Dimeric FAP targeting agents comprising a (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold, a 1,3,5-triazine or -triazinane linking moiety and a therapeutic or diagnostic agent for the diagnosis or treatment of tumors

Abstract

The present invention relates to dimeric FAP targeting agents of formulae (I) or (II) wherein Z is a FAP-binding moiety comprising a (4-quinoinolyl) glycinyl-2-cyanopyrrolidine scaffold and Q is a therapeutic and / or diagnostic agent for the treatment and / or diagnosis of tumors. An exemplary compound is e.g. eFAP-34

Description

[0001] Title: Dimeric FAP targeting agents BACKGROUND The invention relates to compounds for targeting fibroblast activation protein (FAP) in cancer-associated fibroblasts (CAFs), in particular to dimeric FAP targeting agents comprising a (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold. Various FAP targeting agents based on the (4-quinoinolyl)glycinyl-2- cyanopyrrolidine scaffold have been developed and researched in the prior art to image and treat tumors (see Lindner et al. Cancers 2021, 13, 5744). Early FAP targeting agents are disclosed in Jansen et al. ACS Med. Chem. Lett.2013, 4, 491- 496 and in Jansen et al. J. Med. Chem. 2014, 57, 3053–3074, the latter describing fluorinated (4-quinolinoyl)-glycyl-2-cyanopyrrolidine scaffolds and UAMC-1110, a FAP inhibitor with nanomolar affinity to FAP. For the FAP targeting agent to be clinically relevant, it must be functionalized with a payload such as a radioisotope, a fluorescent dye, a cytotoxic drug, or the like. To this end, the quinolinoyl moiety of the scaffold is generally used. The current reference compound in clinic is FAPI-46 (Loktev et al. Journal of Nuclear Medicine October 2019, 60 (10) 1421-1429). FAPI-46 was developed after the development of FAPI-04 (see Lindner et al. J. Nucl. Med. 2018; 59:1415-1422) and demonstrated improved tumor-to-organ ratios vis-à-vis FAPI-04. Other functionalized FAP targeting compounds are described in WO2021 / 160825 and Millul et al. PNAS 2021 Vol. 118 No. 16 e2101852118 and referred to as OncoFAP. These compounds are functionalized on the quinoinolyl using a bridging nitrogen extended to a carboxylic acid group that allows connection to the payload. A drawback of this carboxylic acid group is that most metal chelating groups, prosthetic groups, optical dyes etc. are not readily available as carboxylic acid reactive. They are usually commercially available as amine reactive. Therefore, an additional linker (-NHCH2-CH2-NH-) is used in the OncoFAP compounds to expose an amine that can react with the payload. Yet other FAP targeting compounds are described in WO 2019 / 083990. Dimeric FAP targeting compounds, which comprise two (4- quinoinolyl)glycinyl-2-cyanopyrrolidine FAP-binding moieties and a payload are described by Li et al. (European Journal of Nuclear Medicine and Molecular Imaging, 49, 2705–2715 (2022), Zhao et al. (Journal of Nuclear Medicine, Vol. 63, No.6, June 2022, 862-668), Galbiati et al., (Journal of Nuclear Medicine December 2022, 63 (12) 1852-1858), Moon et al. (Am J Nucl Med Mol Imaging 2021;11(6):476- 491) and Ballal et al. (Pharmaceuticals 2021, 14, 1212). Despite the recent advantages, there remains a need to provide an improved platform and improved FAP targeting agents based on the (4- quinoinolyl)glycinyl-2-cyanopyrrolidine scaffolds. Earlier research and development have however shown that FAP imposes strict structural requirements on its inhibitors and that steric or electronic parameters are not sufficient to rationalize the assay data (Jansen et al. J. Med. Chem. 2014, 57, 3053–3074). Developing new FAP targeting agent is accordingly challenging as it is hard if not impossible to predict which substituents and which position on the (4- quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold is allowed to give good inhibitors. An object of the present invention is to provide a platform for multivalent compounds and such multivalent compounds that show improved FAP binding affinity and / or tumor uptake, including tumor-to-organ distribution. Furthermore, an object of the present invention is to provide a platform that enables access to such compounds. SUMMARY The present inventors have found that dimeric FAP targeting agents having a central core comprising a 1,3,5-triazine moiety (herein also referred to as triazine) or a 1,3,5-triazinane (herein also referred to as triazinane) gives entry into a variety of FAP targeting agents showing good FAP binding affinity and / or tumor uptake, including good tumor-to-organ distribution. Moreover, dimeric FAP targeting agents based on the triazine or triazinane core show good solubility and stability and can relatively easily be prepared in good yield when compared to other dimeric compound such as those based on a tetrazine core. Further, the present inventors found that if one or more hydrophilic linkers are used in dimeric FAP inhibitors to link the payload / or FAP binding moieties to the core (and each other) leads to good FAP binding affinity and / or tumor uptake, including good tumor-to-organ distribution. The present inventors have also surprisingly found that substituting the 8thposition of the (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold with a carbon or oxygen atom gives entry into a variety of FAP targeting agents showing good FAP binding affinity and / or tumor uptake, including good tumor-to-organ distribution. The present invention is accordingly directed to compound, or a pharmaceutically acceptable salt thereof according to formula (I) or formula (II) wherein L1, L2and L3each individually represent a linker; Q comprises a payload; and Each Z represents a FAP-binding moiety. Compound (I) is based on a triazinane core, while compound (II) is based on a triazine core. DETAILED DESCRIPTION The present invention is in particular directed to a compound, or a pharmaceutically acceptable salt thereof according to formula (I) or formula (II) wherein L1, L2and L3each individually represent a linker; Q comprises a payload, preferably a therapeutic agent, a diagnostic agent or a combination thereof; each Z independently represents a FAP-binding moiety comprising a scaffold according to formula (Z) wherein X represents NH, CH2or O; R1represents H, Me, CH(CH3)C2H5, CH2CH(CH3)2, CH(CH3)2, CH2OH, CH2SH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, (CH2)mCO2H, (CH2)mNH2, wherein m is 1-4; and R2and R3each independently represent H or F. The wiggle symbol ( ) herein indicates the position at with a particular moiety is bound to the remainder of the compound. Thus, for example, for Z, the wiggle symbol indicates that X is bound to the linker L1or L2. FAP-binding moiety Z The basic structure of the FAP-binding moiety is depicted below with the numbering of the carbon atoms in the quinoinolyl moiety indicated. The X moiety, and thus the remainder of the compound as well, is preferably positioned on the 5, 6, 7, or 8 carbon atom of the quinoinolyl moiety. In a preferred embodiment however, the present compound comprises a (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold that is substituted on the 8th position of the quinoinolyl moiety with a bridging carbon or oxygen atom (herein also referred to as the scaffold). The bridging carbon or oxygen atom is connected or allows connection to the payload via the linker L1or L2and the triazinane or triazine core. It may be appreciated that this scaffold may comprise further substituents such as fluorides and others, known for the FAP inhibitors based on the (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold. As detailed in co-pending application PCT / NL2023 / 050491, which is incorporated herein by reference, this leads to particular FAP binding affinity and / or tumor uptake, including good tumor-to-organ distribution. Hence, in a preferred embodiment, each Z in formulae (I) and / or (II) independently represents a FAP-binding moiety according to formula (Za), wherein X represents CH2or O, preferably O. Of the (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold of the present invention, preferably at least one of R2and R3is F, more preferably at least R2is F (such that the atom to which R2and R3are connected has the (S) configuration or is achiral), most preferably R2and R3are both F. The R1substituent is preferably H. In preferred embodiments, the FAP-binding moiety is conjugated in the compound via at least a spacer R4, as illustrated with formula (Zb)

[0002] wherein R4represents a spacer, preferably an aliphatic spacer. The spacer represented by R4preferably comprises a nitrogen atom, as illustrated in formula (Zc), wherein R4’represents an optionally substituted hydrocarbylene or an optionally substituted alkylene ether, preferably an alkylene, more preferably C1-C8alkylene, that can be used to connect the (4- quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold. The spacer (R4and R4’) can be substituted or interrupted with one or more heteroatoms such as one or more of OH, NH2, SO2, and halogens such as F, Cl, Br and I. The spacer represented by R4and R4’is preferably based on an aliphatic C1-C8amino terminated spacer. It was found that such a spacer leads to particularly good FAP binding affinities and tumor uptake. Accordingly, a particularly preferred embodiment of the compound of the present invention wherein each Z independently has a structure according to formula (Zd), wherein n is 1-6, preferably 1.

