Cytotoxic or radiopharmaceutical compound with sulfur fluoride exchange group

Abstract

A pharmaceutical compound has the structure (A) or (B), wherein - F1 is absent, H or a pharmacokinetic modulator group, - F2 is a substrate ligand of fibroblast activation protein (FAP), - F3 is absent and F2 is conjugated with F4 by a single covalent bond, or F3 is a self-immolative bivalent spacer conjugated with each F2 and F4 by a single covalent bond, or F3 is a self-immolative trivalent spacer conjugated with F2 by a single covalent bond and with F4 by two single covalent bonds, - F4 comprises one or two sulfur fluoride exchange groups, - F5 is absent, a substituted or unsubstituted alkyl or heteroalkyl, a substituted or unsubstituted aryl or heteroaryl, or a FAP ligand, - F6 is absent, a bivalent spacer, or a pharmacokinetic modulator group, and - F7 is absent, a chelator for complexation of a radioisotope, or a leaving group for substitution with a radioisotope.

Description

[0001] - 1 / 91 - rad24 11.12.2024 Cytotoxic or Radiopharmaceutical Compound with Sulfur Fluoride Exchange Group The present invention pertains to a pharmaceutical compound and a radioligand for cancer diagnosis and treatment. The pharmaceutical compound of the invention comprises a sulfur fluoride exchange group ‒ also designated as SuFEx warhead ‒ for irreversible covalent binding in tumor tissue and an initiator group that is enzymatically cleaved by fibroblast activation protein (FAP). Before enzymatic cleavage of the initiator group by pathologically overexpressed FAP, the sulfur fluoride exchange group, respectively the SuFEx warhead is hindered and stabilized against premature hydrolysis under physiological conditions by blood components, such as glutathione (GSH) or albumin. The pharmaceutical compound of the present invention can have the structure ‒ F1 is absent, H or a pharmacokinetic modulator group, ‒ F2 is a substrate ligand of fibroblast activation protein (FAP), ‒ F3 is absent and F2 is conjugated with F4 by a single covalent bond, or F3 is a self- immolative bivalent spacer conjugated with each F2 and F4 by a single covalent bond, or F3 is a self-immolative trivalent spacer conjugated with F2 by a single covalent bond and with F4 by two single covalent bonds, ‒ F4 comprises one or two sulfur fluoride radicals selected independently of one another from the group comprising - 2 / 91 - rad24 11.12.2024 , ‒ F5 is absent, a substituted or unsubstituted alkyl or heteroalkyl, a substituted or unsubstituted aryl or heteroaryl, or a FAP ligand, ‒ F6 is absent, a bivalent spacer, or a pharmacokinetic modulator group, and ‒ F7 is absent, a chelator for complexation of a radioisotope, or a leaving group for substitution with a radioisotope. The compound of the present invention can have a structure selected from the group comprising structures 1A to 20A , , , , , , - 3 / 91 - rad24 11.12.2024 , , , . Upon ligation to FAP, the covalent bond between the FAP ligand F2 and the self-immolative spacer F3 or between F2 and F4 is enzymatically cleaved and a therapeutic agent with structure 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B,17B, 18B, 19B or 20B , , , , - 4 / 91 - rad24 11.12.2024 released. Reference numbers 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A and 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B correspond in such manner that, after cleavage by FAP, compound 1A releases therapeutic agent 1B, compound 2A releases therapeutic agent 2B, compound 3A releases therapeutic agent 3B, … , and compound 20A releases therapeutic agent 20B. Inventive compounds with different structures can release identical therapeutic agents, where 4B = 12B = 19B, 6B = 14B, 7B = 15B, 8B = 16B, 9B = 13B = 17B = 20B, 10B = 18B. Generally, compounds 1A to 20A with high stability under physiological conditions are preferred. Therapeutic agents 1B to 20B comprise a reactive sulfur fluoride group or SuFEx warhead that readily and irreversibly binds to biomolecules in tumor tissue, especially serine proteases. Depending on the structure and physico-chemical properties of groups F5, F6 and F7 therapeutic agents 1B to 20B induce biological or radiological damage in tumor tissue. Biological cytotoxicity is caused by protease inhibition analogously to that of phenylmethylsulfonyl fluoride (PMSF) and 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF). Depending on their chemical structure and function, compounds of the present invention are also designated as "cytotoxic protease inhibitor", "protease inhibitor", "protease inhibitor prodrug", "prodrug", "precursor for complexation of a radioisotope", "precursor", "radioligand" or "radiotracer". Many cancer tumors comprise a tumor micro environment or stroma that surrounds cancer cells (carcinogenic cells). The tumor stroma includes various non-malignant cell types and accounts for up to 90% of the total tumor mass. It plays an important role in the supply of cancer cells as well as in tumor progression and metastasis. Major components of the tumor stroma are the extracellular matrix (ECM), endothelial cells, pericytes, macrophages, immune regulatory cells and activated fibroblasts, commonly referred to as cancer- - 5 / 91 - rad24 11.12.2024 associated fibroblasts (CAFs). During tumor progression, CAFs change their morphology and biological function. These changes are induced by intercellular communication between cancer cells and CAFs. CAFs create an environment that promotes cancer cell growth. It has been shown that therapies which merely target cancer cells are inadequate. Effective therapies must also address the tumor microenvironment and in particular CAFs. In more than 90% of all human epithelial tumors CAFs overexpress fibroblast activation protein (FAP). Contrary thereto, FAP expression in healthy tissue is practically negligible. Hence, FAP constitutes a promising cellular receptor for targeted drug delivery and theranostic radiopharmaceuticals or radioligands. In particular, FAP-targeted cancer drugs are equipped with a suitable cytotoxin or radioistope such as18F,68Ga,177Lu or225Ac. The entire content of all prior art documents cited in this patent application is incorporated by reference. In particular, the chemical synthesis methods described in the cited prior art documents are used directly or in an analogous, suitably adapted manner to prepare the pharmaceutical compounds of the present invention. The role of FAP in vivo is not fully understood, however, it is known to be a serine protease with unique enzymatic activity. It exhibits both dipeptidyl peptidase (DPP) and prolyl oligopeptidase (PREP or POP) activity. Hence, for CAF targeting, substrates and inhibitors of DPP, PREP and FAP come into consideration as homing ligands. A suitable FAP ligand must possess high selectivity over related enzymes, such as dipeptidyl peptidases DPPII, DPPIV, DPP8, DPP9 and homologous prolyl oligopeptidases (PREP) that are ubiquitous in healthy tissue. In order to target CAFs a drug or radioligand is equipped with a ligating moiety or ligand having high binding affinity for FAP. Depending on their interaction FAP-ligands are classified as inhibitors or substrates. Inhibitor ligands bind at the FAP enzymatic cleft for prolonged time periods whereas substrate ligands are efficiently cleaved and subsequently released. The binding, cleavage and dissociation kinetics depend on various factors such as FAP and ligand concentration as well as reaction rate constants, particularly konfor ligation and kofffor dissociation. According to Jiménez-Franco et al., the tumor release rate ‒ or conversely the tumor retention ‒ of a therapeutic radioligand comprising a radioisotope, such as177Lu or225Ac with half-life (t1 / 2) of 6.7 and 9.9 days, determines its therapeutic efficacy (cf. L.D. Jiménez- Franco, G. Glatting, V. Prasad, W.A. Weber, A.J. Beer, P. Kletting; Effect of Tumor Perfusion and Receptor Density on Tumor Control Probability in177Lu-DOTATATE Therapy: An In Silico Analysis for Standard and Optimized Treatment; Journal of Nuclear Medicine January 2021, 62 (1) 92-98; DOI: https: / / doi.org / 10.2967 / jnumed.120.245068). The longer the radioligand remains in the tumor tissue, the greater its therapeutic effectiveness. Accordingly, the prior art endeavors to improve the therapeutic efficacy of FAP-targeted radioligands by endowing them with prolonged "tumor retention" or greater "avidity" and "affinity". Tumor retention and avidity are assessed in vivo or ex vivo via radiological - 6 / 91 - rad24 11.12.2024 measurement of the signal uptake value (SUV) or biodistribution via radio dosimetry of excised tissue. Contrary thereto, affinity is quantified in vitro by enzymatic assay methods and expressed as ratio kon / koff of kinetic rate constants kon and koff for ligation with and dissociation from FAP, respectively. For small molecules, such as prior art radioligands and that of the present invention, kon approaches the diffusion limit of 108M-1·s-1. For irreversibly binding radioligands, such as the radioligands of the invention, koffequals zero and affinity (kon / koff) becomes infinite. Therefore, for the radioligand of the invention affinity is not a meaningful measure for tumor retention and therapeutic potency. In the radioligand of the present invention chemical modification of structural groups F1, F3, F5, F6 and F7 ‒ as opposed to the FAP substrate ligand F2 and the sulfur fluoride group F4 ‒ does not essentially affect their core pharmaceutical function, tumor retention and therapeutic efficacy. Examples of FAP substrate ligands F2 of the invention are shown beneath (a) (b) (c) Examples (a), (b), (c) of characteristic FAP substrate motifs F2 covalently coupled to an optional pharmacokinetic modulator group F1 and an optional self-immolative bivalent spacer F3 with X = H or CH3, Y1= H or F , and Y2= H or F. Small molecule inhibitors and substrates with high affinity and selectivity for FAP are known since 2014 (cf. K. Jansen, L. Heirbaut, R. Verkerk, J.D. Cheng, J. Joossens, P. Cos, L. Maes, A.- M. Lambeir, I. De Meester, K. Augustyns, P. Van der Veken; Extended Structure−Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP); J. Med. Chem.2014 Apr 10; 57(7): 3053–74, DOI 10.1021 / jm500031w; A. De Decker, G. Vliegen, D. Van Rompaey, A. Peeraer, A. Bracke, L. Verckist, K. Jansen, R. Geiss-Friedlander, K. Augustyns, H. De Winter, I. De Meester, A.