It was used in the next step without further purification. LC-MS ( ESI positive): m/z (%) = 344.1 (100, [M+H] ³⁺ ), 357.6 (45, [M+ACN+H] ³⁺ ), 515.5 (18, [M+H] ^{2 +} ), 1029.5 ( ₃ , [M+H] ⁺ ), _calcd for C50 _H56 F4 N12 _O8 : _1028.43 [M] ⁺ .

The synthesis of the tag precursor DOTA.NPyr.(FAPi) ₂ is shown in Scheme 15 below. DOTA(tBu) ₃ .NPyr.(FAPi) ₂ (2,2',2''-(10-(2-((S)-3-(Bis(2-((4-((4-(( 2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidine-1 -yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid tert-butyl ester) DOTA(tBu) ₃ -NHS (33.5 mg, 50 µmol, 1.25 eq) was dissolved in dry DMF (1 mL) together with NPyr.(FAPi) ₂ (41.2 mg, 40 µmol, 1.0 eq) and DIPEA (50 µL) was added. The mixture was stirred under an argon atmosphere at 40° C. for 3 d and then all solvents were completely removed in vacuo. A yellow oil was obtained and used directly in the next stage without further purification. HPLC-MS (ESI positive): m/z (%) = 396.71 (35, [M+H] ⁴⁺ ), 396.96 (33, [M+H] ⁴⁺ ), 397.21 (15, [M+H ] ⁴⁺ ), 509.92 (48, [M- ^t Bu+H] ³⁺ ), 510.25 (42, [M- ^t Bu+H] ³⁺ ), 510.59 (20, [M- ^t Bu+H] ^{3 +} ), 528.61 (100, [M+H] ³⁺ ), 528.94 (95, [M+H] ³⁺ ), 529.27 (50, [M+H] ³⁺ ), 529.61 (17, [M+H ] ³⁺ ), 792.40 (30, [M+H] ²⁺ ), 792.91 (28, [M+H] ²⁺ ), 793.41 (13, [M+H] ²⁺ ), 1583.80 (18, [M +H] ⁺ ), 1584.81 (17, [M+H] ⁺ ), 1585.81 (8, [M+H] ⁺ ), 1605.79 (8, [M+Na] ⁺ ), 1606.79 (8, [M+Na ] ⁺ ), calculated for: _C78 _H106 F4 _N16 _O15 : _1582.80 [M] ⁺ . DOTA.NPyr.(FAPi) ₂ (2,2',2''-(10-(2-((S)-3-(Bis(2-((4-((4-((2-(( S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidin-1-yl)- 2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTA(tBu) ₃ .NPyr.(FAPi) ₂ was added 50 µL Milli-Q ^® water, 50 µL TIPS and 1.5 mL TFA (TFA:TIPS:H ₂ O (94:3:3)) and stirred at RT for 12 h. Subsequently, 4x each about 10 mL MeOH added and the solvents removed again in vacuo. The crude product was purified by semi-preparative RP-HPLC (21-22% ACN in 20 min, t _R = 18.5-19.5 min). 5.6 mg (4.0 μmol, 10%) of a yellow solid were obtained. LC-MS (ESI positive): m/z (%) = 354.55 (95, [M+H] ⁴⁺ ), 364.750 (59, [M+ACN+H] ⁴⁺ ), 472.60 (100, [M +H] ³⁺ ), 708.55 (13, [M+H] ²⁺ ), 1415.50 (5, [M+H] ⁺ ), calcd for C66H82F4N16O15: 1414.61 [M] ⁺ . The synthesis of the tag precursor DOTAGA.NPyr.(FAPi) ₂ is shown in Scheme 16 below. DOTAGA(tBu) ₄ .NPyr.(FAPi) ₂ (2,2',2''-(10-(5-((S)-3-(Bis(2-((4-((4-(( 2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidine-1 -yl)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTAGA(tBu ) ₄ (23.5 mg, 33.5 µmol, 1.0 eq), NHS (8.0 mg, 70 µmol, 2.0 eq) and HBTU (26.5 mg, 70 µmol, 2.0 eq) were dissolved in dry DMF (0.5 mL) and heated overnight at 30 °C shaken. NHS (4.5 mg, 39.0 µmol, 1.26 eq) and HBTU (13.5 mg, 35.6 µmol, 1.06 eq) were added again. 4 h later it was mixed with a solution of NPyr.