[0003] In other embodiments, the compound is according to formula (Z’) or (Z”). Linkers L1, L2and L3The linkers L1, L2and L3serve to link the one or more payloads and the FAP binding moieties. The linkers may assist in the solubility of the compound. For instance, 4-amino-3-hydroxybutanoic acid (GABOB) and (oligo)ethylene glycol can be used to helps water solubility and lower lipophilicity (as observed by the logP values). The linker may be cleavable or non-cleavable (see for instance Kovtun et al. Cancer Letters 255 (2007) 232–240, Beck et al. Nature Reviews Drug Discovery 16 (2017) 315–337 and WO2021 / 160825) or a combination of both (i.e. one or more cleavable parts linking one or more payloads, and one or more other non-cleavable parts linking one or more other payloads or scaffolds). Generally, linkers L1and L2are non-cleavable and L3may optionally be cleavable. In particular embodiments, L1, L2and L3are independently, partially or fully, based on linear or branched amino acids, more preferably on glycine, alanine, β-alanine, 3-aminopropionic acid, 4-aminobutyric acid, 4-amino-3-hydroxybutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8- aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, and the like, a peptide spacer (Xaa)1-4, wherein each Xaa is independently a proteinogenic or non-proteinogenic amino acid residue selected from the group consisting of L-amino acids, D-amino acids of proteinogenic amino acids, Nε,Nε,Nε- trimethyl-lysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), ornithine (Orn), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2- amino-3-guanidinopropionic acid (Agp), β-alanine, 4-aminobutyric acid, 5- aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2- aminoadipic acid ( 2-Aad), 3-aminoadipic acid (3-Aad), 4- (aminomethyl)cyclohexane-1-carbonylic acid (Amcha), 4-amino-1-carboxymethyl- piperidine (Pip), 2-(piperazin-1-yl)acetic acid (Pipa), 2-(4-(2-aminoethyl)piperazin- 1-yl)acetic acid, cysteic acid, diglycolic acid (DGA), and NH2(CH2)2[O(CH2)2]qC(O)OH (wherein q = 1-36). Most preferably, L1and L2both represent NH2(CH2)2[O(CH2)2]qC(O)OH, wherein q = 1-36, more preferably NH2(CH2)2[O(CH2)2]qC(O)OH, wherein q = 2-6. The compound comprising the linker based on the amino acid NH2(CH2)2[O(CH2)2]qC(O)OH gave good FAP binding affinity. It may be appreciated that, the term ‘based on’ herein means that the linkers are described in their free, unreacted form but that the linkers in the compounds are bound to the triazinane and / or triazine core and FAP-binding moiety with the amine and carboxylic acid groups. Typically, these listed linkers L1and L2are bound with their amine group to the triazinane and / or triazine core of the compound, and with their carboxylic acid group to FAP-binding moiety. In an embodiment, the linkers L1, L2and / or L3comprise a moiety having a structure as shown in any of formulae La-Lp. Lo and / or Lp are preferred, in particular for L1and / or L2. and wherein further Y1is selected from the group consisting of C and N, preferably N for formula La, Lg and Lh and C for formula Ld; Y2is selected from the group consisting of C, N, and O, preferably N and C; more preferably C; and q is in the range of 1 to 36, preferably 1 to 6. In a yet further preferred embodiment, the linkers L1, L2and / or L3comprises a moiety having a structure according to any of formulae Laa, Lfa, Lfb, Lfc ,Lga, Lha, Lhb, Lhc, and Lma, which are specific versions of formulae La, Lf, Lg, Lh, and Lm respectively. For Lfb, Lfc, Lhb and Lhc, q can be in the range of 1 to 36, preferably 1 to 6.

[0004] It may be appreciated that unless the stereochemistry of an atom has been specifically indicated herein, the stereochemistry of said atom is undefined which indicated that said structure represents all possible stereoisomers for said atom. For instance, structure Lfa represents at least two diastereoisomers: the trans and cis-isomers. However, preferably, the linker represented by this formula has the trans-configuration, as indicated by formula Lfa’ below. In particular embodiments, the linker L3may comprise a cleavable linker section comprising an in vivo cleavable moiety. Such linker section is particularly preferred when the payload comprises a drug that benefits from delivery and release from the scaffold on a target location, e.g. near or in a tumor cell (see for instance Kovtun et al. Cancer Letters 255 (2007) 232–240, Beck et al. Nature Reviews Drug Discovery 16 (2017) 315–337, and WO2021 / 160825). Enzyme-sensitive cleavable linkers sections are accordingly preferred linker sections and most preferred are cleavable sections that are sensitive to enzymes that are overexpressed in tumors, e.g. glutathione. Examples of cleavable moieties that can be comprised in the cleavable linker section include amides, ester, carbamates, hydrazones, thiazolidine, methylene alkoxy carbamate and disulfides. The cleavable moiety may comprise one or more of such moieties and for example may include a peptide, oligosaccharide or another oligomeric sequence that can selectively be cleaved in vivo. In preferred embodiments, the cleavable moiety comprises a disulfide moiety or a terminal thiol that enables disulfide linkage to the payload that comprises a terminal thiol as well (e.g. mertansine or DM1). In an embodiment, the cleavable linker section is based on or comprises linear or branched mercapto carboxylic acids such as thioglycolic acid, thiolactic acid (also known as 2-mercaptopropionic acid), 3-mercaptopropionic acid (3-MPA), 4-mercaptobutanoic acid (SPDB), 4-mercaptopentanoic acid (SPP), 4-mercapto-2- sulfobutanoic acid (Sulfo-SPDB), and the like. The cleavable linker section may comprise a self-immolative moiety, which by a cascade of reactions is capable of releasing the payload unfunctionalized after activation (see for instance R.V. Gonzaga et al. Journal of Pharmaceutical Sciences 109 (2020) 3262-3281). Examples of suitable self-immolative moieties include p-amino benzyl carbamate (PAB) either coupled to a valine-citrulline (Val-Cit-PAB), glycine-proline (Gly-Pro- PAB), Ala-Ala-Asn-PAB, DGA-Lys-PAB or β-glucuronide and those based on the Grob fragmentation (herein referred to as Grob fragmentable moieties, see for instance Ferhati et al. Org. Lett. 2021, 23, 21, 8580–8584). The linker L3binds the payload to the triazinane and / or triazine core. To achieve selectivity in connecting the linker L3with the payload and linkers L1and L2with the FAP-binding moiety, several synthetic strategies can be employed. One approach to obtain selectivity may be through the use of orthogonal protecting groups. In such embodiment, the linkers L1and L2may for instance be linked to the FAP-binding moiety whilst L3still carries a protecting group. Then, as a next step, L3may be deprotected and coupled to the payload. Suitable protecting group strategies are commonly known and for instance described in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Another strategy is using L1and L2that allow orthogonal coupling reactions vis-à-vis linker L3, for example via a click reaction. In such embodiment, for example, the linkers L1and L2may for instance be linked to the FAP-binding moiety via an amide bond while L3carries an azide that can be orthogonally reacted with an alkyne or another moiety allowing a click reaction. In preferred embodiments, the linker L3has a structure according to any of formulae (L3a), (L3b), (L3c) and (L3d), wherein (Q) indicates the relative position of the payload Q; r is in the range of 1-6, preferably 1-3, more preferably 3; and p is in the range of 1-6, preferably 1-3, more preferably 2. The structure of linker L3is preferably the reaction product of an orthogonal reaction (in the art also referred to a click reaction) between the triazinane and / or triazine core that carried an azide functionality and the payload carrying an alkyne functionality, e.g. via a copper-catalyzed alkyne-azide Huisgen’s cycloaddition or copper-free reaction between an azide and a bicyclo[6.1.0]non-4- yne, BCN, or dibenzocyclooctyne, DBCO. Linkers (L3b) and (L3d) are preferably used for the triazinane core, while linkers (L3a) and (L3c) are preferably used for the triazine core. The linker L3may also be based on a moiety having the structure according to any of formulae (L3e), (L3f), (L3g), (L3h), (L3i), (L3j), (L3k), (L3l), (L3m) and (L3n) wherein (Q) indicates the relative position of the payload Q; r is in the range of 1-6. Linkers (L3e) and (L3f) can for instance be used to link carboxylic acid terminated payloads, while linkers (L3g), (L3h), (L3m) and (L3n) can be used to enable disulfide linkage to the payload that comprises a terminal thiol as well (e.g. mertansine or DM1). Linkers (L3k) and (L3l) can for instance be used to link amine terminated payloads. Linkers (L3i) and (L3j) can for instance be used to link alkyne terminated payloads. The compound of formula (Ia), (Ib), (Ic), (IIa), (IIb) or (IIc) is accordingly particularly preferred. Herein, r is in the range of 1-6, preferably 1-3, more preferably 3; and p is in the range of 1-6, preferably 1-3, more preferably 2.

[0005] Even more preferred is the compound of formula (Iaa), (IIaa), (Iba), (IIba), (Ibb), (IIbb), (Ibc), (IIbc), (Ica), or (IIca), wherein the linkers L1and L2are based on the amino acid NH2(CH2)2[O(CH2)2]qC(O)OH, optionally in combination with Pipa (see e.g. (Ibc) and (IIbc)) or Amcha (see e.g. (Ibb) and (IIbc)), as illustrated below. Combination of the amino acid NH2(CH2)2[O(CH2)2]qC(O)OH linker with Amcha or Pipa gave particularly good results, hence such compounds are yet even more preferred. The linkers L1and L2of these compounds comprise moieties having a structure according to Lfb and Lhb, which are therefore particularly preferred. Although not separately illustrated below, the compounds of structures (Iaa), (IIaa), (Iba), (IIba), (Ica) and (IIca) may also comprises such linkers, meaning that the ethylene oxide moieties (formula Lp) can be used in combination with Pipa (formula Lha) or Amcha (formula Lfa).