-M. Lambeir, P. Van der Veken, Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP), ACS Med. Chem. Lett.2019, 10, 8, 1173–1179). These ligands comprise a modified glycine-proline unit and therewith coupled quinoline group. Theranostic radiopharmaceuticals or radioligands consist of a precursor compound and a therewith conjugated or complexed radioisotope such as18F and68Ga or177Lu. The precursor compound comprises a ligand for a relevant cellular receptor such as somatostatin receptor 2 (SSR2), prostate specific membrane antigen (PSMA) or FAP. - 7 / 91 - rad24 11.12.2024 For labeling with radioisotopes such as64Ga and177Lu the precursor compound also includes a chelator such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 6-amino-1,4-diazepine-triacetic acid (DATA). For cancer radioendotherapy FAP-targeted radioligands comprising a highly ionizing beta- or α-emitter such as177Lu or225Ac with half-life (t1 / 2) of 6.7 and 9.9 days, respectively, constitute promising treatment modalities. Various radioligands comprising one or more PSMA or FAP inhibitor-homing-ligands conjugated with a chelator such as DOTA or DATA for complexation of radioisotopes such as68Ga and177Lu are known in the prior art. Banerjee et al. propose multivalent radioligand compounds comprising a DOTA chelator and two or more therewith conjugated PSMA inhibitor ligands (cf. S.R. Banerjee, M. Pullamb- hatla, H. Shallal, A. Lisok, R.C. Mease, M.G. Pomper; A Modular Strategy to Prepare Multivalent Inhibitors of Prostate-Specific Membrane Antigen (PSMA); Oncotarget 2011; 2: 1244 - 1253; doi: 10.18632 / oncotarget.415). Known FAP inhibitors feature a C-terminal reactive functionality, such as carbonitrile which covalently binds to the hydroxyl group of the catalytic serine (Ser624) of FAP. However, these molecules form a transient covalent bond with FAP that is hydrolyzed after a short time, commonly quantified via the dissociation rate koff. Accordingly, known FAP inhibitors detach from their target receptor FAP and are subsequently washed out from tumor tissue. WO 2019 / 083990 A2 discloses a compound of formula B‒L‒A, wherein B is a targeting ligand for FAP-α, B is a radiolabeled functional group suitable for PET imaging or radiotherapy and L is a linker having bi-functionalization adapted to form a chemical bond with B and A. WO 2019 / 154886 A1 pertains to radioligands comprising FAP-ligands, such as FAPI-46 (CAS No.2374782-04-2). WO 2021 / 016392 A1 and WO 2022 / 258637 A1 are directed to multivalent FAP-targeted imaging and treatment agents for cancers and other fibrotic diseases. WO 2019 / 083990 A2 (pages 48-51), WO 2019 / 154886 A1 (pages 61-75), WO 2021 / 016392 A1 (pages 63-71) and WO 2022 / 258637 A1 (pages 37-49) describe synthesis methods, which in conjunction with Examples 1 and 2 of the present application enable the skilled person to prepare the precursors of the invention. Accordingly, the disclosure of WO 2019 / 083990 A2 (pages 48-51), WO 2019 / 154886 A1 (pages 61-75), WO 2021 / 016392 A1 (pages 63-71) and WO 2022 / 258637 A1 (pages 37-49) is incorporated by reference. Sulfonyl fluoride electrophiles have found significant utility as reactive probes in chemical biology and molecular pharmacology. As warheads they possess the right balance of biocompatibility (including aqueous stability) and protein reactivity. Their functionality is privileged in this regard as they are known to modify not only reactive serines (resulting in their common use as protease inhibitors), but also context-specific threonine, lysine, - 8 / 91 - rad24 11.12.2024 tyrosine, cysteine and histidine residues (cf. A. Narayanan, L.H. Jones; Sulfonyl fluorides as privileged warheads in chemical biology; Chem. Sci., 2015, 6, 2650). Protease inhibitors phenylmethylsulfonyl fluoride (PMSF) and 4-(2-aminoethyl)-benzene- sulfonyl fluoride (AEBSF) are potent cytotoxins. Due to their cytotoxicity and metabolic instability they are not suitable for therapeutic use. The present invention harnesses a FAP-cleavable substrate F2 in conjunction with a sulfur fluoride group F4 for the design of metabolically stable and FAP-activatable prodrug compounds containing a payload that is either a cytotoxic protease inhibitor or a radioisotope. Methods for synthesis of compounds that contain a sulfur fluoride group are described in: ‒ X. Wu, W. Zhang, G. Sun, X. Zou, X. Sang, Y. He, B. Gao; Turning sulfonyl and sulfonimidoyl fluoride electrophiles into sulfur(VI) radicals for alkene ligation; Nature Communications (2023) 14:5168; https: / / doi.org / 10.1038 / s41467-023-40615-0; ‒ D.-D. Liang, D.E. Streefkerk, D. Jordaan, J. Wagemakers, J. Baggerman, H. Zuilhof; Silicon- Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope, Enantioselectivity, and Mechanism; Angew. Chem. Int. Ed.2020, 59, 7494 – 7500; https: / / doi.org / 10.1002 / anie.201915519. The disclosure of the above cited articles by Wu et al. and Liang et al. and particularly the therewith associated supporting information is incorporated by reference in the present patent application. Known drugs for chemotherapy and radioligand therapy (RLT) warrant further improvement of their therapeutic index, in particular the ratio of tumor to whole-body dose. Accordingly, the present invention has the object to provide pharmaceutical compounds that enable efficient and selective delivery of cytotoxic protease inhibitors or radioisotopes to tumor tissue. For cytotoxic protease inhibitors and radioisotopes, respectively radioligands high tumor uptake, prolonged tumor retention and increased ratio of tumor- absorbed to whole-body-absorbed dose are sought. This object is achieved through a pharmaceutical compound having the structure , wherein ‒ F1 is absent, H or a pharmacokinetic modulator group, ‒ F2 is a substrate ligand of fibroblast activation protein (FAP), ‒ F3 is absent and F2 is conjugated with F4 by a single covalent bond, or F3 is a self- immolative bivalent spacer conjugated with each F2 and F4 by a single covalent bond, or F3 is a self-immolative trivalent spacer conjugated with F2 by a single covalent bond and with F4 by two single covalent bonds, - 9 / 91 - rad24 11.12.2024 ‒ F4 comprises one or two sulfur fluoride radicals selected independently of one another from the group comprising ‒ F5 is absent, a substituted or unsubstituted alkyl or heteroalkyl, a substituted or unsubstituted aryl or heteroaryl, or a FAP ligand, ‒ F6 is absent, a bivalent spacer, or a pharmacokinetic modulator group, and ‒ F7 is absent, a chelator for complexation of a radioisotope, or a leaving group for substitution with a radioisotope. Expedient embodiments of the precursor compound of the invention are characterized by one of the following features or a combination of two or more of the following features insofar the combined features are not mutually exclusive or contradictory and according to which: ‒ F1 is absent; ‒ F1 is H; ‒ F1 comprises a naphthol radical having the structure ; - 10 / 91 - rad24 11.12.2024 ‒ F1 comprises a radical having the structure wherein the terminal amine group (‒NH‒) is coupled to F2; ‒ F1 comprises a radical having the structure wherein the terminal amine group (‒NH‒) is coupled to F2; ‒ F1 comprises a radical having the structure wherein the terminal amine group (‒NH‒) is coupled to F2 and l = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; - 11 / 91 - rad24 11.12.2024 ‒ F1 is a radical having the structure wherein the terminal amine group (‒NH‒) is coupled to F2 and l = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F1 comprises a radical of type ‒[CH2]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F1 comprises a radical of type ‒(NH)‒[CH2]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F1 comprises a radical of type ‒(NH)‒[CH2]p‒(NH)‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F1 comprises a radical of type ‒[CH2CH2O]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F1 comprises a radical of type ‒(NH)‒[ CH2CH2O]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F1 comprises a radical of type ‒(NH)‒[ CH2CH2O]p‒(NH)‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F1 comprises a radical of ethylene diamine having the structure ; ‒ F1 comprises a radical having the structure ; - 12 / 91 - rad24 11.12.2024 – F1 comprises a radical of a peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids independently selected from the group comprising Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA or γ-Aminobutyric acid, Homoserine, DOPA or 3,4-Dihydroxyphenyl- alanine, Citrulline, β-Alanine and Thyroxine; – F1 comprises a phenylalanine radical; – F1 comprises a radical having the structure ; – F1 comprises an N,N-dimethylarginine radical; – F1 comprises a radical having the structure ; – F1 comprises a radical having the structure ; - 13 / 91 - rad24 11.12.2024 – F1 comprises a radical having the structure ; – F1 comprises a radical having the structure ; – F1 comprises a radical having the structure wherein ‒ each Piis present for 1 ≤ i ≤ k and absent for i > k with k = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; ‒ each Qjis present for 1 ≤ j ≤ h and absent for j > h with h = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; ‒ each Pswith s = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, if present, independently of one another is selected from the group comprising ‒CH2‒, ‒CH2CH2O‒, ‒N(H)‒ , ‒N(CH3)‒, ‒O‒, ‒S‒, ‒C(O)‒ and ‒C(CH3)‒ ; ‒ each Qtwith t = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, if present, independently of one another is selected from the group comprising ‒CH2‒, ‒CH2CH2O‒, ‒N(H)‒, ‒N(CH3)‒, ‒O‒, ‒S‒, ‒C(O)‒ and ‒C(CH3)‒ ; - 14 / 91 - rad24 11.12.2024 ‒ T is absent or a radical selected from the group comprising , ; ‒ F1 comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty- eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine or forty linearly conjugated radicals selected independently of one another from the group comprising ‒CH2‒ , ‒C(=O)‒ , ‒CH(‒CH3)‒ , ‒CH(‒CH2COOH)‒ , ‒CH=CH‒ , ‒NH‒ , ‒N(‒CH3)‒ , ‒O‒ , ‒CH2CH2O‒ and radicals of C4‒C10 aryl or heteroaryl, substituted C4‒C10 aryl or heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids; – F1 comprises a terminal radical selected from –H, –OH, –CH3 or –NH2 ; ‒ F2 is a radical selected from the group comprising , , wherein X = –H or –CH3 , Y1= –H or –F , Y2= –H or –F , and Z is a radical selected from the group comprising - 15 / 91 - rad24 11.12.2024 , , , , ; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; - 16 / 91 - rad24 11.12.2024 ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4;