(FAPi) ₂ (41.2 mg, 40 µmol, 1.0 eq) and DIPEA (50 µL) in dry DMF (1 mL). The mixture was stirred at 40° C. for 3 d and then all solvents were completely removed in vacuo. A yellow oil was obtained and used directly in the next stage without further purification. HPLC-MS (ESI positive): m/z (%) = 428.73 (100, [M+H] ⁴⁺ ), 428.98 (32, [M+H] ⁴⁺ ), 429.23 (25, [M+H ] ⁴⁺ ), 571.64 (16, [M+H] ³⁺ ), 571.97 (10, [M+H] ³⁺ ), 856.45 (5, [M+H] ²⁺ ), 856.95 (5, [M +H] ²⁺ ), 1711.89 (2, [M+H] ⁺ ), 1712.89 (2, [M+H] ⁺ ), 1733.87 (2, [M+Na] ⁺ ), 1734.87 (2, [M+ Na] ⁺ ), _calcd for: C85 _H118 F4 _N16 _O17 : _1710.88 [M] ⁺ . DOTAGA.NPyr.(FAPi) ₂ (2,2',2''-(10-(4-((S)-3-(bis(2-((4-((4-((2-(( S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidin-1-yl)- 1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTA(tBu) ₃ .NPyr.(FAPi) ₂ was added 50 µL of Milli-Q ^® water , 50 µL TIPS and 1.9 mL TFA (TFA:TIPS:H ₂ O (95:2.5:2.5)) and stirred at RT for 8 h. Then 4 times about 10 mL MeOH were added and the solvents were removed again in vacuo. The crude product was purified by semi-preparative RP-HPLC (21% ACN isocratic, t _R = 23-24 min). 3.0 mg (2.0 μmol, 6%) of a yellow solid were obtained. LC-MS (ESI positive): m/z (%) = 372.55 (100, [M+H] ⁴⁺ ), 382.90 (38, [M+ACN+H] ⁴⁺ ), 496.60 (76, [M +H] ³⁺ ), 744.40 (5, [M+H] ²⁺ ), calcd for C ₆₉ H ₈₆ F ₄ N ₁₆ O ₁₇ : 1486.63 [M] ⁺ . Example 4: DOTA.PEG2.Glu.(FAPi) ₂ , DOTAGA.PEG2.Glu.(FAPi) ₂ The following describes the synthesis of the tag precursors DOTA.PEG2.Glu.(FAPi) ₂ , DOTAGA.PEG2.Glu.(FAPi ) ₂ described. The initial synthetic steps are identical for both compounds and a representative synthesis is shown in Scheme 17. Fmoc-PEG2.Glu(OBzl) ₂ ((1-(9H-Fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oyl)-L-glutamic acid dibenzyl ester) The Fmoc -N-amido-dPEG2-acid (450.0 mg, 1.1 mmol, 1.00 eq.) and DIPEA (182.0 mg, 240 µL, 1.4 mmol, 1.25 eq.) were dissolved in dry DMF (9.0 mL) and HBTU (470.3 mg, 1.2 mmol, 1.10 eq.) and HOBt (167.6 mg, 1.2 mmol, 1.10 eq.) were added. The colorless solution was stirred under an argon atmosphere at 25° C. for 24 h. After one hour, dibenzyl glutamate (460.6 mg, 1.4 mmol, 1.25 eq.) and DIPEA (320.5 mg, 422 µL, 4.5 mmol, 2.20 eq.) dissolved in dry DMF (3.0 mL) were added. After the reaction had ended, the solvent was removed under reduced pressure and the yellowish oil was purified by column chromatography (DCM:MeOH (100:2)). The Fmoc-PEG2.Glu(OBzl) ₂ (795.1 mg, 1.1 mmol, 99%) was obtained as a colorless oil. LC-MS (ESI positive): m/z (%) = 709.4 (100, [M+H] ⁺ ), 710.2 (15, [M+H] ⁺ ), calculated for C ₄₁ H ₄₄ N ₂ O ₉ : 708.30 [M] ⁺ . Fmoc-PEG2.Glu ((1-(9H-Fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oyl)-L-glutamic acid) Fmoc-PEG2.Glu( OBzl) ₂ (196.4 mg, 0.3 mmol, 1.00 eq.) was dissolved in dry tetrahydrofuran (THF) (2.0 mL) and palladium on activated carbon (10 wt% Pd, 30.0 mg, 0.3 mmol, 1.00 eq.) was added. It was then stirred under a hydrogen atmosphere for 24 hours. The suspension was filtered through Celite, the residue washed with THF and the solvent removed under reduced pressure. The Fmoc-PEG2.Glu (122.2 mg, 231.3 μmol, 82%) was obtained as a colorless oil and used in the next step without further work-up. LC-MS (ESI positive): m/z (%) = 529.25 (100, [M+H] ⁺ ), 530.15 (12, [M+H] ⁺ ), calculated for C ₂₇ H ₃₂ N ₂ O ₉ : 528.21 [M] ⁺ . Fmoc-PEG2.Glu.