[0006]

[0007] Payload Q The present invention is not particularly limited to specific payloads, diagnostic and therapeutic agents. Advantageously, the present invention allows a large variety of payloads to be used in combination with the scaffold, without compromising the FAP affinity and / or tumor uptake of the compound. It may be appreciated that appropriate payloads and agents can be selected based on the desired use such as diagnosis and treatment. The payloads that are known for previously developed FAP targeting agents as for instance disclosed in WO2019 / 154859 and WO2021 / 160825 can also suitably be used with the present invention. In a particular embodiment, the payload comprises a radioisotope complexed to a chelator. The radioisotope may be any suitable radioisotope. See for instance Tornesello et al., Molecules 2017, 22(8), 1282, US 2021 / 0402016A1, WO2021 / 005125A1 and Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290 and references cited therein. The radioisotope may be an α- or β-particle emitter, an Auger emitter, a positron emitter and / or a γ-emitter. The α-particle emitters and β- particle emitters, such as90Y,212Pb,177Lu,188Re,186Re,67Cu,64Cu,195mPt,212Bi,213Bi,211At,225Ac,131I and the like can be used for therapy. Suitable γ-emitters such as99mTc,67Ga,111In and the like can be used for SPECT imaging, while positron emitters such as68Ga,64Cu,18F and the like are useful for PET imaging. Accordingly, the radioisotope M for the present invention is preferably selected from the group consisting of18F,123I,124I,125I,131I,76Br,77Br,212Pb,203Pb,64Cu,67Cu,212Bi,68Ga,213Bi,225Ac,243Am,211At,217At,154Dy,148Gd,146Sm,147Sm,149Tb,152Tb,155Tb,161Tb,165Er,72As,77As,47Sc,188Re,186Re,105Rh,109Pd,199Au,175Yb,142Pr,114mIn,94mTc,99mTc,227Th,229Th,59Fe,60Cu,61Cu,62Cu,67Ga,44Sc,89Zr,90Nb,86Y,90Y,111In,177Lu,117mSn,153Gd,153Sm, and166Ho, preferably from the group consisting of18F,64Cu,67Ga,68Ga,90Y,111In,177Lu,212Pb and225Ac, most preferably from the group consisting of18F,68Ga,111In,212Pb,225Ac and177Lu. In the field, various chelators are known to bind radioisotopes. The chelator for the present invention is a pharmaceutically acceptable chelator. The chelator is typically selected based on the radioisotope that is desired for the diagnosis or treatment, as not all chelators are equally suitable for all radioisotopes. Typical the radioisotope chelator comprises a cyclic or branched polyaminopolycarboxylic moiety or amide derivative thereof. See for instance Tornesello et al., Molecules 2017, 22(8), 1282, US2021 / 0402016A1, WO2021 / 005125A1 and Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290 and references cited therein. In preferred embodiments of the present invention, the radioisotope chelator is based on compounds selected from the group consisting of - DOTA (1,4,7,10-tetraazacyclodocecane-N,N′,N′′,N′′′-tetraacetic acid, also known as tetraxetan) and derivatives such as p-SCN-Bn-DOTA (2-(4- isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid); - PSC (1,4,7,10-tetraazacyclododecane-7-acetamide-1,4,10-triacetic acid); - DO3A (1,4,7,10-tetraazacyclodocecane-N,N′,N′′-triacetic acid); - DOTAGA (1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid); - DO3AM (2,2′,2′′-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetamide); - DOTAM (2-[4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetrazacyclododec-1- yl]acetamide) and derivatives such as p-SCN-Bn-TCMC (2-(4- isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2- carbamoylmethyl)cyclododecane); - NOTA (1,4,7-triazacyclononane-N,N′,N′′-triacetic acid); - NODAGA (1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane); - NODASA (1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid); - CB-DO2A (4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane); - 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris-(carboxymethyl)- 1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)-amino]acetic acid); - TCMC (1,4,7,10-tetrakis(carbamoylmethyl)1,4,7,10-tetraazacyclododecane); - DTPA (diethylenetriaminepentaacetic acid) and DTPA derivatives such as CHX- A’’-DTPA (2-(p-isothiocyanatobenzyl)cyclohexyldiethylenetriaminepentaacetic acid and 1B4M-DTPA; - TETA (1,4,8,11-tetraazacyclotetradecane 1,4,8,11-tetraacetic acid) and analogues and derivatives such as C-NETA; - NE3TA ((7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) and derivatives such as C-NE3TA; - CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11 tetraazabicyclo[6.6.2]hexadecane); - NETA ({4-[2-(bis-carboxymethylamino)-ethyl]7-carboxymethyl-[1,4,7]triazonan- 1-yl)-acetic acid); and NETA derivatives such as 3p-C-NETA (see Sun et al. ACS Omega 2020, 5, 44, 28615–28620) - H2azapa (N,N′-[1-benzyl-1,2,3-triazole-4-yl]methyl-N,N′-[6-(carboxy)pyridin-2- yl)-1,2-diaminoethane) and other picolinic acid derivatives such as H2dedpa (1,2- [6-(carboxy)-pyridin-2-yl)methylamino)ethane, H4octapa (N,N′-bis(6-carboxy-2- pyridylmethyl)- - ethylenediamine-N,N′-diacetic acid), H4Py4pa, H4Pypa, H6phospha, H4CHXoctapa, H5decapa (N,N′′-[[6-(carboxy)pyridin-2-yl]methyl]- - diethylenetriamine-N,N′,N′′-triacetic acid), and H4neunpa-p-Bn-NO2; - SHBED (N,N′-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N′-diacetic acid); - HBED (N,N′-bis(2-hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid); - H2-MACROPA (N,N′-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6); - PCTA (3,6,9,15-tetraazabicyclo[ 9.3.1]pentadeca-1(15),11,13-triene-3,6,9- triacetic acid); - Me-3,2-HOPO (see Ramdahl, Bioorganic & Medicinal Chemistry Letters 26 (2016) 17, 4318-4321); - CB-TE1A1P (1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8- (methanecarboxylic acid)); - CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid); - MM-TE2A (N-monomethyl 1,8-N,N′-bis-(carboxymethyl)-1,4,8,11- tetraazacyclotetradecane); - DM-TE2A (N,N′-dimethyl 1,8-N,N′-bis-(carboxymethyl)-1,4,8,11- tetraazacyclotetradecane); - sarcophagine and sarcophagine derivatives such as SarAr (1-N-(4-aminobenzyl)- 3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine, diamSar, AmBaSar, and BaBaSar; - TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) and analogues such as NOPO (1,4,7-triazacyclononane-1,4- bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2- carboxyethyl)phosphinic acid]); - AAZTA (1,4-bis(hydroxycarbonyl methyl)-6-[bis(hydroxylcarbonylmethyl)] amino-6-methyl perhydro-1,4-diazepine); - DATA and DATA derivatives; - CP256 (4-acetamido-N1,N7-bis-[(3-hydroxy-1,6-dimethyl-4-methylene-1,4- dihydropyridin-2-yl)methyl]-4-(3-[(3-hydroxy-1,6-dimethyl-4-methylene-1,4- dihydropyridin-2-yl)methylamino]-3-oxopropyl)heptanediami) and its derivative YM103 (4-(3-[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido]propanamido)-N1,N7-bis[(3-hydroxy-1,6-dimethyl-4-methylene- 1,4-dihydropyridin-2-yl)methyl]-4-(3-[(3-hydroxy-1,6-dimethyl-4-methylene-1,4- dihydropyridin-2-yl)methylamino]-3-oxopropyl)heptanediamide); - PCTA (6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid); - BCPA (see Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290); - DFO (desferrioxamine) and DFO derivatives ; - a trithiol chelate; - mercaptoacetyl; - hydrazinonicotinamide; - dimercaptosuccinic acid; - 1,2-ethylenediylbisL-cysteine diethyl ester; - methylenediphosphonate; - hexamethylpropyleneamineoxime; - hexakis(methoxy isobutyl isonitrile); and analogues thereof. Most preferred are the DOTA, NOTA and DO3AM chelators as these chelate particularly suit well to18F,68Ga,111In,177Lu,225Ac and212Pb. Preferably, the chelator is bound to the linker via one of the carboxylic acid groups of the chelator, leading to an amide bond. However, it may also be bound via one of its carbon atoms. For linkage to a carbon atom, the chelator may be appropriately equipped with an isothiocyanate functionality, for instance an isothiocyanatobenzyl. Examples of such equipped chelators include pSCN-Bn- DOTA and p-SCN-Bn-TCMC. The chelator can also contain a BCN or DBCO group for click reaction, see for instance below in the Examples for eFAP-37 and eFAP-38. In preferred embodiments, the linker is bound to one of the carboxylic acid groups of the chelator. In embodiments, Q has a structure according to any of formula Qa-Qh, preferably Qa, Qg or Qh, more preferably Qa or Qg, most preferably Qg.