[0002] - 17 / 91 - rad24 11.12.2024 ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; - 18 / 91 - rad24 11.12.2024 ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F2 comprises a radical having the structure wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; - 19 / 91 - rad24 11.12.2024 ‒ F1 and F2 are covalently coupled and comprise a radical having the structure ; wherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; ‒ F1 and F2 are covalently coupled and comprise a radical having the structure ; ‒ F3 comprises an amine group (‒NH‒) covalently coupled to F2; ‒ F3 comprises a terminal amine (‒NH‒) covalently coupled to F2; ‒ F3 comprises a radical having the structure wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2; ‒ F3 comprises a radical having the structure wherein the terminal oxy group (‒O‒) is oriented toward F2; - 20 / 91 - rad24 11.12.2024 ‒ F3 comprises a radical having the structure wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2 and B1 is a radical selected from the group comprising , , ‒ F3 comprises a radical having the structure wherein the terminal oxy group (‒O‒) is oriented toward F2 and B1 is a radical selected from the group comprising , , ‒ F3 comprises a radical selected from the group comprising , - 21 / 91 - rad24 11.12.2024 , , , wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2; ‒ F3 comprises a radical having the structure , wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2; ‒ F3 comprises a radical having the structure , wherein the terminal oxy group (‒O‒) is oriented toward F2; ‒ F3 comprises a radical having the structure wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2 and B2 is a radical selected from the group comprising - 22 / 91 - rad24 11.12.2024 , , ‒ F3 comprises a radical having the structure , wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2; ‒ F3 comprises a radical having the structure , wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2; ‒ F3 comprises a radical having the structure , wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2; ‒ F3 comprises a radical having the structure - 23 / 91 - rad24 11.12.2024 wherein the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2 and B2 is a radical selected from the group comprising , , ‒ F3 comprises a radical having the structure , wherein R10is OH or a pharmacokinetic modulator group and the terminal amine (‒NH‒) is oriented toward F2 or covalently coupled to F2; ‒ R10is a pharmacokinetic modulator group comprising one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty- five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine or forty linearly conjugated radicals selected independently of one another from the group comprising ‒CH2‒ , ‒C(=O)‒ , ‒CH(‒CH3)‒ , ‒CH(‒CH2COOH)‒ , ‒CH=CH‒ , ‒NH‒ , ‒N(‒CH3)‒ , ‒O‒ , ‒CH2CH2O‒ and radicals of C4‒C10 aryl or heteroaryl, substituted C4‒C10aryl or heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids; ‒ F3 comprises a self-immolative spacer extension conjugated to F2; ‒ F3 comprises a self-immolative spacer extension conjugated to F4; ‒ F3 comprises a self-immolative spacer extension comprising one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve linearly conjugated radicals selected - 24 / 91 - rad24 11.12.2024 independently of one another from the group comprising ‒CH2‒ , ‒C(=O)‒ , ‒CH(‒CH3)‒ , ‒NH‒ , ‒N(‒CH3)‒ and ‒O‒ ; ‒ F3 comprises a self-immolative spacer extension having the structure ‒ F3 comprises a radical having the structure , wherein the terminal amine (‒NH‒) is covalently coupled to F2 or oriented toward F2; ‒ F3 comprises a radical having the structure , wherein the terminal oxy group (‒O‒) is oriented toward F2; ‒ F4 is a radical having the structure , wherein ‒ S' and S" independently of one another are absent or bivalent spacers comprising one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, - 25 / 91 - rad24 11.12.2024 fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty linearly conjugated radicals selected independently of one another from the group comprising ‒CH2‒ , ‒C(=O)‒ , ‒CH(‒CH3)‒ , ‒CH(‒CH2COOH)‒ , ‒CH=CH‒ , ‒NH‒ , ‒N(‒CH3)‒ , ‒O‒ and ‒CH2CH2O‒ , and radicals of C4‒C10 aryl or heteroaryl, substituted C4‒C10 aryl or heteroaryl, ‒ F', F" are each a sulfur fluoride radical selected independently of one another from the group comprising and – TL is a trivalent linker selected from the group comprising radicals of an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alcohol, aminoalkylcarboxylic acid, dipeptide or tripeptide, or TL is a trivalent linker selected from the group of radicals comprising , , - 26 / 91 - rad24 11.12.2024 ; ‒ F3 and F4 are covalently coupled and comprise a radical having the structure ‒ S' and S" independently of one another are absent or bivalent spacers comprising one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty linearly conjugated radicals selected independently of one another from the group comprising ‒CH2‒ , ‒C(=O)‒ , ‒CH(‒CH3)‒ , ‒CH(‒CH2COOH)‒ , ‒CH=CH‒ , ‒NH‒ , ‒N(‒CH3)‒ , ‒O‒ and ‒CH2CH2O‒ , and radicals of C4‒C10 aryl or heteroaryl, substituted C4‒C10aryl or heteroaryl, ‒ F', F" are each a sulfur fluoride radical selected independently of one another from the group comprising - 27 / 91 - rad24 11.12.2024 and – TL is a trivalent linker selected from the group comprising radicals of an alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alcohol, aminoalkylcarboxylic acid, dipeptide or tripeptide, or TL is a trivalent linker selected from the group of radicals comprising , , ; ‒ F3 and F4 are covalently coupled and comprise a radical having the structure ; - 28 / 91 - rad24 11.12.2024 ‒ F3 and F4 are covalently coupled and comprise a radical having the structure ; ‒ F3 and F4 are covalently coupled and comprise a radical having the structure , wherein m = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F3 and F4 are covalently coupled and comprise a radical having the structure , wherein m = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; - 29 / 91 - rad24 11.12.2024 ‒ F3 and F4 are covalently coupled and comprise a radical having the structure ; ‒ F3 and F4 are covalently coupled and comprise a radical having the structure ; ‒ F3 and F4 are covalently coupled and comprise a radical having the structure ; ‒ F5 is a substituted or unsubstituted C1 to C12 alkyl or heteroalkyl; ‒ F5 is a substituted or unsubstituted C4to C10aryl or heteroaryl; ‒ F5 is a FAP substrate ligand; ‒ F5 is ‒[CH2]v‒ with v = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; ‒ F5 is ‒CH=CH[CH2]v‒ with v = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; ‒ F5 is ‒CH2CH=CH[CH2]v‒ with v = 1, 2, 3, 4, 5, 6, 7, 8 or 9; ‒ F5 is ‒O[CH2]v‒ with v = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; - 30 / 91 - rad24 11.12.2024 ‒ F5 is ‒NH[CH2]v‒ with v = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; ‒ F5 is a radical selected from the group comprising , ‒ F5 is a radical selected from the group comprising , wherein X = –H or –CH3 , Y1= –H or –F , Y2= –H or –F , the pyrrolidine group is covalently coupled to F4 and Z is a radical selected from the group comprising , , , - 31 / 91 - rad24 11.12.2024 , ‒ wherein the quinoline group is covalently coupled to F6 or F7; ‒ F5 has the structure wherein the quinolinoxy group is covalently coupled to F6 or F7; ‒ F5 has the structure wherein the quinolinamine group is covalently coupled to F6 or F7; - 32 / 91 - rad24 11.12.2024 ‒ F5 has the structure wherein the quinolinamine group is covalently coupled to F6 or F7; ‒ F5 has the structure wherein the quinoline group is covalently coupled to F6 or F7; ‒ F5 has the structure wherein the quinoline group is covalently coupled to F6 or F7; - 33 / 91 - rad24 11.12.2024 ‒ F5 has the structure wherein the quinoline group is covalently coupled to F6 or F7; ‒ F5 has the structure wherein the quinoline group is covalently coupled to F6 or F7; ‒ F5 has the structure wherein the quinolinoxy group is covalently coupled to F6 or F7; - 34 / 91 - rad24 11.12.2024 ‒ F5 has the structure wherein the quinolinamine group is covalently coupled to F6 or F7; ‒ F5 has the structure wherein the quinolinamine group is covalently coupled to F6 or F7; ‒ F5 and F6 are covalently coupled and comprise a radical having the structure ; - 35 / 91 - rad24 11.12.2024 ‒ F5 and F6 are covalently coupled and comprise a radical having the structure ; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; - 36 / 91 - rad24 11.12.2024 ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; - 37 / 91 - rad24 11.12.2024 ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; - 38 / 91 - rad24 11.12.2024 ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; ‒ F3, F4 and F5 are covalently coupled and comprise a radical having the structure wherein the terminal amine is covalently coupled to F2; – F6 is –H, –OH, =O, –CH3, =NH or –NH2; ‒ F6 comprises a radical having the structure ‒[CH2]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F6 comprises a radical having the structure ‒(NH)‒[CH2]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F6 comprises a radical having the structure ‒(NH)‒[CH2]p‒(NH)‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F6 comprises a radical having the structure ‒[CH2CH2O]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F6 comprises a radical having the structure ‒(NH)‒[ CH2CH2O]p‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F6 comprises a radical having the structure ‒(NH)‒[ CH2CH2O]p‒(NH)‒ with p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; – F6 comprises a radical of a peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids selected independently of one another from the group comprising Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA or γ-Aminobutyric acid, Homoserine, DOPA or 3,4-Dihydroxyphenylalanine, Citrulline, β-Alanine and Thyroxine; - 39 / 91 - rad24 11.12.2024 ‒ F6 comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty- eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine or forty linearly conjugated radicals selected independently of one another from the group comprising ‒CH2‒ , ‒C(=O)‒ , ‒CH(‒CH3)‒ , ‒CH(‒CH2COOH)‒ , ‒CH=CH‒ , ‒NH‒ , ‒N(‒CH3)‒ , ‒O‒ , ‒CH2CH2O‒ and radicals of C4‒C10aryl or heteroaryl, substituted C4‒C10aryl or heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids; – F6 comprises a phenylalanine radical; ‒ F6 comprises a naphthol radical having the structure ; ‒ F6 comprises a radical having the structure ; ‒ F6 comprises a radical having the structure wherein the terminal amine group (‒NH‒) is coupled to F2; - 40 / 91 - rad24 11.12.2024 ‒ F6 comprises a radical having the structure wherein the terminal amine group (‒NH‒) is coupled to F2 and l = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; ‒ F6 has the structure wherein the terminal amine group (‒NH‒) is coupled to F2 and l = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; – F6 comprises a radical having the structure