(FAPi) ₂ ((9H-Fluoren-9-yl)methyl ((11S)-19-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl )-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-11-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl )carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-9,14-dioxo- 3,6-dioxa-10,15-diazanonadecyl)carbamate) Fmoc-PEG2.Glu (32.0 mg, 60.0 µmol, 1.00 eq .) was dissolved in dry DMF (1.0 mL) together with HOBt (20.4 mg, 150.0 µmol, 2.50 eq.) and EDC*HCl (28.8 mg, 150.0 µmol, 2.50 eq.) and stirred under an argon atmosphere at room temperature. After 1 h, a colorless solution of FAPi*TFA (65.4 mg, 120.0 µmol, 2.00 eq.), DIPEA (23.3 mg, 30 µL, 180.0 µmol, 3.00 eq.) and dry DMF (0.5 mL) was added. Another 3 hours later, HOBt (7.8 mg, 60.0 µmol, 1.00 eq.) and EDC*HCl (11.4 mg, 60.0 µmol, 1.00 eq.) were added again. Shortly thereafter, further FAPi*TFA (16.5 mg, 30.0 µmol, 0.50 eq.), dissolved in DIPEA (7.8 mg, 10 µL, 60.0 µmol, 1.00 eq.) and 0.5 mL dry DMF, was added. The next day, half an equivalent of HOBt (3.9 mg, 30.0 µmol, 0.50 eq.) and EDC*HCl (5.7 mg, 30.0 μmol, 0.5 eq.) was added and the reaction ended after a further 4 h. The DMF was removed under reduced pressure and after purification by column chromatography (CHCl ₃ :MeOH (100:10)) Fmoc-PEG2.Glu.(FAPi) ₂ (79.1 mg, 58.4 µmol, 97%) was obtained as a slightly yellowish solid. LC-MS (ESI positive): m/z (%) = 452.50 (31, [M+H] ³⁺ ), 678.45 (100, [M+H] ²⁺ ), 679.25 (13, [M+H ] ²⁺ ), 1355.85 (9, [M+H] ⁺ ), _calcd for C69 _H74 F4 _N12 _O13 : _1354.54 [M] ⁺ . PEG2.Glu.(FAPi) ₂ ((2S)-2-(3-(2-(2-aminoethoxy)ethoxy)propanamido)-N ¹ ,N ⁵ -bis(4-((4-((2-( 2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)pentanediamide) Fmoc-PEG2.Glu.(FAPi) ₂ (67.0 mg, 50.0 µmol, 1.00 eq.) was dissolved in 1.0 mL dry DMF and 10% piperidine (0.1 mL) was added. The slightly yellowish solution was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. PEG2.Glu.(FAPi) ₂ was obtained in quantitative yield, which was used without further purification. LC-MS (ESI positive): m/z (%) = 378.40 (100, [M+H] ³⁺ ), 567.35 (26, [M+H] ²⁺ ), 1133.35 (3, [M+H ] ⁺ ), calculated for C ₅₄ H ₆₄ F ₄ N ₁₂ O ₁₁ : 1132.48 [M] ⁺ . The synthesis of the tag precursor DOTA.PEG2.Glu.(FAPi) ₂ is shown in Scheme 18 below. DOTA(tBu) ₃ .PEG2.Glu.(FAPi) ₂ (2,2',2''-(10-(2-(((S)-1,5-bis((4-((4-( (2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentane-2- yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) PEG2.Glu.(FAPi) ₂ (13.4 mg, 20.0 µmol, 1.00 eq.) was dissolved in DMF (0.4 mL) and 1 vol% DIPEA (10.4 mg, 14 µL, 82.3 µmol) and then the DOTA(tBu) ₃ -NHS (22.7 mg, 20.0 µmol , 1.00 eq.) added. It has been for three days Stirred at 35°C and then the DMF removed under reduced pressure. The yellowish-brown oil was reacted further without further work-up. HPLC-MS (ESI positive): m/z (%) = 432.70 (55, [M+H] ⁴⁺ ), 576.60 (26, [M+H] ³⁺ ), 864.90 (18, [M+Na ] ²⁺ ), _1687.84 (1, [M+H] ⁺ ), 1709.82 (1, [M+Na] ⁺ ), _calcd for C82 _H114 F4 _N16 _O18 : _1686.84 [M] ⁺ . DOTA.PEG2.Glu.(FAPi) ₂ (2,2',2''-(10-(2-(((S)-1,5-bis((4-((4-((2-( (S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)amino) -2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTA(tBu) ₃ .PEG2.Glu.