[0008] wherein m are individually 0-6, preferably 1 or 2; A1-A4are independently selected from the group consisting of H, alkyls, aliphatic acids, such as carboxylic acids like CH2CO2H and CO2H, and amides and esters thereof, preferably A1-A3are CH2CO2H and A4is CO2H; A5represents a fluoride-18 containing group or precursor, such as 1,4-butane sultone-1-yl (1,2λ6-oxathiane-2,2-dione-3-yl or 2,2-dioxido-1,2-oxathian-3-yl), CH(SO3H)(CH2)3F and / or N(CH3)2)CH2BF3; (M) represents the radioisotope; (L3) indicates the relative position of the linker L3. Of the structures according to any of formula Qa-Qh, A1-A4are preferably independently selected from the group consisting of H, (C1-C6)-alkyl, (C1- C6)-alkylene-(CO2A6), (C1-C6)-alkylene-(C(O)NA6A7), wherein A6and A7are independently selected from the group consisting of H and (C1-C6)-alkyls, preferably H. Most preferably, A1-A3are CH2CO2H and A4is CO2H to aid water solubility of the compound. In a further preferred embodiment, A1-A4are all the same and selected from the group consisting of -CH2CO2H and -CH2C(O)NH2. In particular embodiment, the chelator may be combined with a fluoride label, as illustrated in formula (Qh) wherein A5represents CH(SO3H)(CH2)3F and / or N(CH3)2)CH2BF3. This fluoride may be an18F isotope, suitable in imaging such as PET imaging. The compound may also comprise precursors for the preparation of such a compound, as illustrated in formula (Qh) wherein A5represents 1,4-butane sultone (1,2λ6-oxathiane-2,2-dione). The payload may be a fluoride-18 containing group or precursor therefor such as 1,4-butane sultone-1-yl (1,2λ6-oxathiane-2,2-dione-3-yl or 2,2-dioxido-1,2- oxathian-3-yl), CH(SO3H)(CH2)3F and / or N(CH3)2)CH2BF3. Such payload can directly, or after conversion in case of a precursor, be applied in PET imaging. The payload may be a dye, preferably a fluorescent dye such as a dye selected from the group consisting of cyanines, phtalocyanines, rhodamines, fluoresceins, xanthenes, coumarines, styryls, porphines, fluorescent organometallic complexes, oxanines, perylenes, acridines, boron-dipyrromethenes, and the like. Particularly suitable fluorescent dyes include cyanines and / or phtalocyanines. Preferred dyes are CY5 dyes, in particular sulfo-CY5, FNIR-Tag, CyTE-777, CyTE-807, IRDye 800CW, ZW800-1. Preferably, the dye is bound to the linker via one of the carboxylic acid groups of the dye, leading to an amide bond. However, it may also be bound via one of its carbon atoms. For linkage to a carbon atom, the dye may be appropriately equipped with an isothiocyanate functionality, for instance an isothiocyanatobenzyl. In preferred embodiments, the linker is bound to one of the carboxylic acid groups of the dye. In embodiments, Q has a structure according to any of formula (Qi)- (Qm), wherein (L3) indicates the relative position of the linker L3.. wherein The payload may be a drug, preferably a cytotoxic or cytostatic drug. Examples thereof include some of the radioisotopes described herein-above, as well as molecular drugs. Suitable drugs are also those described in WO2021 / 160825, which is incorporated herein in its entirety. Particular suitable drugs include Hsp90 inhibitors such as geldanamycin analogues, radicicol analogues, Zelavespib (PU-H71), Onalespib (AT13387), SNX-0723, HSP990, YC-72-AB85, Luminespib (AUY922), VER-49009, NMS-E973, Mertansine (DM1), N2'-Deacetyl-N2'-(3- mercapto-1-oxopropyl)-maytansine (DM4), doxorubicin, idarubicin, PNU, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), Exatecan, Exatecan derivative DXD, SN-38 (active metabolite of irinotecan), pyrrolo[2,1- c][1,4]benzodiazepine (PBD), SG3199 (PDB dimer), Duocarmycin, Bortezomib, AVA2727D, Tubulysin A, and Calicheamicin,. Most preferably, the drug comprises Mertansine (DM1), DM4, MMAE, Exatecan, SN38, Bortezomib and Doxorubicin. The drugs can suitably by prepared for binding to the linker, as is known to the skilled person. For instance, if the drug comprises a thiol, as e.g. is the case for DM1 and DM4, this thiol can suitably be used. In embodiments, Q has a structure according to any of formula (Qn)- (Qt), wherein (L3) indicates the relative position of the linker L3. Bortezomib (Qs) Exemplary compounds In a particularly preferred embodiment, the pharmaceutical compound, or a pharmaceutically acceptable salt thereof, has a structure according to any of formulae eFAP-34, eFAP-35, eFAP-36 and eFAP-37 below. These compounds preferably comprise a radioisotope, more preferably a111In,68Ga,177Lu, Pb212or225Ac radioisotope. The compounds eFAP-34 to eFAP-38 are particularly suitable for use in radioisotope-based tumor therapy and / or radionuclide-based tumor imaging, especially in view of their favorable tumor retention.

[0009]

[0010]

[0011]

[0012]

[0013]

[0014] Preparation The compounds of the present inventions can suitably be prepared by orthogonally conjugating the FAP-binding moieties to the core (typically forming linkers L1and L2) in one reaction, and conjugating the payload to the core (typically forming linker L3in another reaction. An exemplary synthetic pathway for the compound comprising linker L3a or L3b is schematically illustrated in Figures 3A and 3B. In a first step, the FAP-binding moiety is connected to linkers L1and L2(which are terminated with carboxylic acid or activated esters) via an amide bond formation. In a next step, the payload is conjugated to the core via a copper-free click reaction using a payload-BCN (bicyclo[6.1.0]nonyne) reagent. Further details are provided in the Example section herein-below. A particular aspect of the invention is accordingly an intermediate compound that is suitable for preparing the compound as described herein. Said intermediate compound comprises a structure according to any of formulae (IIIa), (IVa), (IIIb), (IVb), (IIIaa), (IVaa), (IIIab) and (IVab), wherein L1, L2, Z, q and r are as defined for the compound.