[0003] - 41 / 91 - rad24 11.12.2024 – F6 comprises an N,N-dimethylarginine radical; – F6 comprises a radical having the structure – F6 comprises a radical having the structure – F6 comprises a radical having the structure - 42 / 91 - rad24 11.12.2024 – F6 comprises a radical having the structure ; – F6 comprises a radical having the structure wherein ‒ each Piis present for 1 ≤ i ≤ k and absent for i > k with k = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; ‒ each Qjis present for 1 ≤ j ≤ h and absent for j > h with h = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; ‒ each Pswith s = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, if present, independently of one another is selected from the group comprising ‒CH2‒, ‒CH2CH2O‒, ‒N(H)‒ , ‒N(CH3)‒, ‒O‒, ‒S‒, ‒C(O)‒ and ‒C(CH3)‒ ; ‒ each Qtwith t = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, if present, independently of one another is selected from the group comprising ‒CH2‒, ‒CH2CH2O‒, ‒N(H)‒, ‒N(CH3)‒, ‒O‒, ‒S‒, ‒C(O)‒ and ‒C(CH3)‒ ; ‒ T is absent or a radical selected from the group comprising , ; ‒ F6 comprises an ethylene diamine radical having the structure ; - 43 / 91 - rad24 11.12.2024 ‒ F6 comprises a radical having the structure ; ‒ F7 comprises a radical selected from the group comprising , , wherein F1 is ‒OH or ‒NH2, F2 is ‒OH or ‒NH2, F3 is ‒OH or ‒NH2, F4 is ‒OH or ‒NH2; ‒ F7 comprises a radical selected from the group comprising , - 44 / 91 - rad24 11.12.2024 , wherein F1 is ‒OH or ‒NH2, F2 is ‒OH or ‒NH2, F3 is ‒OH or ‒NH2, F4 is ‒OH or ‒NH2, and at least one of F1, F2 and F3 is ‒NH2 or at least one of F1, F2, F3 and F4 is ‒NH2 ; ‒ F7 comprises a radical selected from the group comprising radicals (I), (II), (III), (IV), (V) and (VI) with (III) (IV) - 45 / 91 - rad24 11.12.2024 ‒ the precursor compound comprises a chelator radical selected from the group comprising

[0004] - 46 / 91 - rad24 11.12.2024 ; – F7 comprises a radical selected from the group comprising radicals (XI), (XII), (XIII) and (XIV) with (XIII) (XIV)