(FAPi) ₂ 50 µL water, 50 µL TIPS and Added 1.5 mL trifluoroacetic acid (TFA). The brown solution was stirred at room temperature for 5 h and the solvents removed under reduced pressure. The dark brown oil obtained was purified by semipreparative RP-HPLC (22-23% ACN in 20 min, t _R = 16-17 min) and DOTA.PEG ₂ .Glu.(FAPi) ₂ (1.8 mg, 1.2 µmol, 6%) obtained as a yellowish solid. LC-MS (ESI positive): m/z (%) = 380.60 (66, [M+H] ⁴⁺ ), 507.30 (100, [M+H] ³⁺ ), 760.30 (12, [M+H ] ²⁺ ), _1519.55 ( ₄ , [M+H] ⁺ ), 1541.75 (7, [M+Na] ⁺ ), _calcd for C70 H90 F4 N16 _O18 : _1518.66 [M] ⁺ . The synthesis of the tag precursor DOTAGA.PEG2.Glu.(FAPi) ₂ is shown in Scheme 19 below. DOTAGA(tBu) ₄ .PEG2.Glu.(FAPi) ₂ (2,2',2''-(10-((20S)-28-((4-((2-(2-cyano-4,4 - difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-20-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-2,2-dimethyl-4,8,18,23-tetraoxo-3,12,15-trioxa-9,19, 24-triazaoctacosan-5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTAGA(tBu) ₄ (10.0 mg, 14.3 µmol, 1.00 eq.). dissolved with HBTU (10.8 mg, 28.6 µmol, 2.00 eq.) in 0.8 mL dry MeCN, NHS (3.3 g, 28.6 µmol, 2.00 eq.) added and the colorless solution stirred under an argon atmosphere. After 6 h, more HBTU (5.4 mg, 14.3 µmol, 1.00 eq.) and NHS (1.6 mg, 14.3 µmol, 1.00 eq.) were added. .Glu.(FAPi) ₂ (8.2 mg, 8.7 µmol, 1.00 eq.) was dissolved in 0.4 mL dry MeCN and 1.0 mL dry DMF, 1 vol% DIPEA (19 mg, 25 µL, 147.0 µmol) was added and added to the red DOTAGA(tBu)4-NHS solution (11.4 mg, 14.3 µmol, 1.65 eq. in 1.1 mL MeCN). The reaction was stirred at 40 °C for 24 h and then further PEG2.Glu.(FAPi) ₂ (8.2 mg, 8.7 µmol, 1.00 eq.) was added. After a further 24 h, the solvent was removed under reduced pressure and a yellowish oil was obtained, which was used in the next step without further work-up. HPLC-MS (ESI positive): m/z (%) = 454.99 (100, [M+H] ⁴⁺ ), 606.31 (55, [M+H] ³⁺ ), 908.97 (34, [M+H ] ²⁺ ), 1815.93 (4, [M+H] ⁺ ), 1837.91 (2, [M+Na] ⁺ ), _calcd for _C89 _H126 F4 N16 _O20 : _1814.93 [M] ⁺ . DOTAGA.PEG2.Glu.(FAPi) ₂ (2,2',2''-(10-((20S)-28-((4-((2-(2-cyano-4,4-difluoropyrrolidine-1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-20-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl))-2 - oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-2,2-dimethyl-4,8,18,23-tetraoxo-3,12,15-trioxa-9,19,24-triazaoctacosane- 5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTAGA(tBu) ₄ .PEG ₂ .Glu.(FAPi) ₂ were added 50 µL water, 50 µL TIPS and Added 1.5 mL trifluoroacetic acid (TFA). The dark brown solution was stirred at room temperature for 6 hours and the solvents removed under reduced pressure. A brown oil was obtained, which was purified by semipreparative RP-HPLC (22% ACN isocratic, tR = 17-18 min). DOTAGA.PEG2.Glu.(FAPi) ₂ (2.3 mg, 1.5 µmol, 10%) was obtained as a yellowish solid. LC-MS (ESI positive): m/z (%) = 398.70 (93, [M+H] ⁴⁺ ), 531.30 (100, [M+H] ³⁺ ), 796.20 (8, [M+H ] ²⁺ ), 1591.85 (3, [M+H] ⁺ ), _calcd for _C73 _H94 F4 N16 _O20 : _1590.68 [M] ⁺ .