[0015] Medical use Over 90% of solid tumors contain cancer associated fibroblasts overexpressing FAP. Therefore, the compound of the present invention can be used for the diagnosis and treatment of a broad variety of tumors, including sarcoma, breast, lung, ovarian, head-and-neck, prostate, colorectal, and the like, and even rare or hard-to-treat cancers such as pancreatic and / or brain cancers. The compound or a pharmaceutically acceptable salt thereof, can be for use as a medicament. More specifically, for use in a medical treatment or diagnosis (including imaging) of tumors. Whether it can be used in treatment or diagnosis mostly depends on the used payload, as described herein. Accordingly, a further aspect of the present invention is directed to a method for the treatment or diagnosis of tumors, in particular FAP overexpressing tumors. Said method comprises administration of the compound or a pharmaceutically acceptable salt thereof to a patient in a pharmaceutically acceptable dose. It may be appreciated that for any moiety that may optionally be substituted or interrupted as described herein, such a moiety may also be unsubstituted or uninterrupted. Furthermore, when a compound is described herein, its salts, prodrugs, metabolites, and the like are also referred to, unless specifically noted otherwise. When the stereochemistry of an atom in a structure is undefined (e.g. C–R1), the structure refers to all stereoisomers individually of said atom. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The term "and / or" includes any and all combinations of one or more of the associated listed items. It will be understood that the terms "comprises" and / or "comprising" specify the presence of stated features but do not preclude the presence or addition of one or more other features. For the purpose of clarity and a concise description features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the invention may include embodiments having combinations of all or some of the features described. The present invention can be illustrated by the following non-limited examples and embodiments. GENERAL The chemicals and solvents were purchased from commercial suppliers and used without further purification. Reactions were magnetically stirred and monitored by thin-layer chromatography (TLC) on Merck aluminum-backed pre- coated plates (silica gel 60 F254). Melting points were determined using a Stuart SMP20. Liquid chromatography-mass spectrometry (LC-MS) was carried out on an Agilent 1260 Infinity II electrospray ionization (ESI) LC-MS system equipped with an Agilent®, InfinityLab Poroshell 120 EC-C18 column (2.7 μm, 3.0 x 100 mm). Products were eluted using a gradient of acetonitrile (ACN; 5 – 100%) in H2O containing 0.1% formic acid (FA) at a flow rate of 0.5 mL / min for 8 minutes and monitored at 220 nm, 254 nm, and 280 nm by an UV detector. Nuclear magnetic resonance (NMR) spectra were recorded in deuterated dimethyl sulfoxide (DMSO- d6) and chloroform-d (CDCl3) on a Bruker AVANCE 400 or a Nanalysis 60 Pro at ambient temperature. Chemical shifts are given as δ values in ppm, and coupling constants J are given in Hz. The splitting patterns are reported as s (singlet), d (doublet), t (triplet), q (quadruplet), qt (quintuplet), m (multiplet), and br (broad signal). Raw NMR data was processed using MestreNova 13. Purification of the compounds was carried out on a preparative HPLC 1260 Infinity II system from Agilent using a preparative column (50 × 21.2 mm, 5 μm) and a gradient elution of ACN (10% to 95% in H2O, containing 0.1% FA at a flow rate of 10 mL / min over 10 min. Instant thin-layer chromatography (iTLC-SG) plates on silica gel impregnated glass fiber sheets were eluted with sodium citrate (0.1 M, pH 5). The plates were analyzed by bSCAN radio-chromatography scanner from Brightspec equipped with a sodium iodide detector. The radioactive samples used for the determination of LogD7.4, in vitro assays and in vivo studies were counted using a Wizard 2480 gamma counter. Activity measurements were performed using the VDC-405 dose calibrator. Quality control of the radiolabeled compounds, as well as the analysis of their stability, were carried out on an ultra-high performance liquid chromatography (UHPLC) Acquity Arc system from Waters equipped with a diode array detector, a radio-detector from Canberra and an analytical C18 Gemini®column (250.0 × 4.6 mm, 5 μm) eluted with a gradient of ACN (5 to 95% in H2O, containing 0.1% trifluoroacetic acid TFA) at a flow rate of 1 mL / min over 30 min. Preparation of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine- 1,2-dicarboxylate Step 1: (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2) 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (0.95 g, 4.07 mmol) was added to a cooled (0 °C) solution of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2- dicarboxylate (0.95 g, 3.88 mmol) in DCM (10 ml), followed by the addition of catalytic TEMPO (6 mg, 0.04 mmol). After 5 min the mixture was allowed to reach room temperature, stirred for another 30 minutes and filtrated over Celite. The organic layer was washed with 10 mL saturated potassium carbonate solution, sodium thiosulfate, brine, dried over anhydrous sodium sulfate, filtrated and evaporated. The crude compound 2 (0.65 g, 70%) was used without further purification.1H NMR (400 M Hz, CDCl3): δ 4.77 (dd, 1H, J = 36.8, 8 Hz), 3.88 (br s, 2H), 3.75 (s, 3H), 2.90 (s, 1H), 2.57 (dd, 1H, J = 18.8, 2.4 Hz), 1.46 (s, 9H). ESI-MS: m / z 376.2 [M + MeOH + H]+. Step 2: (S)-1-Tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2- dicarboxylate (3) A solution of 2 (0.23 g, 0.946 mmol) in DCM (3 mL) was treated with a solution of diethylaminosulfur trifluoride (DAST, 0.197 mL, 1.607 mmol) in DCM (2 mL) at room temperature. Ethanol (0.011 mL, 0.189 mmol) was added and the mixture was stirred for 18 h at rt. The solution was poured into saturated sodium bicarbonate, extracted with DCM (3 x 15 mL), dried (Na2SO4), filtered and evaporated in vacuo. Chromatography on silica gel (100% DCM) afforded the product as a yellowish oil (0.150 g, 61%).1H NMR (400 MHz, CDCl3): δ 4.55-4.45 (m, 1H), 3.90-3.60 (m, 2H), 3.75 (s, 3H), 2.81-2.61 (m, 1H), 2.45 (dq, 1H, J = 13.6, 5.2 Hz,), 1.44 (br s, 9H). ESI-MS: m / z 266.1 [M + H]+. Preparation of the intermediate 10 Intermediate 10 was prepared according to the scheme of Figure 1. Step 1: (S)-1-(Tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (4) 3 (2.06 g, 7.78 mmol) was dissolved in MeOH (10 mL) and a solution of NaOH (0.67 g, 17.18 mmol) in MeOH (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 min. Upon completion, the reaction mixture was acidified using 1N HCL to pH 2 and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4and concentrated in vacuo. It yielded an off-white solid product (1.62 g, 6.44 mmol, 86%).1H NMR (60 MHz, DMSO-d6): δ 4.33 (dd, 1H, J = 9.3, 4.4 Hz), 3.68 (t, 2H, J = 13.2 Hz), 2.76-2.12 (m, 2H), 1.34 (s, 9H). mp: 118-119 ºC. ESI-MS: m / z 152.1 [M + H - Boc]+. Step 2: Tert-butyl (S)-2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylate (5) 4 (1.55 g, 6.15 mmol) was dissolved in DCM (dry, 30 mL) and HONSu (0.88 g, 7.65 mmol) was added and stirred at room temperature until fully dissolved. DCC (1.55 g, 7.52 mmol) was added and stirred at rt for 30 min as slowly insoluble formed in the reaction mixture. NH3(14 mL, 4 M in MeOH) was added dropwise and the reaction mixture was stirred at rt for 3 h. Upon completion, EtOAc (50 mL) was added and the organic layer was washed with sat. aq. NaHCO3(5 x 25 mL), brine (25 mL), dried over MgSO4and concentrated in vacuo. The product was obtained as an off-white solid (1.53 g, 6.02 mmol, 97%).1H NMR (60 MHz, CDCl3): δ 6.50 (br, s, 1H), 5.60 (br, s, 1H), 4.48 (dd, 1H, J = 8.6, 5.8 Hz), 3.76 (td, 2H, J = 12.4, 5.2 Hz), 2.74 (td, 2H, J = 13.6, 4.6 Hz), 1.46 (s, 9H). mp: 127–128 ºC. ESI-MS: m / z 151.1 [M + H - Boc]+. Step 3: (S)-4,4-Difluoropyrrolidine-2-carboxamide (6) 5 (1.19 g, 4.69 mmol) was dissolved in DCM (10 mL) and TFA (5 mL). The reaction mixture was stirred at rt for 2.5 h. Upon completion, all volatiles were removed. Cold ether was added and 6 was recovered as a white solid (0.98 g, 3.66 mmol, 78%).1H NMR (60 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.70 (s, 1H), 4.55-4.17 (t, 1H, J = 7.8 Hz), 3.54 (d, 2H, J = 12.0 Hz), 2.45 (m, 2H). mp: > 130 ºC. ESI-MS: m / z 151.0 [M + H]+. Step 4: Tert-butyl (S)-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamate (7) 6 (0.93 g, 3.47 mmol) was dissolved in DMF (30 mL). Boc-Gly-OH (0.81 g, 4.62 mmol), HBTU (1.64 g, 4.32 mmol) and DIPEA (3.0 mL, 2.3 g, 17.6 mmol) were added and the reaction mixture was stirred overnight. EtOAc (50 mL) was added and the organic layer was washed with brine (5 x 25 mL), dried over MgSO4and concentrated in vacuo. The crude reaction mixture was redissolved in THF (30 mL) and cooled to -15 ºC. Pyridine (1.00 mL, 12.4 mmol) and TFAA (1.00 mL, 7.19 mmol) were added and the reaction mixture and was stirred for 5 h, allowing to reach rt. EtOAc (50 mL) and H2O (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with water and brine, dried over MgSO4and concentrated in vacuo. The product was purified by flash chromatograph (silica gel, Hexane / EtOac 1:1).7 was obtained as a yellow solid (200 mg, 0.69 mmol, 25%).1H NMR (60 MHz, CDCl3): δ 5.48 (s, 1H), 4.94 (t, 1H, J = 6.3 Hz), 3.70-4.15 (m, 4H), 2.42-2.94 (m, 2H), 1.40 (s, 9H). mp: 128-129 ºC. ESI-MS: m / z 190.1 [M + H - Boc]+. Step 5: 8-(3-((Tert-butoxycarbonyl)amino)propoxy)quinoline-4-carboxylic acid (9) 8 (0.25 g, 1.32 mmol) was dissolved in DMF (25 mL). 3-(Boc-amino)- propylbromide (0.94 g, 4.0 mmol) and Cs2CO3(1.31 g, 4.0 mmol) were added. The reaction mixture was stirred at rt for 2.5 h. Upon completion, EtOAc (50 mL) was added and the organic layer was washed with brine (5 x 25 mL), dried over MgSO4and concentrated in vacuo. The residue was redissolved in MeOH (10 mL) and NaOH (78 mg, 2.0 mmol) was added. The reaction mixture was stirred at rt for 35 minutes. The reaction mixture was concentrated in vacuo and the product was purified using prep-HPLC.9 was obtained as a light-yellow solid (0.26 g, 0.75 mmol, 57%).1H NMR (60 MHz, DMSO-d6): δ 8.94 (d, 1H, J = 4.2 Hz), 8.16 (d, 1H, J = 8.3 Hz), 7.88 (d, 1H, J = 4.3 Hz), 7.55 (t, 1H, J = 8.1 Hz), 7.18 (d, 1H, J = 7.4 Hz), 4.16 (t, 2H, J = 5.9 Hz), 3.39-2.91 (m, 2H), 1.93 (t, 2H, J = 6.1 Hz), 1.32 (s, 9H). mp: > 130 ºC. ESI-MS: m / z 346.7 [M + H]+. Step 6: Tert-butyl (S)-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)carbamate (10) 7 (0.18 g, 0.61 mmol) was dissolved in DCM (3 mL) and TFA (3 mL). The reaction mixture was stirred at rt for 45 min. Upon completion, all volatiles were removed under a gentle air flow.9 (0.2 g, 0.58 mmol), HBTU (0.34 g, 0.87 mmol) and DIPEA (0.35 mL) were added to the residue redissolved in DMF (5 mL). The reaction mixture was stirred at rt overnight. EtOAc (50 mL) was added and the organic layer was washed with brine (5 x 25 mL), dried over MgSO4and concentrated in vacuo. The product was purified using flash chromatography (Silica gel, Hexane / EtOac 1:1) to yield 10 as a light-yellow sticky oil (0.23 g, 0.44 mmol, 72%).1H NMR (60 MHz, CDCl3): δ 8.69 (d, 1H, J = 4.2 Hz), 7.64 (m, 2H), 7.45-7.02 (m, 2H), 6.86 (d, 1H, J = 7.3 Hz), 6.30 (s, 1H), 4.82 (s, 1H), 4.02 (m, 4H), 3.22 (m, 2H), 2.55 (m, 4H), 2.04 (m, 2H), 1.35 (s, 9H). ESI-MS: m / z 618.0 [M + H]+. Preparation of (S)-8-(3-(4-(aminomethyl)cyclohexane-1- carboxamido)propoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide (8-QCP-Amcha) As illustrated in Figure 2, 10 (65 mg, 125 µmol) was treated with a solution of DCM / TFA (5 mL, 1:1) at rt for 30 min. All volatiles were removed under a gentle air flow to obtain a brown crude solid. The crude was redissolved in DMF (1.5 mL), followed by addition of N-Fmoc-tranexamic acid (1.1 equiv., 46,8 mg), HBTU (2 equiv., 95 mg), DIPEA (100 µL) and DMF (1.5 mL). The reaction was stirred at rt for 1 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-yellow solid. The crude product was treated with a solution of piperidine / DMF (2 mL, 1:5) at rt for 30 min, the solvent was removed under vacuum and the crude product was purified by prep-HPLC to yield 8QCP-AMCHA (30 mg, 53.9 µmol, 43%) as an off- yellow powder. ESI-MS: m / z 557.2 [M + H]+. Example 1: preparation of 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2- (3,5-bis(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-3- oxopropyl)thio)acetyl)-1,3,5-triazinan-1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8- octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6- yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-34) As illustrated in Figure 4, 8QCP-SH (5.5 mg, 10.8 µmol) was dissolved in DMF (1 mL), followed by the addition of TADB-N3(1.3 mg, 3.1 µmol, prepared as described in Van de Langemheen et al. ChemBioChem. 