[0005] - 47 / 91 - rad24 11.12.2024 ‒ F7 comprises a radical selected from the group comprising radicals (VII), (VIII), (IX) and (X) with ‒ F7 comprises a radical having the structure (XV) wherein D1is ‒H, ‒CH3 or ‒NH2 ; – F7 is a chelator selected from the group comprising H4pypa, EDTA (Ethylenediamine tetraacetate), EDTMP (Ethylenediaminetetra(methylenephosphonic acid)), DTPA (Diethylenetriamine pentaacetate) and derivatives thereof, NOTA (1,4,7-triazacyclo- nonane-1,4,7-triacetic acid) and derivatives thereof, such as NODAGA (1,4,7-triazacyclo- nonane,1-glutaric acid-4,7-acetic acid), TRAP (Triazacyclononane-phosphinic acid), NOPO (1,4,7-triazacyclononane-1,4-bis[methylene-(hydroxymethyl)-phosphinic acid]-7-[meth- ylene-(2-carboxyethyl)-phosphinic acid]), DOTPH(1,4,7,10-tetraazacyclododecane- - 48 / 91 - rad24 11.12.2024 1,4,7,10-tetrakis[methylenephosphinic acid]) and derivatives thereof, such as DOTPI (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethylphosphinic acid)]) and DOTPI(azid)4, TRITA (Trideca-1,4,7,10-tetraamine-tetraacetate), TETA (Tetradeca-1,4,8,11-tetraamine-tetraacetate) and derivatives thereof, PEPA (Pentadeca- 1,4,7,10,13-pentaamine pentaacetate), HEHA (Hexadeca-1,4,7,10,13,16-hexaamine- hexaacetate) and derivatives thereof, HBED (N,N'-Bis-(2-hydroxybenzyl)ethylene- diamine-N,N'-diacetate) and derivatives thereof such as HBED-CC (N,N'-Bis-[2-hydroxy-5- carboxyethyl)benzyl)ethylene-diamine-N,N'-diacetate), DEDPA and derivatives thereof, such as H2dedpa (1,2-[[6-(Carboxyl)pyridine-2-yl]methylamine]ethane) and H4octapa (1,2-[[6-(Carboxyl)pyridine-2-yl]methylamine]ethane-N,N'-diacetate), DFO (Deferox- amine) and derivatives thereof, Trishydroxypyridinone (THP) and derivatives thereof, such as H3THP-Ac and H3THP-mal (YM103), TEAP (Tetraazycyclodecane-phosphinic acid) and derivatives thereof, Sarcophagin SAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaaza- bicyclo[6.6.6]-eicosan-1,8-diamine) and derivatives thereof, such as (NH2)2SAR (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 N4-derivates, PnAO (6-(4-Isothiocyanatobenzyl)-3,3,9,9,-tetramethyl-4,8-diaza-undecane-2,10-dione- dioxime) and derivatives thereof, such as BMS181321 (3,3‘-(1,4-Butanediyldiamino)- bis(3-methyl-2-butanone)dioxime), MAG2 (Mercaptoacetyl-glycyl-glycine) and derivatives thereof, MAG3 (Mercaptoacetyl-glycyl-glycyl-glycine) and derivatives thereof, such as N3S-adipate, MAS3 (Mercaptoacetyl-seryl-seryl-serine) and derivatives thereof, MAMA (N-(2-Mercaptoethyl)-2-[(2-mercaptoethyl)amino]acetamide) and derivatives thereof, EC (Ethylene dicysteine) and derivatives thereof, dmsa (Dimercaptosuccinic acid) and derivatives thereof, DADT (Diamine dithiol), DADS (Diamine disulfide), N2S2-chelators and derivatives thereof, Aminothiol and derivatives thereof; salts of the preceding chelators; HYNIC (Hydrazinonicotinamide) and derivatives thereof; – F7 is a leaving group for substitution with a radioisotope selected from the group comprising dinitrogen, dialkyl ether, perfluoroalkylsulfonates, triflate, iodide, tosylates, mesylates, sulfonates, bromide, hydrogen, alcohols, chloride, nitrate, phosphate, inorganic esters, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, hydroxide, alkoxides, amides, hydride, arenide, alkanide and sulfur fluorides. The invention has the further object to provide a radioligand for cancer diagnosis and treatment. This object is achieved through ‒ a radioligand comprised of any of the above described precursor compounds including a chelator and a therewith complexed radioisotope or radioactive compound selected from the group comprising44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y, - 49 / 91 - rad24 11.12.2024 ‒ a radioligand comprised of any of the above described precursor compounds wherein a leaving group F7 is substituted with18F,131I or211At. Expedient embodiments of the radioligand of the invention are characterized by one of the following features or a combination of the following features insofar the combined features are not mutually exclusive or contradictory and according to which: – the radioisotope is68Ga; – the radioisotope is177Lu; – the radioisotope is225Ac; – the radioisotope is212Pb; – the radioisotope is161Tb; – the radioisotope is64Cu or67Cu; – the radioactive compound is18FAl (aluminum fluoride); – the radioligand comprises a chelator radical having the structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) and a therewith complexed radioisotope selected from the group comprising44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,90Nb, 111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,212Pb,213Bi and 225Ac; – the radioligand comprises a chelator radical having the structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) and a therewith complexed radioisotope selected from the group comprising68Ga,161Tb,177Lu,212Pb and225Ac; – the radioligand comprises a chelator radical having the structure (XI), (XII), (XIII) or (XIV) and therewith complexed radioactive compound18FAl (aluminum fluoride); – the radioligand comprises a chelator radical having the structure (XV) and therewith complexed radioisotope64Cu or67Cu. The compound according to the present invention comprises a sulfur fluoride group F4 that is bound to and sterically hindered by either the self-immolative spacer F3 or the FAP substrate ligand F2. Upon ligation to FAP the substrate ligand F2 is enzymatically cleaved from either F3 or F4. If present, the self-immolative spacer F3 disassembles and dissociates from F4. In either case an active compound of type F4‒F5, F4‒F5‒F6 or F4‒F5‒F6‒F7 with a terminal, sterically unhindered and highly reactive sulfur fluoride group F4 is released. Subsequently, the fluorine ion (F‒) of the terminal sulfur fluoride group F4 is readily abstracted by a nucleophile, such as the O‒radical of a serine hydroxy group. This promotes formation of a permanent covalent bond between the terminal sulfur radical and an amino acid nucleophilic radical. Therefore, when activated by FAP, the resulting protease inhibitor - 50 / 91 - rad24 11.12.2024 or radioligand remains in the tumor tissue for an extended time period and exerts its inhibitory or radiological cytotoxicity. The basic concept of the invention is illustrated in the beneath scheme which depicts an exemplary radioligand comprised of FAP substrate F2 (N-[2-[(2S)-2-carbonyl-4,4- difluoropyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide), self-immolative spacer F3 (7-amino-3-ethyl-2H-1-benzopyran-2-one or alternatively 7-amino-3-(propan-2-yl)-2H-1- benzopyran-2-one radical), methylsulfonimidoyl fluoride (‒CH2S(F)(=O)=N‒) group F4, phenyl radical F5, bivalent spacer F6 (5-acetamido-N-ethylpentanamide), DOTA-chelator F7 and a therewith complexed radioisotope177Lu3+. The self-immolative spacer F3 sterically hinders the methylsulfonimidoyl fluoride group F4 and protects it from hydrolysis under physiological conditions by glutathione (GSH) and proteins such as albumin, which are abundant in plasma. In diseased tissue with significant pathologic FAP expression F2 is (a) enzymatically cleaved which effects self-immolative release (b) of the moiety F4‒F5‒F6‒F7 and the therewith complexed radioisotope177Lu3+. Dissociation (c) of the F4‒F5‒F6‒F7[177Lu3+] moiety from F3 abrogates steric hindrance of the terminal methylsulfonimidoyl fluoride (‒CH2S(F)(=O)=NH) group F4 and renders it reactive. Subsequently, the methylsulfonimidoyl fluoride group F4 readily forms an irreversible covalent bond (d) with various amino acid residues. Thereby, the radioactive payload177Lu3+is retained in tumor tissue for an extended time period. The prodrug compound of the invention protects the sulfonimidoyl fluoride group ( ‒S(F)(=O)(=NH)‒ ) against premature reaction with blood components, such as glutathione (GSH) or albumin. This enables proper systemic circulation and extravasation into tumor tissue with significant FAP-overexpression. FAP-induced cleavage of the FAP substrate F2 - 51 / 91 - rad24 11.12.2024 and subsequent dissociation of the self-immolative spacer F3 exposes the highly reactive methylsulfonimidoyl fluoride group F4 to biomolecules, in particular serine proteases, and leads to formation of an irreversible covalent bonds. Thereby the cleavage product F4‒F5‒F6‒F7[177Lu3+] , comprised of the methylsulfonimidoyl fluoride group F4, phenyl residue F5, bivalent spacer F6, DOTA-chelator F7 and therewith complexed radioisotope177Lu3+are retained in tumor tissue for extended time periods. In the compound of the present invention the optional group F1 and the optional bivalent spacer F6 mainly serve as pharmacokinetic modulator and steric spacer between the sulfon- imidoyl fluoride carrying residue F4‒F5‒ and the DOTA-chelator ‒F7, respectively. Notwithstanding, the bivalent spacer F6 can also be readily configured to adapt pharmaco- kinetic properties, such as hydrophilicity, logP and logD in a wide range. In cases where F1 is absent or optimized for efficient ligation of F2 to FAP, the bivalent spacer F6 can be configured in a manner that compensates incidental shortcomings of F1 with regard to pharmacokinetics. The same applies for pharmacokinetic deficiencies attributable to one or more of groups F2, F3, F4, F5, F7. Pharmacokinetic adaptation of F1 and / or F6 does not interfere with the principal chemical function of either F2, F3, F4, F5 or F7. Numerous chelators for complexation of radioisotopes, in particular chelators based on the DOTA- and DATA-scaffold, are readily available from commercial vendors (e.g. https: / / www.macrocyclics.com / ). Many of the commercially available chelators comprise a terminal OH‒ or NH2‒group for facile coupling with a linker (cf. Example 7). Likewise, a large variety of heterobifunctional linkers are commercially available either as ready-made compound, crosslinking kit or service (e.g. from https: / / www.carbolution.de / , https: / / bezwadabiomedical.com / , https: / / broadpharm.com, https: / / p3bio.com / amino- acids / fmoc-amino-acids / , https: / / www.thermofisher.com, https: / / www.profacgen.com). Some vendors offer comprehensive libraries of Fmoc- and tBu-protected amino acids. The Crosslinking Technical Handbook, ThermoFisher® Scientific (2022; https: / / assets.thermo- fisher.com / TFS-Assets / BID / Handbooks / bioconjugation-technical-handbook.pdf) describes numerous linker chemistries and bioconjugation strategies. The synthesis of a FAP substrate according to the present invention is illustrated beneath in Example 1. Auxiliary methods for covalent bond formation between F6 and a chelator F7 or group F4 are presented in Examples 2 and 3. If required, methoxy groups may be dealkylated using known protocols such as described in S.A. Weissman, D. Zewge; Recent advances in ether dealkylation; Tetrahedron 61 (2005) 7833-7863; and