Example 5: DOTA.Glu.Glu.(FAPi) ₂ , DOTAGA.Glu.Glu.(FAPi) ₂ The synthesis of the tag precursors DOTA.Glu.Glu.(FAPi) ₂ and DOTAGA.Glu.Glu.(FAPi) ₂ is illustrated below in Scheme 20. The first synthetic steps are identical for both compounds. Fmoc-Glu(OtBu).Glu(OBzl) ₂ ((S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoyl) -L-glutamic acid dibenzyl ester) Fmoc-Glu-OtBu (400.0 mg, 0.94 mmol, 1.00 eq.) was dissolved in dry DMF (2.0 mL) and DIPEA (151.9 mg, 200 µL, 1.2 mmol, 1.25 eq.) and HATU (393.2 mg, 1.0 mmol, 1.10 eq.) was added. The solution was then stirred at 25° C. under an argon atmosphere. After one hour, dibenzyl glutamate (384.7 mg, 1.2 mmol, 1.25 eq.) and DIPEA (267.3 mg, 352 µL, 2.1 mmol, 2.20 eq.) dissolved in dry DMF (1.0 mL) were added. The next day, HATU (357.4 mg, 0.9 mmol, 1.00 eq.) and DIPEA (121.5 mg, 156 µL, 0.9 mmol, 1.00 eq.) were added again. Three days later, 1.00 eq. HATU and one hour later a solution of dibenzyl glutamate (153.87 mg, 0.5 mmol, 0.50 eq.) and 1.00 eq. Added DIPEA in 0.5 mL DMF. After a further day at 25°C, the solvent was removed under reduced pressure and the product purified by column chromatography (cyclohexane:ethyl acetate (CH:EA, 3:1)). The Fmoc-Glu(OtBu).Glu(OBzl) ₂ (657.3 mg, 0.89 mmol, 95%) was obtained as a slightly yellowish solid. LC-MS (ESI positive): m/z (%) = 679.20 (27, [M- ^t Bu+H] ⁺ ), 680.30 (11, [M- ^t Bu+H] ⁺ ), 735.50 (100, [M+H] ⁺ ), 736.15 (15, [M+H] ⁺ ), _calcd for C43 _H46 N2 _O9 : _734.32 [M] ⁺ . Fmoc-Glu(OtBu).Glu ((S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoyl)-L-glutamic acid ) Fmoc-Glu(OtBu).Glu(OBzl) ₂ (25.0 mg, 34.0 µmol, 1.00 eq.) was dissolved in 1.0 mL dry THF and palladium on activated carbon (10 wt % Pd, 7.25 mg, 78.0 µmol, 2.00 eq. ) added. The suspension was stirred under a hydrogen atmosphere overnight and filtered through Celite the next day. The residue was washed with THF, which was then removed under reduced pressure. Fmoc-Glu(OtBu).Glu (17.8 mg, 32.1 µmol, 94%) was obtained as a colorless solid. LC-MS (ESI positive): m/z (%) = 499.05 (57, [M- ^t Bu+H] ⁺ ), 500.15 (11, [M- ^t Bu+H] ⁺ ), 555.25 (100, [M+H] ⁺ ), 556.15 (21, [M+H] ⁺ ), _calcd for C29 _H34 N2 _O9 : _554.23 [M] ⁺ . Fmoc-Glu(OtBu).Glu.(FAPi) ₂ (N ² -(((9H-Fluoren-9-yl)methoxy)carbonyl)-N ⁵ -((2S)-1,5-bis((4- ((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentane-2 -yl)-L-glutamic acid tert-butyl ester) Fmoc-Glu(OtBu).Glu (33.3 mg, 60.0 µmol, 1.00 eq.) was combined with HOBt (20.4 mg, 15.0 µmol, 2.50 eq.) and EDC*HCl (28.8 mg, 15.0 µmol, 2.50 eq.) dissolved in dry DMF (2.5 mL) and stirred under an argon atmosphere at room temperature for 1 h. Then FAPi*TFA (65.4 mg, 12.0 µmol, 2.00 eq.) and DIPEA (23.3 mg, 31 µL, 18.0 µmol, 3.00 eq.) dissolved in dry DMF (0.5 mL) were added. The next day, another equivalent of HOBt (7.8 mg, 60.0 µmol, 1.00 eq.) and EDC*HCl (11.4 mg, 60.0 µmol, 1.00 eq.) and 30 min later half an equivalent of FAPi*TFA (16.5 mg, 30.0 µmol , 0.50 eq.) dissolved in one equivalent of DIPEA (7.8 mg, 10 µL, 60.0 µmol, 1.00 eq.) and 0.5 mL DMF added. 