2017; 18(4) : 387-395) and DIPEA (10 µL). After 30 min, the solvent was removed under vacuum and the crude product was purified by prep-HPLC to yield (8QCP-SH)2-TADB (2.9 mg, 2.2 µmol, 41%) as an off-white powder. ESI-MS: m / z 1346.3 [M + H]+. The powder was redissolved in ACN / H2O (1 mL, 1:1), followed by the addition of BCN-DOTAGA (1.1 eq, 1.7 mg). The reaction was stirred at 37 ℃ for 30 min, the solvent was purified by prep-HPLC to yield eFAP-34 (1.4 mg, 0.7 µmol, 31%) as an off-white powder. ESI-MS: m / z 1956.5 [M + H]+. Example 2: preparation of 2,2',2''-(10-(4-((2-(((((5aS,6R,6aR)-1-(2- (3,5-bis(2-((6-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-6- oxohexyl)thio)acetyl)-1,3,5-triazinan-1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8- octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6- yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-35) 8QCP-SH (4.1 mg, 7.5 µmol) was dissolved in DMF (1 mL), followed by the addition of TADB-N3(1 mg, 2.4 µmol) and DIPEA (10 µL). After 30 min, the solvent was removed under vacuum and the crude product was purified by prep- HPLC to yield (8QCP-SH)2-TADB (2.2 mg, 1.6 µmol, 44%) as an off-white powder. ESI-MS: m / z 1346.3 [M + H]+. The powder was redissolved in ACN / H2O (1 mL, 1:1), followed by the addition of BCN-DOTAGA (1.1 eq, 1.3 mg). The reaction was stirred at 37 ℃ for 30 min, the solvent was purified by prep-HPLC to yield eFAP-35 (1.8 mg, 0.9 µmol, 54%) as an off-white powder. ESI-MS: m / z 2040.8 [M + H]+. Example 3: preparation of 3,3'-(((((((5-(2-azidoacetyl)-1,3,5- triazinane-1,3-diyl)bis(2-oxoethane-2,1-diyl))bis(azanediyl))bis(ethane-2,1- diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))dipropionic acid (PEG2-TADB- PEG2, Platform 1) As illustrated in Figure 5, TADB-N3(8 mg, 19 µmol) was dissolved in DMF (1 mL), followed by addition of NH2-PEG2-tBu (3 equiv., 13 mg), DIPEA (30 µL). The reaction was stirred at rt for 2 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was treated with a solution of DCM / TFA (3 mL, 1:1) at rt for 30 min. All volatiles were removed under a gentle air flow to obtain a light-white crude solid. The crude was purified by prep-HPLC to yield Platform 1 (6.3 mg, 10.4 µmol, 55%), as a light-white oil. ESI-MS: m / z 605.2 [M + H]+. Example 4: preparation of 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2- (3,5-bis(16-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)-12-oxo-6,9-dioxa-3,13- diazahexadecanoyl)-1,3,5-triazinan-1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8- octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6- yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-36) 10 (15 mg, 29 µmol) was treated with a solution of DCM / TFA (3 mL, 1:1) at rt for 30 min, all volatiles were removed under a gentle air flow to obtain a brown crude solid (8QCP-NH2). The crude was redissolved in DMF (1 mL), followed by addition of PEG2-TADB-PEG2(1.5 eq, 26 mg), HBTU (2 eq, 23.6 mg), DIPEA (30 µL) and DMF (1.5 mL). The reaction was stirred at rt for 1 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over MgSO4and concentrated under vacuum to obtain an off-white solid. The crude product was redissolved in ACN / H2O (1 mL, 1:1), followed by the addition of BCN-DOTAGA (1.1 eq, 2.6 mg). The reaction was stirred at 37 ℃ for 30 min, the solvent was purified by prep- HPLC to yield eFAP-36 (2.7 mg, 1.2 µmol, 34%) as an off-white powder. ESI-MS: m / z 2099.2 [M + H]+. Example 5: preparation of 3,3'-((((((6-((3-azidopropyl)amino)- 1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(ethane-2,1- diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))dipropionic acid (Platform 2, PEG2-triazine-PEG2). As illustrated in Figure 6, 2,4,6-Trichloro-1,3,5-triazine (25 mg, 13.5 µmol) was dissolved in DMF (1 mL), followed by addition of NH2-PEG2-tBu (2.3 equiv., 72.7 mg), DIPEA (117 µL) . The reaction was stirred at rt for 2 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 3-azidopropan-1-amine (2.2 eq, 29.7 mg). The reaction was stirred at rt for 24 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was treated with a solution of DCM / TFA (3 mL, 1:1) at rt for 30 min. All volatiles were removed under a gentle air flow to obtain a light-white crude solid. The crude was purified by prep-HPLC to yield Platform 2 (3 mg, 8.6 µmol, 64%), as a light-white oil. ESI-MS: m / z 530.2 [M + H]+. Example 6: preparation of 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(3- ((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-3- oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2-yl)amino)propyl)- 1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6- yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-37) 10 (15 mg, 29 µmol) was treated with a solution of DCM / TFA (3 mL, 1:1) at rt for 30 min, all volatiles were removed under a gentle air flow to obtain a brown crude solid. The crude was redissolved in DMF (1 mL), followed by addition of PEG2-triazine-PEG2(1.5 eq, 23 mg), HBTU (2 eq, 23.6 mg), DIPEA (30 µL) and DMF (1.5 mL). The reaction was stirred at rt for 1 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Na2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was redissolved in ACN / H2O (1 mL, 1:1), followed by the addition of BCN-DOTAGA (1.1 eq, 2.6 mg). The reaction was stirred at 37 ℃ for 30 min, the solvent was purified by prep- HPLC to yield eFAP-37 (3 mg, 1.5 µmol, 39%) as an off-white powder. ESI-MS: m / z 2024.1 [M + H]+. Example 7: preparation of 2,2',2''-(10-(4-((3-(1-(2-(3,5-bis(2-((3-((3- ((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-3- oxopropyl)thio)acetyl)-1,3,5-triazinan-1-yl)-2-oxoethyl)-1,9-dihydro-8H- dibenzo[b,f][1,2,3]triazolo[4,5-d]azocin-8-yl)-3-oxopropyl)amino)-1- carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-38) (8QCP-SH)2-TADB (0.8 eq, 1 mg) was dissolved in ACN / H2O (1 mL, 1:1), followed by the addition of DBCO-DOTAGA (1.1 eq, 0.6 mg). The reaction was stirred at 37 ℃ for 30 min, the solvent was purified by prep-HPLC to yield eFAP-38 (0.5 mg, 0.25 µmol, 31%) as an off-white powder. ESI-MS: m / z 1996.7[M + H]+. Example 8: preparation of 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-(3-((3-((4- ((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-3- oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2-yl)amino)hexyl)amino)-1- carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-50) As illustrated in Figure 7, 2,4,6-Trichloro-1,3,5-triazine (60 mg, 32.5 µmol) was dissolved in DMF (1.5 mL), followed by addition of NH2-PEG2-tBu (2.2 equiv., 167.0 mg) and DIPEA (210 µL). The reaction was stirred at rt for 2 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was treated with a solution of DCM / TFA (4 mL, 1:1) at rt for 30 min. All volatiles were removed under a gentle air flow to obtain a light-white oil. The oil was redissolved in DMF (1 mL), followed by addition of N-Boc-1,6-diaminohexane (1.5 equiv., 9.6 mg) and DIPEA. The reaction was stirred at rt for 24 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 8QCP-NH2(2.5 equiv., 25 mg, obtainable from intermediate 10, as illustrated in Figure 4 and described for eFAP-36), HBTU (2 equiv., 14 mg), and DIPEA (30 µL). The reaction was stirred at rt for 2 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-yellow solid. The crude product was treated with a solution of DCM / TFA (2 mL, 1:1) at rt for 30 min. All volatiles were removed under a gentle air flow to obtain a light-yellow solid. The solid was redissolved in DMF (1 mL), followed by the addition of DOTAGA anhydride (2,2′,2”- (10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid, 1.2 equiv., 4.6 mg) and DIPEA (40 µL). After 1 h, the solvent was removed under vacuum and the crude product was purified by prep-HPLC to yield eFAP-50 (5 mg, 2.8 µmol, 33%), as an off-white powder. ESI-MS: m / z 1803.5 [M + H]+. Example 9: preparation of 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-(3-(((4- ((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)carbamoyl)cyclohexyl)methyl)amino)-3- oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2-yl)amino)hexyl)amino)-1- carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-51) As illustrated in Figure 8, 2,4,6-trichloro-1,3,5-triazine (60 mg, 32.5 µmol) was dissolved in DMF (1.5 mL), followed by addition of NH2-PEG2-tBu (2.2 equiv., 167.0 mg) and DIPEA (210 µL). The reaction was stirred at rt for 2 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was treated with a solution of DCM / TFA (4 mL, 1:1) at rt for 30 min. All volatiles were removed under a gentle air flow to obtain a light-white oil. The oil was redissolved in DMF (1 mL), followed by addition of N-Boc-1,6-diaminohexane (1.5 equiv., 9.6 mg) and DIPEA. The reaction was stirred at rt for 24 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 8QCP-AMCHA (2.5 equiv., 25 mg), HBTU (2 equiv., 14 mg), and DIPEA (30 µL). The reaction was stirred at rt for 2 h, diluted with EtOAc (15 mL), washed with water (3 x 5 mL), dried over Mg2SO4and concentrated under vacuum to obtain a light-yellow solid. The crude product was treated with a solution of DCM / TFA (2 mL, 1:1) at rt for 30 min. All volatiles were removed under a gentle air flow to obtain a light-yellow solid. The solid was redissolved in DMF (1 mL), followed by the addition of DOTAGA anhydride (2.5 equiv., 25 mg) and DIPEA (40 µL). After1 h, the solvent was removed under vacuum and the crude product was purified by prep-HPLC to yield eFAP-51 (2 mg, 1.0 µmol, 33%), as an off-white powder. ESI-MS: m / z 1041.1 [M + 2H]2+. Example 10: preparation of 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-(3-(4-(2- ((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-2- oxoethyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2- yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-52) As illustrated in Figure 9, eFAP-52 can be obtained from a similar procedure as described in Example 9 for eFAP-51. RADIOLABELING, ANALYSES AND RESULTS Radiolabeling with [111In] InCl3Precursor (1 nmol) was added to a mixture of [111In]InCl3(20 MBq), ascorbic acid / gentisic acid (10 μL, 50 mM), sodium acetate (2.5 M, 1 μL, pH 8), and water containing kolliphor (2.0 mg / mL, 58.6 μL). The labeling mixture (pH 4.5) was incubated at 90 °C for 15 min. Then, it was cooled down for 5 min, and the radiochemical yield (RCY) was determined by iTLC on silica gel-impregnated glass- fiber sheets. Diethylenetriaminepentaacetic acid (4 mM, 5 μL) was added to complex-free indium-111. The radiochemical purity (RCP) of the111In-labeled peptides was measured by radio-HPLC. Results are shown in Table 1. In vitro stability The radiolabeled compounds (~ 2 MBq) were mixed with 300 µL of PBS (0.1 M, pH 7.4) or mouse serum at 37 °C for 1, 4 and 24 h. At each time point, the proteins in the serum sample were precipitated by addition of acetonitrile (300 μL), and the solution was centrifuged for 5 min at 13,000 rpm (twice). The supernatant was loaded onto a radio-HPLC system for analysis. The samples in PBS were directly analyzed by radio-HPLC without any pre-treatment. All the experiments were performed in triplicate. Results are shown in Table 1 and Figures 10A-10L. LogD7.4The distribution coefficient of the compounds was determined by the shake-flask method. The experiment was performed in triplicate for each compound. The radiolabeled compounds (∼0.3 MBq) were added to a mixture of phosphate-buffered saline (PBS) / n-octanol (1 mL, v / v = 1:1) in Eppendorf vials. The Eppendorf vials were vortexed vigorously and centrifuged for 3 min at 10,000 rpm. n-Octanol was separated from PBS and poured into new vials. Samples from each phase (10 μL) were poured into glass tubes and measured with a gamma counter. The LogD7.4value was calculated using the following equation: LogD7.4= log10 ([counts in organic phase] / [counts in aqueous phase]). Results are shown in Table 1. Table 1. RCYs, RCPs, stability studies in PBS and mouse serum and determination of the partition coefficient (LogD7.4). In vitro inhibition assay on human and mouse FAP Enzymatic activity of human FAP (hFAP) and mouse FAP (mFAP) on the Z-GP-AMC substrate was measured at room temperature on a Hidex microplate reader by monitoring the fluorescence at an excitation wavelength of 360 nm and an emission wavelength of 465 nm. The reaction mixture contained 20 µM substrate, 20 nM FAP, assay buffer (50 mM Tris, 100 mM NaCl, 1 mM EDTA, pH 7.4) and tested compound (serial dilution from 10-6to 10-12) in a total volume of 50 µL. The IC50 value is defined as the concentration of inhibitor required to reduce the enzyme activity by 50% after addition of the substrate. All the eFAP compounds tested exhibited IC50 values for human FAP below 2 nM. Results with FAPI-46 obtained in the same assay is included for comparison. Table 2. Determination of the IC50 values of the eFAP drugs for human and murine FAP based on an enzymatic assay. In vitro inhibition assay on DPP4 Enzymatic assay of DPP4 contained substrate H-Gly-Pro-AMC (100 μM), DPP4 (0.5 nM), assay buffer (50 mM Tris, 100 mM NaCl, pH = 8 (1% v / v DMSO)), and inhibitors of interested with serial dilution from 10-4M to 10-10M to a total volume of 50 μL. Sitagliptin (10-4M) and assay buffer 1% v / v DMSO were used as a positive and negative control, respectively. H-Gly-Pro-AMC (100 μM) in assay buffer 1% v / v DMSO was used as a baseline control. Plates were incubated at 37°C under dark conditions for 30 min and followed by measurement on a Hidex microplate reader by monitoring the fluorescence at an excitation wavelength of 360 nm and an emission wavelength of 465 nm. All experiments were performed in triplicate and repeated three times. Data obtained from the enzymatic assays were Log-transformed and normalized for the positive (0%) and negative (100%) control, and fitted using Y=100 / (1+10^((LogIC50-X)*HillSlope)), where the value represents the concentration of inhibitor required to reduce the enzyme activity by 50% after addition of the substrate. The results are given in Table 3. Table 3. Determination of the IC50 values of eFAP compounds for DPP4 based on an enzymatic assay. Cell uptake / blocking experiments using U87cells. Cells were seeded in 6-well plates 24 h before the experiment (7 × 105cells / well). The following day, adhered cells were incubated with 10−9M of [111In]In-labeled compound in 1 mL of culture medium for 90 min at 37 °C. Compounds were also evaluated with a block of 50-fold excess non-labelled compound. The membrane- bound fraction (MF) was collected by incubating cells with an acid buffer (50 mM glycine, 100 mM NaCl, pH 2.8) for 10 min at rt. The internalized fraction (IF) was determined by lysing the cells with 1 M NaOH for 5 min at rt. Both fractions were measured in a gamma counter, and data were analyzed in GraphPad Prism v9 and expressed as percentage of added dose. Results are provided in Figure 11 and Table 4. Table 4. Cell uptake / blocking using U87 cells In vivo study Five-week-old male NMRI-Foxn1 nu / nu mice (Janvier; Le Genest-Saint- Isle, France) were housed in individually ventilated cages with a maximum of three mice per cage. After one week of acclimatization, mice were subcutaneously inoculated with HT1080-huFAP on the right shoulder and HT1080-WT on the left shoulder. The animals received 200 µL of [111In]In-eFAP-51 (n=4 per group) or [111In]In-FAPI-46 (n=4 per group) (20 MBq / 1 nmol) by intravenous injection through the tail vein, and at 1, 4, 24 and 48 h SPECT / CT imaging was performed, biodistribution studies were performed at 48 h. Blood was collected by orbital puncture under isoflurane / O2anesthesia, immediately followed by cervical dislocation. Hereafter the two tumor xenografts, pancreas, liver, GI-tract (stomach, small intestine, cecum, colon), kidneys (left and right), lungs, heart, muscle, and bone (femur), were collected, weighed, and measured in a y-counter (PerkinElmer), alongside 10 µL of the injected activity as standard. Figure 12 shows the SPECT / CT images. Figure 13 shows the results of the biodistribution studies after 48 h. The results are expressed as the percentage injected dose per gram (% ID / g).