A. Boto, D. Hernández, R. Hernández, E. Suárez; Selective Cleavage of Methoxy Protecting Groups in Carbohydrates; J. Org. Chem.2006, 71, 1938-1948. - 52 / 91 - rad24 11.12.2024 In the present invention ‒ the term "radical" refers to a monovalent, bivalent, trivalent or multivalent atom, molecule, residue, chemical group, chemical unit, chemical structure or chemical moiety that is covalently coupled to or covalently conjugated with one, two, three or more radicals of atoms, molecules, chemical groups, chemical units, chemical structures or chemical moieties of the same or different types; ‒ the terms "sulfur fluoride exchange group", "SuFEx warhead" and "sulfur fluoride radical" are used interchangeably and refer to a chemical unit comprising a radical of type ; ‒ radicals can be conjugated by one, two, three or more single covalent bonds, each with two shared electrons, or by one, two, three or more double covalent bonds, each with four shared electrons; ‒ radicals of atoms, molecules, chemical groups or chemical units are specified by structural formulas or by letters, digits, brackets, hyphens and equal signs; ‒ unless otherwise indicated, the symbols C, F, H, N and S have their usual meaning according to standard chemical notation and refer to a carbon, fluorine, hydrogen, nitrogen or sulfur atom or radical; ‒ radicals can also be denoted by symbols and hyphens, for example ‒NH‒ or ‒NH2 for amine radicals, ‒CH2‒ for methylen radicals, and ‒CO‒ , ‒C(O)‒ , ‒C=O‒ , ‒O=C‒ , ‒C(=O)‒ or ‒O(=C)‒ for carbonyl radicals, wherein a terminal hyphen corresponds to one shared electron of a single covalent bond or one "half" of a single covalent bond, and a terminal equal sign corresponds to two shared electrons of a double covalent bond or one "half" of a double covalent bond; ‒ the terms "radioligand" and "radiotracer" have the same meaning and are used interchangeably. EXAMPLES The general synthetic pathway outlined beneath in Scheme 1 rests on: A. De Decker, G. Vliegen, D. Van Rompaey, A. Peeraer, A. Bracke, L. Verckist, K. Jansen, R. Geiss-Friedlander, K. Augustyns, H. De Winter, I. De Meester, A.-M. Lambeir, - 53 / 91 - rad24 11.12.2024 P. Van der Veken, Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP), ACS Med. Chem. Lett.2019, 10, 8, 1173–1179). X = H or F , Xaa = Gly or D-Ala , LP = residue of self-immolative linker with protecting group Scheme 1: Synthesis of FAP-cleavable moiety and self-immolative linker conjugate Commercially available compound 1 (i.e. Boc-L-proline or Boc-4,4-difluoro-L-proline) is coupled with protected self-immolative linker precursor NH2‒LP (see also Example 2). Resulting compound 2 is deprotected to obtain intermediate 3. The latter is coupled to Boc- protected D-alanine or glycine, thus, yielding protected conjugate 4. Acidolytic deprotection of compound 4 yields intermediate 5, from which conjugate 6 is synthesized by acylating the free amine group with quinoline-4-carboxylic acid. Reagents and conditions: (a) 1-chloro-N,N,2-trimethyl-1-propenylamine TEA, DCM:THF (1:1), rt; (b) HCl or TFA, DCM, rt; (c) Boc-Xaa, T3P, DIPEA, DCM, rt; (d) TFA, DCM, rt; (e) quinoline-4-carboxylic acid, T3P, DIPEA, DCM. As illustrated in Scheme 1 the self-immolative linker precursor NH2-LP can be readily prepared from commericially available 6-Amino-2-oxochromene-3-carboxylic acid (CAS no.91587-88-1) through reduction with LiAlH4. - 54 / 91 - rad24 11.12.2024 The synthesis outlined beneath in Scheme 2 is based on: R. Weinstain, E. Segal, R. Satchi-Fainarob, D. Shabat; Real-time monitoring of drug release; Chem. Commun., 2010, 46, 553–555; and N.C. Lim, J.V. Schuster, M.C. Porto, M.A. Tanudra, L. Yao, H.C. Freake, C. Brückner; Coumarin- Based Chemosensors for Zinc(II): Toward the Determination of the Design Algorithm for CHEF-Type and Ratiometric Probes; Inorganic Chemistry, 2005, Vol.44, No.6, 2018-2030. Scheme 2: Synthesis of coumarin-based self-immolative linker and conjugation with FAP-cleavable moiety (i) 2,4-Dihydroxybenzaldehyde 7 (0.74 g, 5.36 mmol) is dissolved in EtOH (15 mL). Diethyl glutaconate (1.0 mL, 5.65 mmol) is added, followed by 3 drops of piperidine (dried over KOH pellets). The obtained solution is refluxed for 24 h. The reaction mixture is allowed to slowly cool to room temperature and then chilled to -20 °C. The yellow crystals formed are filtered off and dried to yield 3-(7-Hydroxy-2-oxo-2H-chromen-3-yl)acrylic acid ethyl ester 8 (1.24 g, 89% yield). (ii) Acrylic acid ethyl ester 8 (0.200 g, 0.77 mmol) is dissolved in dry pyridine (4 mL), and acetic anhydride (4 mL) is added. The reaction mixture is stirred at ambient temperature for 0.5 h, subsequently poured onto ice and stirred for additional 10 min. The resulting white precipitate is filtered and dried yielding 3-(7-Acetoxy-2-oxo-2H-chromen-3-yl)acrylic acid ethyl ester 9 (0.210 g, 90%). (iii) Acrylic acid ethyl ester 9 (2.20 g, 7.28 mmol) is dissolved in THF (200 mL). OsO4(2 mL of 4% w / w in water) is added to the mixture and stirred for 0.5 h. NaIO4(3.42 g, 16 mmol) is added, and the suspension is stirred at ambient temperature. Once the starting material is consumed (ca.5 d), the solution is dried by rotary evaporation. The resulting solid is - 55 / 91 - rad24 11.12.2024 partitioned between water and CH2Cl2. The organic layer was taken to dryness by rotary evaporation. Intermediate acetic acid 3-formyl-2-oxo-2H-chromen-7-yl ester 10 is isolated as a white solid (1.40 g, 83%) using column chromatography (silica-solvent gradient from CH2Cl2to CH2Cl2 / 5% CH3CN). (iv) Ester 10 (620 mg, 2.66 mmol) is dissolved in 32% NH4OH solution in water and aceto- nitrile (MeCN) is slowly added until the reaction mixture becomes homogenous. The reaction is followed to completion (20 minutes) by TLC (EtOAc:Hex 1:1). EtOAc is added and the solution is washed twice with HCl [1M]. The organic phase is dried over MgSO4, then filtered and the solvent removed under reduced pressure to give compound 11 (456 mg, 90%). (v) Compound 11 is conjugated with FAP-cleavable moiety F2 via common amide (peptide) bond formation to obtain compound 12. (vi) Conjugate 12 (100 mg, 0.53 mmol, 1 eq) is dissolved in MeOH (4 mL) and sodium borohydride (30 mg, 0.79 mmol, 1.5 eq) is added. The reaction is monitored to completion (10 minutes) by TLC (EtOAc:Hex 1:1). The reaction mixture is diluted with EtOAc, washed once with saturated NH4Cl solution, dried over MgSO4, then filtered and the solvent is removed under reduced pressure. The crude product is purified by column chromatography on silica gel (EtOAc:Hex 1:1) to give compound 13 (70‒86% yield). Example 3: Synthesis of 7-amino-3-(1-hydroxyethyl)-2H-chromen-2-one The synthetic route depicted beneath in Scheme 3 is based on: D. Xiao, L. Zhao, F. Xie, S. Fan, L. Liu, W. Li, R. Cao, S. Li, W. Zhong, X. Zhou; A bifunctional molecule-based strategy for the development of theranostic antibody-drug conjugate; Theranostics 2021, 11(6): 2550-2563; doi: 10.7150 / thno.51232. Scheme 3: Synthesis of 7-amino-3-(1-hydroxyethyl)-2H-chromen-2-one Synthesis of 3-acetyl-7-nitro-2H-chromen-2-one (1): To a stirring mixture of 2-hydroxy-4- nitrobenzaldehyde (5.00 g, 30 mmol) and ethyl acetoacetate (4.6 mL, 36 mmol), 349 μL of piperidine are added. After reflux for 1.5 h, the yellowish solid precipitate is filtered off, subsequently washed with ethanol to afford intermediate 1 (4.00 g, 57.1% yield). Synthesis of 3-(1-hydroxyethyl)-7-nitro-2H-chromen-2-one (2): To a solution of intermediate 1 (2.40 g, 10.30 mmol) in methanol and tetrahydrofuran (1:1, 200 mL total) is added sodium borohydride (390 mg, 10.30 mmol) and cerium chloride (2.54 g, 10.3 mmol) at 0 °C. After completion of the reaction within 1.5 h, the solvent is concentrated in vacuo and the crude - 56 / 91 - rad24 11.12.2024 product purified by column chromatography (1:1.5 EtOAc / hexanes) to give intermediate 2 as yellow solid (1.80 g, 74.3 % yield). Intermediate 2 (500 mg, 2.13 mmol), Iron(III) chloride hexahydrate (115 mg, 0.45 mmol), hydrazine hydrate (1.50 g, 25.6 mmol) and active carbon (305 mg, 25.6 mmol) are mixed in absolute ethanol (30 mL) and refluxed for 2 h. The solution is filtered and the filtrate concentrated in vacuo and the crude product purified by column chromatography (1:1 EtOAc / hexanes) to yield 3 as white solid (300 mg, 68.8 % yield). The synthetic strategy outlined beneath in Scheme 4 follows: P.K. Sahoo, S.S. Gawali, C. Gunanathan; Iron-Catalyzed Selective Etherification and Trans- etherification Reactions Using Alcohols; ACS Omega 2018, 3, 124−136. R1 = aryl , R2, R3 = alkyl or aryl Scheme 4: Iron(III)-catalyzed etherification of two different alcohols Secondary alcohol (0.5 mmol), primary alcohol (0.5 mmol), Fe(OTf)3 (0.025 mmol, 5 mol %) and NH4Cl (0.025 mmol, 5 mol %) in DCM (2 mL) are heated at 45 °C for 1 to 24 h. Fe(NO3)3· 9 H2O (0.025 mmol, 5 mol %) is used as catalyst. Reaction is carried out at 70 °C. Product is isolated via column chromatographic purification with typical yield between 40 and 93 %. Sulfonimidoyl fluoride compounds are prepared according the synthesis methods described by Wu et al. (X. Wu, W. Zhang, G. Sun, X. Zou, X. Sang, Y. He, B. Gao; Turning sulfonyl and sulfonimidoyl fluoride electrophiles into sulfur(VI) radicals for alkene ligation; Nature Communications (2023) 14:5168; https: / / doi.org / 10.1038 / s41467-023-40615-0) as depicted beneath in Scheme 5 in a generic manner. - 57 / 91 - rad24 11.12.2024 Scheme 5: General procedure for synthesis of sulfonimidoyl fluoride Example 6: Conjugation of alcohol and amine through N-O bond formation The reaction strategy outlined beneath in Scheme 6a‒6e bears on: J. Hill, A.A. Hettikankanamalage, D. Crich; Diversity-Oriented Synthesis of N,N,O-Tri- substituted Hydroxylamines from Alcohols and Amines by N−O Bond Formation; J. Am. Chem. Soc.2020, 142, 14820−14825. Scheme 6a: Synthesis of 2-hydroperoxytetrahydro-2H-pyran H2SO4 (18.4 M, 0.05 mL, 0.92 mmol, 0.01 eq) is added to a stirred solution of H2O2 (50% v / v) (3.8 mL, 58.8 mmol, 2 eq.) at 0 °C. The solution is stirred for 10 min, after which, 3,4-dihydro- pyran (2.68 mL, 29.4 mmol, 1 eq.) is added dropwise at 0 °C and the solution is stirred for 1 h. Following, the reaction mixture is diluted with Et2O (15 mL) and quenched by addition of saturated NH4Cl (30 mL) solution. The resulting biphasic mixture is transferred to a separatory funnel and the layers separated. The aqueous layer is extracted with ethyl acetate (5 × 40 mL) and the organic layers are combined, dried over Na2SO4, filtered, and concentrated in vacuo. The obtained residue is purified by flash column chromatography on silica (eluent: 5:95 EtOAc:Hexanes) to obtain the compound 2-hydroperoxytetrahydro-2H- pyran as a colorless oil (2.04 g, 17.3 mmol, 59%). - 58 / 91 - rad24 11.12.2024 Scheme 6b: Synthesis of 2-hydroperoxy-2-methyltetrahydro-2H-pyran (MTHP) CH3MgCl 3.0 M solution