24 h later HOBt (3.9 mg, 30.0 µmol, 0.50 eq.) and EDC*HCl (5.7 mg, 30.0 µmol, 0.50 eq.) were added again and after one hour further FAPi*TFA (16.5 mg, 30.0 µmol, 0.50 eq .) and DIPEA (3.9 mg, 5 µL, 30.0 µmol, 0.50 eq.) dissolved in DMF (0.5 mL). This step was repeated one more time the next day. The slightly yellowish solution was then stirred for a further day and then the solvent removed under reduced pressure. Fmoc-Glu(OtBu).Glu.(FAPi) ₂ (86.7 mg, 62.8 µmol, 79%) was obtained as a yellowish solid by means of column chromatography (CHCl ₃ :MeOH (100:10)). LC-MS (ESI positive): m/z (%) = 461.25 (32, [M+H] ³⁺ ), 691.45 (100, [M+H] ²⁺ ), 692.25 (12, [M+H ] ²⁺ ), 1381.95 (12, [M+H] ⁺ ), calcd for C ₇₁ H ₇₆ F ₄ N ₁₂ O ₁₃ : 1380.56 [M] ⁺ . Glu(OtBu).Glu.(FAPi) ₂ (N ⁵ -((2S)-1,5-bis((4-((4-((2-(2-cyano-4,4-difluoropyrrolidine-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)-L-glutamic acid tert-butyl ester) Fmoc-Glu(OtBu).Glu. (FAPi) ₂ (72.2 mg, 52.2 µmol, 1.00 eq.) was dissolved in dry DMF (1.0 mL), 10% piperidine (0.1 mL) was added and the mixture was stirred at room temperature for 90 min. The solvent was then removed under reduced pressure and a yellowish oil was obtained, which was used directly in the next stage without further purification. LC-MS (ESI positive): m/z (%) = 387.10 (99, [M+H] ³⁺ ), 580.35 (37, [M+H] ²⁺ ), 1159.30 (4, [M+H ] ⁺ ), calculated for C ₅₆ H ₆₆ F ₄ N ₁₂ O ₁₁ : 1158.49 [M] ⁺ . The synthesis of the tag precursor DOTA.Glu.Glu.(FAPi) ₂ is shown in Scheme 21 below. DOTA(tBu) ₃ .Glu(OtBu).Glu.(FAPi) ₂ (2,2',2''-(10-(2-(((2S)-5-(((2S)-1,5 -bis((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1 ,5-dioxopentan-2-ylamino)-1-(tert-butoxy)-1,5-dioxopentan-2-ylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1, 4,7-triyl)triacetic acid tert-butyl ester) The DOTA(tBu) ₃ -NHS (17.5 mg, 26.1 µmol, 1.00 eq.) was dissolved in 1.0 mL dry DMF and that in 0.5 mL DMF and 1 vol% DIPEA (11.4 mg, 15 µL, 88.2 µmol) dissolved Glu(OtBu).Glu.(FAPi) ₂ (30.3 mg, 26.1 µmol, 1.00 eq.) was added. The slightly yellowish solution was stirred under an argon atmosphere at 40° C. for 24 h and then the solvent was removed under reduced pressure. The yellowish oil obtained was then dissolved in 0.5 mL dry DMF and DIPEA (3.4 mg, 4 µL, 26.1 µmol, 1.00 eq.) was added. DOTA (17.5 mg, 26.1 µmol, 1.00 eq.), HATU (14.9 mg, 39.2 µmol, 1.50 eq.) and DIPEA (6.7 mg, 9 µL, 52.2 µmol, 2.00 eq.) were placed in 0.5 mL of dry DMF, stirred for one hour and then added. The yellowish solution was stirred under an argon atmosphere at 30° C. for 24 h and then HATU (1.50 eq.) and DIPEA (2.00 eq.) were added. After a further 6 h at 40 °C, another Add HATU (1.50 eq.) and DIPEA (2.00 eq.). The next day, the solvent was removed under reduced pressure and a yellowish oil was obtained, which was further reacted without further work-up. HPLC-MS (ESI positive): m/z (%) = 429.47 (9, [M+H] ⁴⁺ ), 571.96 (10, [M+H] ³⁺ ), 857.43 (3, [M+H ] ²⁺ ), _calcd for C84 _H116 F4 _N16 _O18 : _1712.94 [M] ⁺ . DOTA.Glu.Glu.