Claims

Claims 1. Compound, or a pharmaceutically acceptable salt thereof according to formula (I) or formula (II)wherein L1, L2and L3each individually represent a linker; Q represents a payload, preferably a therapeutic agent, a diagnostic agent or a combination thereof; each Z independently represents a FAP-binding moiety comprising a scaffold according to formula (Z)wherein X represents NH, CH2or O; R1represents H, Me, CH(CH3)C2H5, CH2CH(CH3)2, CH(CH3)2, CH2OH, CH2SH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, (CH2)mCO2H, (CH2)mNH2, wherein m is 1-4; and R2and R3each independently represent H or F.

2. Compound, or a pharmaceutically acceptable salt thereof according to claim 1, wherein each Z independently represents a FAP-binding moiety according to formula (Za)wherein X respesents CH2or O, preferably O; and R1, R2and R3are in accordance with any of the previous claims.

3. Compound, or a pharmaceutically acceptable salt thereof according to any of the previous claims, wherein each Z independently represents a FAP- binding moiety according to formula (Zb)wherein R4represents a spacer, preferably an aliphatic spacer; and X, R1, R2and R3are in accordance with any of the previous claims.

4. Compound, or a pharmaceutically acceptable salt thereof according to any of the previous claims, wherein each Z independently represents a FAP- binding moiety according to formula (Zc)wherein R4’represents an optionally substituted hydrocarbylene or an optionally substituted alkylene ether, preferably an alkylene, more preferably C1-C8alkylene; and X, R1, R2and R3are in accordance with any of the previous claims.

5. Compound, or a pharmaceutically acceptable salt thereof according to any of the previous claims, wherein each Z independently represents a FAP- binding moiety according to formula (Zd)wherein n is 1-6, preferably 1; and X, R1, R2and R3are in accordance with any of the previous claims.

6. Compound, or a pharmaceutically acceptable salt thereof according to any of the previous claims, wherein L1, L2and / or L3independently are at least partially based on linear or branched amino acids, preferably on glycine, alanine, β- alanine, 3-aminopropionic acid, 4-aminobutyric acid, 4-amino-3-hydroxybutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8- aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, and the like, a peptide spacer (Xaa)1-4, wherein each Xaa is independently a proteinogenic or non-proteinogenic amino acid residue selected from the group consisting of a D-amino acid of a proteinogenic amino acid, Nε,Nε,Nε-trimethyl- lysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), ornithine (Orn), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3- guanidinopropionic acid (Agp), β-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9- aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-aminoadipic acid ( 2-Aad), 3-aminoadipic acid (3-Aad), 4-(aminomethyl)cyclohexane-1-carbonyl (Amcha), 4-amino-1-carboxymethyl-piperidinyl (Pip), 2-(piperazin-1-yl)acetic acid(Pipa), 2-(4-(2-aminoethyl)piperazini-1-yl)acetic acid, cysteic acid, diglycolic acid, and NH2(CH2)2[O(CH2)2]qC(O)OH (wherein q = 1-36), preferably wherein L1and L2both represent NH2(CH2)2[O(CH2)2]qC(O)OH, wherein q = 1-36, more preferably NH2(CH2)2[O(CH2)2]qC(O)OH, wherein q = 2-6.