in THF (20 mmol, 6.67 mL, 1.0 eq) is added dropwise over 10 minutes in to a solution of δ-valerolactone (20 mmol, 1.86 mL, 1.0 equiv.) in 40 mL of anhydrous THF at -40 °C under an argon atmosphere. The reaction is stirred for 1 h at -40 °C. After consumption of starting material as indicated by TLC and MS, the reaction mixture is brought to -20 °C and quenched with a saturated solution of NH4Cl (40 mL) followed by diluting with DI water (20 mL) at room temperature. The resulting biphasic mixture is separated and the aqueous layer extracted with EtOAc (5 × 40 mL). The organic layers are combined and dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture is used subsequently without further purification. Sulfuric acid (18.4 M, 109 μL, 2.0 mmol, 0.10 eq.) is added to a stirred solution of 2-methyl- tetrahydro-2H-pyran-2-ol (2.3 g, 20 mmol, 1 eq.) obtained in the previous step in 100 mL of DCM at 0 °C. Aqueous hydrogen peroxide solution (50% w / w) (6.8 mL, 100 mmol, 5.00 eq.) is added dropwise over 5 min and stirred another 10 min at 0 °C. The reaction is brought to room temperature and stirred for 2 h. The reaction is quenched with a saturated NH4Cl solution (40 mL) and the resulting biphasic mixture is separated and the aqueous layer extracted with EtOAc (5 × 40 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue is purified by flash column chromatography on silica (eluent: 0:100 DCM - 8:92 Et2O:DCM) to obtain 2-hydroperoxy-2 methyltetrahydro-2H-pyran as a clear, colorless oil (1.72 g, 13.0 mmol, 65% total yield). Scheme 6c: Synthesis of THP and MTHP monoperoxy acetal of simple alcohol Anhydrous DCM (0.17 - 0.60 M), alcohol (1.0 eq.) and base (1.5 eq.) are added to an oven dried flask under argon atmosphere at 0 °C. The solution is stirred for 10 min, after which, Tf2O (1.2 - 1.5 eq.) is added dropwise. The solution is stirred for 30 to 60 min at 0 °C. Following, HCl (10%, 10 mL) is added and the layers are separated. The organic layer is washed with saturated NaHCO3 (1 × 10 mL). The aqueous layer is extracted with EtOAc (3 × 5 mL) and the organic layers are combined and washed with saturated NaCl solution (1 × 10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The triflate is extracted - 59 / 91 - rad24 11.12.2024 via flash silica column chromatography (eluent: EtOAc: Hexanes) and used in the following step. Lithium tert-butoxide or potassium tert-butoxide (1.2 - 1.5 eq.) is added in a single portion under argon atmosphere (balloon) to a stirred solution of THP or MTHP (1.0 - 2.0 eq.) in anhydrous THF (0.2 - 0.5 M). The solution is stirred for 10 min at 0 °C, after which, a portion of the triflate (1.0 - 2.0 eq.) obtained in the previous step is added dropwise via syringe. The solution is stirred for 1 h at 0 °C, after which, the mixture is allowed to reach room temperature and stirred for an additional 1-24 h. The reaction mixture is quenched with NaHCO3(20 mL) and diluted with EtOAc (10 mL). The layers are separated and the aqueous layer extracted with EtOAc (3 x 5 mL). The combined organic layers are dried over MgSO4 / Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography on silica (eluent: EtOAc:Hexanes) yields the monoperoxy acetal. Scheme 6d: Synthesis of MTHP monoperoxy acetal of complex alcohol Anhydrous DCM (0.13 - 0.50 M), alcohol (1.0 eq.) and pyridine (2.0 eq.) are added to an oven dried flask under argon atmosphere at 0 °C. The solution is stirred for 10 min, thereafter, Tf2O (1.2 - 1.5 eq.) is added dropwise. The solution is stirred for 30 to 60 min at 0 °C and subsequently diluted with a few drops of MeOH and 10% HCl (1 x 10 mL). The layers are separated and the organic layer washed with saturated NaHCO3 (1 × 10 mL). The aqueous layer is extracted with EtOAc (3 × 5 mL) and the organic layers are combined and washed with saturated NaCl solution (1 × 10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The triflate is extracted via flash silica column chromatography (eluent: EtOAc:Hexanes) and used in the following step. NaH (60% dispersion in mineral oil, 1.2 - 1.5 eq.) is added in a single portion under argon atmosphere to a stirred solution of MTHP (1.0 eq.) in anhydrous DMF. The solution is stirred for 10 min at 0 °C, thereafter, the triflate (1.3 eq.) obtained in the previous step is added dropwise via syringe. The solution is stirred for 1 h. The mixture is allowed to settle at room temperature and stirred for an additional 1-16 h. The reaction mixture is then diluted with EtOAc (10 mL) and quenched with saturated NaHCO3 (10 mL). The layers are separated and the aqueous layer extracted with EtOAc (3 × 5 mL). The organic layers are dried over Na2SO4 / MgSO4, filtered, and concentrated in vacuo. The monoperoxy acetal is extracted via flash column chromatography on silica (eluent: EtOAc:Hexanes). - 60 / 91 - rad24 11.12.2024 Scheme 6e: Synthesis of N,N,O-trisubstituted hydroxylamine with N-O bond Amine (0.25 - 11.0 mmol, 2.5 eq.) and 0.25 - 11.0 mL anhydrous THF are added to an oven / flame dried flask at 0 °C under an argon atmosphere. To this solution EtMgBr (3M in diethyl ether) (0.2 - 8.7 mmol, 2.0 eq.) is added dropwise and the reaction mixture is stirred for 10 – 30 min at 0 °C (magnesium amide formation produces substantial amount of gas, hence, at larger scale caution is mandated). The magnesium amide is subsequently transferred via syringe to a stirred solution of THP or MTHP monoperoxyacetal (0.10 - 4.36 mmol, 1.0 eq.) stirred in additional 0.25 - 11.0 mL anhydrous THF (0.2 M total) under argon atmosphere at 0 °C. The solution is stirred until the starting material is consumed as indicated by TLC and MS, after which, the mixture is quenched by addition of ice water and the layers are separated. The aqueous layer is extracted with EtOAc and the combined organics are dried over MgSO4 / Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography on silica or neutral alumina (eluent: EtOAc:Hexanes or DCM:EtOAc) yield the N,N,O-trisubstituted hydroxylamines. Example 7: Amide bond formation A generic example of an amide coupling reaction is shown in scheme 7. Scheme 7: Amide coupling Owing to a virtually unlimited set of readily available carboxylic acid and amine derivatives, amide coupling strategies open up a simple route for the synthesis of novel compounds. The person skilled in the art is aware of numerous reagents and protocols for amide coupling. The most commonly used amide coupling strategy is based on the condensation of a carboxylic acid with an amine. For this purpose, the carboxylic acid is generally activated. Prior to the activation, remaining functional groups are protected. The reaction is carried out in two steps, either in one reaction medium (single pot) with direct conversion of the activated carboxylic acid, or in two steps with isolation of activated "trapped" carboxylic acid and reaction with an amine. The carboxylic reacts here with a coupling agent to form a reactive intermediate which can be reacted in isolated form or directly with an amine. Numerous reagents are available for carboxylic acid activation, such as acid halide (chloride, fluoride), azides, anhydrides or - 61 / 91 - rad24 11.12.2024 carbodiimides. In addition, reactive intermediates formed may be esters such as pentafluorophenyl or hydroxysuccinimido esters. Intermediates formed from acyl chlorides or azides are highly reactive. However, harsh reaction conditions and high reactivity are frequently a barrier to use for sensitive substrates or amino acids. By contrast, amide coupling strategies that utilize carbodiimides such as DCC (dicyclohexylcarbodiimide) or DIC (diisopropylcarbodiimide) open up a broad spectrum of application. Frequently, especially in the case of solid-phase synthesis, additives are used to improve reaction efficiency. Aminium salts are highly efficient peptide coupling reagents having short reaction times and minimal racemization. With some additives, for example HOBt, it is impossible to completely prevent racemization. Aminium reagents are used in an equimolar amount with the carboxylic acid in order to prevent excess reaction with the free amine of the peptide. Phosphonium salts react with carboxylate, which generally requires two equivalents of a base, for example DIEA. A significant 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 a molar ratio of acid and amine and helps to prevent the intramolecular cyclization of linear peptides and excessive use of costly amine components. An extensive summary of reaction strategies and reagents for amide couplings can be found in the following review articles: – Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?; D. G. Brown, J. Boström; 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; V. R. Pattabiraman, J. W. 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 chelators for complexation of radioisotopes, in particular chelators based on the DOTA- and DATA-scaffold, are readily available from commercial vendors (e.g. https: / / www.macrocyclics.com / ; https: / / www.macrocyclics.com / wp-content / uploads / 2022 / 07 / 2022-Product-Catalog.pdf; https: / / www.chematech-mdt.com / wp-content / uploads / - 62 / 91 - rad24 11.12.2024 2020 / 09 / Brochure_Chematech-2020-web.pdf). Many of the commercially available chelators comprise a terminal OH- or NH2-group for facile coupling with a linker. CAS No.1161415-28-6 CAS No.438553-50-3 Scheme 8: Chelator building blocks - 63 / 91 - rad24 11.12.2024 Example 9: DATA5mProchelator Synthesis Scheme 9 illustrates the synthesis of the DATA5mprochelator (cf. J. Seemann, B. Waldron, D. Parker, F. Roesch; DATATOC: a novel conjugate for kit-type68Ga labelling of TOC at ambient temperature; EJNMMI Radiopharmacy and Chemistry (2016) 1:4, DOI 10.1186 / s41181-016-0007-3). Scheme 9: Synthesis of 3tBu-protected DATA5mprochelator (i) Amberlyst-21, EtOH; (ii) CH2O, EtOH; (iii) CH3COOH, Pd(OH)2 / C, H2, EtOH; (iv) BrCH2COOtBu, K2CO3, MeCN; (v) CH3I, K2CO3, DCM : MeCN; (vi) LiOH, THF : H2O - 64 / 91 - rad24 11.12.2024 Examples 10-19: Protease inhibitor prodrug compounds Schemes 10-19 depict exemplary embodiments 10-19 of prodrug compounds of the present invention which upon activation by FAP release a protease inhibitor, such as phenylmethyl- sulfonimidoyl fluoride or 4-(2-aminoethyl)-benzenesulfonimidoyl fluoride. Dotted lines indicate bonds that are enzymatically cleaved by FAP or subsequently dissociate through disassembly of the self-immolative spacer F3. Scheme 10: Exemplary prodrug compound 10 Scheme 12: Exemplary prodrug compound 12 - 65 / 91 - rad24 11.12.2024 Scheme 13: Exemplary prodrug compound 13 Scheme 15: Exemplary prodrug compound 15 - 66 / 91 - rad24 11.12.2024 Scheme 16: Exemplary prodrug compound 16 Scheme 17: Exemplary prodrug compound 17 Scheme 18: Exemplary prodrug compound 18 - 67 / 91 - rad24 11.12.2024 Scheme 19: Exemplary prodrug compound 19