(FAPi) ₂ (2,2',2''-(10-(2-(((1S)-4-(((2S)-1,5-bis((4-( (4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentane-2- yl)amino)-1-carboxy-4-oxobutyl)amino)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTA(tBu) ₃ .Glu( OtBu).Glu.(FAPi) ₂ 50 µL water, 50 µL TIPS and 1.5 mL trifluoroacetic acid (TFA) were added. The yellowish solution was stirred at room temperature for 5 h and the solvents removed under reduced pressure. The crude product was purified by semipreparative RP-HPLC (22-23% ACN in 20 min, t _R = 13-14 min) and DOTA.Glu.Glu.(FAPi) ₂ (6.6 mg, 4.4 µmol, 17%) as yellowish solid obtained. LC-MS (ESI positive): m/z (%) = 373.05 (84, [M+H] ⁴⁺ ), 497.15 (100, [M+H] ³⁺ ), 745.70 (5, [M+H ] ²⁺ ), _1511.35 (1, [M+Na] ⁺ ), _calcd for _C68 H84 F4 N16 _O18 : _1488.61 [M] ⁺ . The synthesis of the tag precursor DOTAGA.Glu.Glu.(FAPi) ₂ is shown in Scheme 22 below. DOTAGA(tBu) ₄ .Glu(OtBu).Glu.(FAPi) ₂ (2,2',2''-(10-((10S,15S)-10-(tert-Butoxycarbonyl)-23-((4 -((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-15-((4-((4-((2- (2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-2,2-dimethyl-4,8,13,18-tetraoxo -3-oxa-9,14,19-triazatricosan-5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTAGA(tBu) ₄ (22.4 mg , 32.6 µmol, 1.00 eq.) was dissolved with HBTU (24.7 mg, 65.3 µmol, 2.00 eq.) in dry MeCN (1.0 mL) and NHS (7.5 mg, 65.3 µmol, 2.00 eq.) was added. The colorless solution was stirred under an argon atmosphere for 4 h and HBTU (12.4 mg, 32.6 μmol, 1.00 eq.) and NHS (3.8 mg, 32.6 μmol, 1.00 eq.) dissolved in DMF (0.2 mL) were added. Then the Glu(OtBu).Glu.(FAPi) ₂ (30.3 mg, 26.1 µmol, 1.00 eq.) dissolved in DMF (1.0 mL) and 1 vol% DIPEA (19 mg, 25 µL, 147.0 µmol) was added. The colorless solution was stirred at room temperature overnight and the next day the solvent was removed under reduced pressure. A yellowish oil was obtained and reacted further without working up. HPLC-MS (ESI positive): m/z (%) = 461.49 (52, [M+H] ⁴⁺ ), 614.99 (100, [M+H] ³⁺ ), 921.97 (56, [M+H ] ²⁺ ), 1841.94 (35, [M+H] ⁺ ), 1863.93 (6, [M+Na] ⁺ ), _calcd for C91 _H128 F4 _N16 _O20 : _1840.94 [M] ⁺ . DOTAGA.Glu.Glu.(FAPi) ₂ (2,2',2''-(10-(4-(((1S)-4-(((2S)-1,5-bis((4-( (4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentane-2- yl)amino)-1-carboxy-4-oxobutyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) To DOTAGA(tBu) 4.Glu(OtBu).Glu.(FAPi) ₂ 50 µL water, 50 µL TIPS and 1.5 mL trifluoroacetic acid (TFA) were added. The yellowish solution was stirred at room temperature for 6 h and the solvents removed under reduced pressure. The crude product was purified by semipreparative RP-HPLC (22% ACN isocratic, t _R = 14-15 min) and DOTAGA.Glu.Glu.(FAPi) ₂ (2.0 mg, 1.3 µmol, 5%) was obtained as a yellowish solid. LC-MS (ESI positive): m/z (%) = 391.10 (78, [M+H] ⁴⁺ ), 401.15 (19, [M+ACN+H] ⁴⁺ ), 521.30 (100, [M +H] ³⁺ ), 781.75 (6, [M+H] ²⁺ ), 1561.65 (3, [M+H] ⁺ ) calcd for C ₇₁ H ₈₈ F ₄ N ₁₆ O ₂₀ : 1560.63 [M] ⁺ . Example 6 Examples of compounds according to the invention without spacer units (S1, S2, S3) are shown below.