7. Compound, or a pharmaceutically acceptable salt thereof according to any of the previous claims, wherein L1, L2and / or L3, preferably at least L1and L2, independently comprise a moiety having a structure as shown in any of formulae La-Lp, preferably Lo and / or Lp;and wherein furtherY1is selected from the group consisting of C and N, preferably N for formula La, Lg and Lh and C for formula Ld; Y2is selected from the group consisting of C, N, and O, preferably N and C; more preferably C; and q is in the range of 1 to 36, preferably 2 to 6, more preferably wherein the linkers L1, L2and / or L3comprises a moiety having a structure according to any of formulae Laa, Lfa, Lfb, Lfc ,Lga, Lha, Lhb, Lhc, and Lmawherein q is in the range of 1 to 36, preferably 1 to 6.

8. Compound, or a pharmaceutically acceptable salt thereof according to any of the previous claims, wherein L3has a structure according to any of formulae (L3a), (L3b), (L3c), (L3d), (L3e), (L3f), (L3g), (L3h), (L3i), (L3j), (L3k), (L3l), (L3m) and (L3n)wherein (Q) indicates the relative position of the payload Q; r is in the range of 1-6, preferably 1-3, more preferably 3; andp is in the range of 1-6, preferably 1-3, more preferably 2.

9. Compound or a pharmaceutically acceptable salt thereof according to any of the previous claims, wherein said compound has a structure according to formula (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IIc), or (IId) preferably according to formula (Iaa), (IIaa), (Iba), (IIba), (Ibb), (IIbb), (Ibc), (IIbc), (Ica), (IIca), (Ida) or (IIda)wherein q is 0 or more, preferably in the range of 1-6, more preferably 2; r is in the range of 1-6, preferably 1-3, more preferably 1 or 3; p is in the range of 0-6, preferably 1-3, more preferably 2; and Z, Q, L1and L2are in accordance with any of the previous claims.

10. Compound according to any of the previous claims, wherein L3comprises a cleavable linker section comprising an in vivo cleavable moiety or forms an in vivo cleavable moiety with the payload, preferably wherein the in vivo cleavable moiety comprises one or more of amides, ester, carbamates, hydrazones, thiazolidine, methylene alkoxy carbamate and disulfides, more preferably wherein the cleavable linker section comprises one or more of linear or branched mercapto carboxylic acids such as thioglycolic acid, thiolactic acid (also known as 2- mercaptopropionic acid), 3-mercaptopropionic acid (3-MPA), 4-mercaptobutanoic acid (SPDB), 4-mercaptopentanoic acid (SPP), 4-mercapto-2-sulfobutanoic acid (Sulfo-SPDB), p-amino benzyl carbamate (PAB), valine-citrulline (Val-Cit-PAB), glycine-proline (Gly-Pro-PAB), Ala-Ala-Asn-PAB, DGA-Lys-PAB, β-glucuronide, and Grob fragmentable moieties.

11. Compound according to any of the previous claims, wherein Q comprises a radioisotope, a fluorescent dye, a drug or a combination thereof, preferably one or more of radioisotopes complexed to chelators, fluorescent dyes, and drugs such as a cytotoxic or cytostatic agents.

12. Compound according to any of the previous claims, wherein Q comprises a radioisotope complexed to a chelator, preferably wherein the radioisotope is an α- or β-particle emitter, an Auger emitter, a positron emitter and / or a γ-emitter andwherein the chelator preferably comprises a cyclic or branched polyaminopolycarboxylic moiety or amide derivative thereof.

13. Compound according to any of the previous claims, wherein Q comprises a dye, preferably a fluorescent dye, more preferably a dye selected from the group consisting of cyanines, phtalocyanines, rhodamines, fluoresceins, xanthenes, coumarines, styryls, porphines, fluorescent organometallic complexes, oxanines, perylenes, acridines, boron-dipyrromethenes, and combinations thereof, even more preferably from cyanines and / or phtalocyanines, yet even more preferably from the group consisting of CY5 dyes, most preferably from the group consisting of sulfo- CY5, FNIR-Tag, CyTE-777, CyTE-807, IRDye 800CW, ZW800-1, and combinations thereof.

14. Compound according to any of the previous claims, wherein Q comprises a drug, preferably Hsp90 inhibitors such as geldanamycin analogues, radicicol analogues, Zelavespib (PU-H71), Onalespib (AT13387), SNX-0723, HSP990, YC-72- AB85, Luminespib (AUY922), VER-49009, NMS-E973, Mertansine (DM1), N2'- Deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM4), doxorubicin, idarubicin, PNU, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), Exatecan, Exatecan derivative for ADC (DXD), SN-38 (active metabolite of irinotecan), pyrrolo[2,1-c][1,4]benzodiazepine (PBD), SG3199 (PDB dimer), Duocarmycin, Bortezomib, Doxorubicin, AVA2727D, Tubulysin A, and Calicheamicin, most preferably wherein the drug comprises Mertansine (DM1), DM4, MMAE, Exatecan, SN38, Bortezomib and Doxorubicin.

15. Compound according to any of the previous claims, wherein Q has a structure according to any of formula Qa-Qh, preferably Qa, Qg or Qh, more preferably Qa or Qg.wherein m are individually 0-6, preferably 1; A1-A4are independently selected from the group consisting of H, alkyls, aliphatic acids, such as carboxylic acids like CH2CO2H and CO2H, and amides and esters thereof, preferably CH2CO2H and / or CO2H;A5represents a fluoride containing group or precursor therefor such as 1,4-butane sultone-1-yl (1,2λ6-oxathiane-2,2-dione-3-yl or 2,2-dioxido-1,2-oxathian-3-yl), CH(SO3H)(CH2)3F and / or N(CH3)2)CH2BF3; (M) represents a radioisotope; (L3) indicates the relative position of the linker L3.

16. Compound, or a pharmaceutically acceptable salt thereof, according to any of the previous claims wherein X represents O, R1represents H and / or at least one of R2and R3represents F, preferably both R2and R3represent F.

17. Compound, or a pharmaceutically acceptable salt thereof, according to any of the previous claims, selected from the group consisting of - 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2-(3,5-bis(2-((3-((3-((4-((2-((S)-2-cyano- 4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)amino)-3-oxopropyl)thio)acetyl)-1,3,5-triazinan-1-yl)-2- oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2- d][1,2,3]triazol-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4- oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-34); - 2,2',2''-(10-(4-((2-(((((5aS,6R,6aR)-1-(2-(3,5-bis(2-((6-((3-((4-((2-((S)-2-cyano- 4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)amino)-6-oxohexyl)thio)acetyl)-1,3,5-triazinan-1-yl)-2- oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2- d][1,2,3]triazol-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4- oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-35); - 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2-(3,5-bis(16-((4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)oxy)-12-oxo-6,9- dioxa-3,13-diazahexadecanoyl)-1,3,5-triazinan-1-yl)-2-oxoethyl)- 1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6- yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-36); - 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(3-((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2- cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2- yl)amino)propyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4- oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-37); - 2,2',2''-(10-(4-((3-(1-(2-(3,5-bis(2-((3-((3-((4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)amino)-3-oxopropyl)thio)acetyl)-1,3,5-triazinan-1-yl)-2- oxoethyl)-1,9-dihydro-8H-dibenzo[b,f][1,2,3]triazolo[4,5-d]azocin-8-yl)-3- oxopropyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl)triacetic acid (eFAP-38); - 2-((E)-2-((E)-3-(2-((E)-1-(6-((6-((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2- yl)amino)hexyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfonatoindolin-2- ylidene)ethylidene)-2-(4-sulfonatophenoxy)cyclohex-1-en-1-yl)vinyl)-3,3- dimethyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5-sulfonate (eFAP-44); - (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-chloro-14-hydroxy-85,14- dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)- oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl N-(3-((3-((6- ((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-3- oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2-yl)amino)hexyl)amino)-3- oxopropyl)disulfaneyl)propanoyl)-N-methyl-L-alaninate (eFAP-45); - 8,8'-((((3,3'-((((((6-((2-(2-(2-(4-((2,2-dioxido-1,2-oxathian-3-yl)methyl)-1H- 1,2,3-triazol-1-yl)ethoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2,4- diyl)bis(azanediyl))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1- diyl))bis(oxy))bis(propanoyl))bis(azanediyl))bis(propane-3,1- diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide) (eFAP-46); - 1-(1-(2-(2-(2-((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)oxy)propyl)amino)-3- oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2- yl)amino)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)-5-fluoropentane-2- sulfonate (eFAP-47);- 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2- yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-50); - 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-(3-(((4-((3-((4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)carbamoyl)cyclohexyl)methyl)amino)-3- oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2-yl)amino)hexyl)amino)-1- carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-51); - 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-(3-(4-(2-((3-((4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)oxy)propyl)amino)-2-oxoethyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazin-2-yl)amino)hexyl)amino)-1- carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-52); and - radioisotope labeled, preferably111In,68Ga,177Lu,225Ac,212Pb radioisotope labeled, eFAP-34, eFAP-35, eFAP-36, eFAP-37, eFAP-38, eFAP-50, eFAP-51 and eFAP-52.

18. Compound, or a pharmaceutically acceptable salt thereof, according to any of the previous claims for medical use, preferably for use in the diagnosis and / or treatment of tumors.

19. Intermediate compound for preparing the compound according to any of the previous claims, wherein said compound comprises a structure according to any of formulae (IIIa), (IVa), (IIIb), (IVb), (IIIaa), (IVaa), (IIIab) and (IVab), preferably according to any of formulae (IIIaa), (IVaa), (IIIab) and (IVab)wherein L1, L2, Z, q and r are as defined in any of the previous claims.

Images