[0006] - 68 / 91 - rad24 11.12.2024 Examples 20-51: Compounds comprising a chelator for radioisotope complexation Schemes 20-51 depict exemplary embodiments 20-51 of compounds, in particular precursor compounds of the present invention that include a chelator for radioisotope complexation. Dotted lines indicate bonds that are enzymatically cleaved by FAP or subsequently dissociate through disassembly of a self-immolative spacer. Scheme 20: Exemplary precursor compound 20 Scheme 21: Exemplary precursor compound 21 - 69 / 91 - rad24 11.12.2024 Scheme 23: Exemplary precursor compound 23 - 70 / 91 - rad24 11.12.2024 Scheme 24: Exemplary precursor compound 24 Scheme 25: Exemplary precursor compound 25

[0007] - 71 / 91 - rad24 11.12.2024 Scheme 26: Exemplary precursor compound 26 Scheme 27: Exemplary precursor compound 27

[0008] - 72 / 91 - rad24 11.12.2024 Scheme 28: Exemplary precursor compound 28 Scheme 29: Exemplary precursor compound 29

[0009] - 73 / 91 - rad24 11.12.2024 Scheme 31: Exemplary precursor compound 31 - 74 / 91 - rad24 11.12.2024 Scheme 32: Exemplary precursor compound 32 Scheme 33: Exemplary precursor compound 33 - 75 / 91 - rad24 11.12.2024 Scheme 34: Exemplary precursor compound 34 Scheme 35: Exemplary precursor compound 35 - 76 / 91 - rad24 11.12.2024 Scheme 36: Exemplary precursor compound 36 Scheme 37: Exemplary precursor compound 37

[0010] - 77 / 91 - rad24 11.12.2024 Scheme 39: Exemplary precursor compound 39 - 78 / 91 - rad24 11.12.2024 Scheme 40: Exemplary precursor compound 40 Scheme 41: Exemplary precursor compound 41 - 79 / 91 - rad24 11.12.2024 Scheme 42: Exemplary precursor compound 42 Scheme 43: Exemplary precursor compound 43 - 80 / 91 - rad24 11.12.2024 Scheme 45: Exemplary precursor compound 45 - 81 / 91 - rad24 11.12.2024 Scheme 46: Exemplary precursor compound 46 Scheme 47: Exemplary precursor compound 47 - 82 / 91 - rad24 11.12.2024 Scheme 48: Exemplary precursor compound 48 Scheme 49: Exemplary precursor compound 49 - 83 / 91 - rad24 11.12.2024 precursor

[0011] - 84 / 91 - rad24 11.12.2024 Scheme 51: Exemplary precursor compound 51

Claims

- 85 / 91 - rad24 11.12.2024 Claims 1. A pharmaceutical compound having the structure, wherein ‒ F1 is absent, H or a pharmacokinetic modulator group, ‒ F2 is a substrate ligand of fibroblast activation protein (FAP), ‒ F3 is absent and F2 is conjugated with F4 by a single covalent bond, or F3 is a self- immolative bivalent spacer conjugated with each F2 and F4 by a single covalent bond, or F3 is a self-immolative trivalent spacer conjugated with F2 by a single covalent bond and with F4 by two single covalent bonds, ‒ F4 comprises one or two sulfur fluoride radicals selected independently of one another from the group comprising‒ F5 is absent, a substituted or unsubstituted alkyl or heteroalkyl, a substituted or unsubstituted aryl or heteroaryl, or a FAP ligand, ‒ F6 is absent, a bivalent spacer, or a pharmacokinetic modulator group, and ‒ F7 is absent, a chelator for complexation of a radioisotope, or a leaving group for substitution with a radioisotope.- 86 / 91 - rad24 11.12.2024 2. The pharmaceutical compound of claim 1, characterized in that F2 is a radical selected from the group comprising , ,wherein X = –H or –CH3 , Y1= –H or –F , Y2= –H or –F , and Z is a radical selected from the group comprising , , , , .- 87 / 91 - rad24 11.12.2024 3. The pharmaceutical compound of claim 1 or 2, characterized in that F2 comprises a radical having the structurewherein the terminal carbonyl group (‒CO‒) is covalently coupled to F3 or F4; 4. The pharmaceutical compound of claim 1, 2 or 3, characterized in that F3 comprises a radical having the structurewherein the terminal amine (‒NH‒) is covalently coupled to F2 or oriented toward F2; 5. The pharmaceutical compound of claim 1, 2 or 3, characterized in that F3 comprises a radical having the structurewherein the terminal oxy group (‒O‒) is oriented toward F2; 6. The pharmaceutical compound of claim 1, 2 or 3, characterized in that F3 comprises a radical having the structure ,wherein the terminal amine (‒NH‒) is covalently coupled to F2 or oriented toward F2.- 88 / 91 - rad24 11.12.2024 7. The pharmaceutical compound of claim 1, 2 or 3, characterized in that F3 comprises a radical having the structure ,wherein the terminal oxy group (‒O‒) is oriented toward F2.

8. The pharmaceutical compound of claim 1, 2 or 3, characterized in that F3 comprises a radical having the structure , ,wherein the terminal amine (‒NH‒) is covalently coupled to F2 or oriented toward F2, or the terminal oxy group (‒O‒) is oriented toward F2.

9. The pharmaceutical compound of any one of claims 1 to 8, characterized in that F1 and F6 independently of one another comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine or forty linearly conjugated radicals selected independently of one another from the group comprising ‒CH2‒ , ‒C(=O)‒ , ‒CH(‒CH3)‒ , ‒CH(‒CH2COOH)‒ , ‒CH=CH‒ , ‒NH‒ , ‒N(‒CH3)‒ , ‒O‒ , ‒CH2CH2O‒ and radicals of C4‒C10aryl or heteroaryl, substituted- 89 / 91 - rad24 11.12.2024 C4‒C10aryl or heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids.

10. The pharmaceutical compound of any one of claims 1 to 9, characterized in that F7 comprises a radical selected from the group comprisingF1 is ‒OH or ‒NH2, F2 is ‒OH or ‒NH2, F3 is ‒OH or ‒NH2, F4 is ‒OH or ‒NH2.

11. The pharmaceutical compound of any one of claims 1 to 9, characterized in that F7 comprises a radical having the structureD1is ‒H, ‒CH3or ‒NH2.

12. The pharmaceutical compound of any one of claims 1 to 9, characterized in that F7 is a leaving group selected from the group comprising dinitrogen, dialkyl ether, perfluoro- alkylsulfonates, triflate, iodide, tosylates, mesylates, sulfonates, bromide, hydrogen, alcohols, chloride, nitrate, phosphate, inorganic esters, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, hydroxide, alkoxides, amides, hydride, arenide, alkanide and sulfur fluorides.- 90 / 91 - rad24 11.12.2024 13. A radioligand comprised of ‒ a precursor compound according to claim 10 or 11 including a chelator and a therewith complexed radioisotope or radioactive compound selected from the group comprising44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,90Nb, 111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,212Pb, 213Bi,225Ac and18FAl, or ‒ a precursor compound according to claim 12 wherein F7 is substituted with18F,131I or211At.

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