Example 7 Examples of compounds according to the invention with a spacer unit (S3) are shown below. Example 8 Examples of compounds according to the invention with two spacer units (S1+S2) are shown below.

Example 9 Examples of compounds according to the invention with three spacer units (S1+S2+S3) are shown below.

Claims

Claims 1. Dimeric marker precursor for nuclear medicine diagnostics and theranostics with the structure TV1-S1-TL-S2-TV2 | S3 | MG wherein TV1 is a first target vector, TV2 is a second target vector, MG is a chelator or linker for complexation or covalent attachment of a radioisotope, S1 is a first spacer, S2 is a second spacer, S3 is a third spacer, and TL is a tris-linker; - TV1 and TV2 are chosen independently from one of the structures [1] to [43] with

wherein - structures [1] to [8] and [43] denote peptides; - X is H or F; - Y = H, CH ₃ , CH(CH ₃ ) ₂ , C(CH ₃ ) ₃ or (CH ₂ ) _n CH ₃ with n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 is; - the Trislinker TL is chosen from one of the structures [52] to [116], with

2. Label precursor according to claim 1, characterized in that 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 (triazacyclononanephosphinic 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-Tetraazacyclododecane-4,7,10)pentanedioic acid) and other DOTA derivatives, TRITA (Trideca-1,4,7,10-tetraamine-tetraacetate), TETA (Tetradeca- 1,4,8,11-tetraamine-tetra-acetate) and its derivatives, PEPA (pentadeca-1,4,7,10,13-pentaaminepentaacetate), HEHA (hexadeca-1,4,7,10,13,16 -hexaamine-hexaacetate) and its derivatives, HBED (N,N'-bis-(2-hydroxybenzyl)ethylene-diamine-N,N'-diacetate ) and its derivatives such as HBED-CC (N,N'-bis-[2-hydroxy-5-carboxyethyl)benzyl)ethylene-diamine-N,N'-diacetate), DEDPA and its derivatives such as H ₂ dedpa (1 ,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane) and H4octapa (1,

2-[[6-(carboxyl)pyridin-2-yl]methylamino]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, such as AAZTA ⁵ ( 5-[(6-Amino)-1,4-diazepan]pentanoic acid - N,N,N',N'-tetraacetate) DATA ^5m (5-[[6-(N-methyl)amino]-1,4- diacetate-1,4-diazepan] pentanoic acid N,N',N'-triacetate); Sarcophagin SAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) and their derivatives such as (NH ₂ ) ₂ SAR (1,8-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 N ₄ -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 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 their derivatives, DADT (diaminodithiol), DADS (diaminodisulfide), N ₂ S ₂ chelators and their derivatives, aminothiols and their derivatives, salts of the above chelators n; Hydrazine Nicotinamide (HYNIC) and hydrazine nicotinamide derivatives.

3. Label precursor according to claim 2, characterized in that MG is DOTA (dodeca-1,4,7,10-tetraamine-tetraacetate), DATA ^5m (1,4-bis(carboxymethyl)-6-[methyl-carboxymethyl-amino ]-6-pentanoic acid-1,4-diazepane) or AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)amino]-6-pentanoic acid-1,4-diazepane). 4. Label precursor according to claim 1, characterized in that MG is selected from 5. Marking precursor according to one or more of claims 1 to 4, characterized in that the spacers S1, S2, S3 independently of one another have a structure which is selected from wherein A, B, C are independently selected from the group comprising amide, carboxamide, phosphinate, alkyl, triazole, thiourea, ethylene, maleimide, amino acid residues, and with s = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and p, q and r are independently chosen from the set {0, 1, 2, 3,

4,

5,

6,

7,

8th,

9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20}. 6. Marking precursor according to one or more of Claims 1 to 4, characterized in that the spacers S1, S2, S3 have the structure independently of one another. 7. Label precursor according to one or more of claims 1 to 4, characterized in that the spacers S1, S2, S3 are independently selected from a peptide, dipeptide or tripeptide group having the structure 8. Marking precursor according to claim 7, characterized in that R ¹ , R ² , R ³ are independently selected from the group consisting of ‒H , ‒CH ₃ , ‒CH(CH ₃ ) ₂ , ‒CH ₂ CH(CH ₃ ) ₂ , ‒CH(CH ₃ )‒CH ₂ CH ₃ , ‒CH ₂ ‒Phe , ‒CH ₂ ‒Phe‒OH , ‒CH ₂ SH , ‒(CH ₂ ) ₂ ‒S‒CH ₃ , ‒CH ₂ OH , ‒(CH)(OH)(CH ₃ ) , ‒(CH ₂ )4NH ₂ , ‒(CH ₂ ) ₃ NH(C=NH)NH ₂ , ‒CH ₂ COOH , ‒(CH ₂ ) ₂ COOH , ‒CH ₂ (C=O)NH ₂ , ‒(CH ₂ ) ₂ (C=O)NH ₂ , 9. Marking precursor according to one or more of Claims 1 to 8, characterized in that TV1 is equal to TV2 (TV1 = TV2).

10. Marking precursor according to one or more of Claims 1 to 8, characterized in that TV1 and TV2 are different from one another (TV1 ≠ TV2).

11. Marking precursor according to claim 10, characterized in that TV1 has one of the structures [9] to [12] and TV2 has one of the structures [13] or [14].

12. Marking precursor according to claim 10, characterized in that TV1 has one of the structures [9] to [12] and TV2 has one of the structures [40] or [41].

13. Radiotracer for nuclear medical diagnostics and theranostics consisting of a label precursor according to any one of claims 1 to 12 and a radioisotope selected from the group consisting of ⁴⁴ Sc, ⁴⁷ Sc, ⁵⁵ Co, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁶ Ga , ⁶⁷ Ga, ⁶⁸ Ga, 8 ⁹ 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, 1 ⁷⁵ Yb, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ²¹¹ At, ²¹² Pb, ²¹³ Bi, ²²⁵ Ac, ²³² Th, ¹⁸ F, ¹³¹ I, or ²¹¹ At.