WO2023057457A1 - Radiolabelled fibroblast activation protein ligands - Google Patents

Abstract

The present invention relates to ligands of Fibroblast Activation Protein (FAP) for the active delivery of radioactive payloads at the site of disease. In particular, the present invention relates to the development of FAP ligands for the targeted delivery of radionuclides, such as ¹⁸Fluorine, ⁶⁸Gallium, ⁶⁴Copper, ¹¹¹Indium, ¹⁷⁷Lutetium, and to diagnostic methods and/or methods for therapy or surgery in relation to a disease or disorder, such as cancer, inflammation or another disease characterized by overexpression of FAP.

Description

RADIOLABELLED FIBROBLAST ACTIVATION PROTEIN LIGANDS

INTRODUCTION

Field

The present invention relates to ligands of Fibroblast Activation Protein (FAP) for the active delivery of radioactive payloads at the site of disease. In particular, the present invention relates to the development of FAP ligands for the targeted delivery of radionuclides, such as ¹⁸Fluorine, ⁶⁸Gallium, ^Copper, ¹¹ ’Indium, ¹⁷⁷Lutetium, and to diagnostic methods and/or methods for therapy or surgery in relation to a disease or disorder, such as cancer, inflammation or another disease characterized by overexpression of FAP. of the Invention

Fibroblast activation protein (FAP) is a membrane -bound gelatinase which promotes tumor growth and progression and is overexpressed in cancer-associated fibroblasts. FAP represents an ideal target for the development of targeted small molecule drug conjugates (SMDCs) and small molecule radio conjugates (SMRCs) due to its low expression in normal organs.

WO2019154886 and WO2019154859 describe heterocyclic compounds as fibroblast activation proteinalpha inhibitors used to treat different cancer types. WO2019118932 describes substituted N-containing cyclic compounds as fibroblast activation protein alpha inhibitors used to treat different pathological conditions. W02019083990 describes imaging and radiotherapeutic targeting fibroblast-activation protein-alpha (FAP-alpha) compounds as FAP-alpha inhibitors used for imaging disease associated with FAP-alpha and to treat proliferative diseases. W02013107820 describes substituted pyrrolidine derivatives used in the treatment of proliferative disorders such as cancers and diseases indicated by tissue remodeling or chronic inflammation such as osteoarthritis, and notes that the 4-isoquinolinoyl and 8-quinolinoyl derivatives described therein are characterized by very low FAP-affinity. W02005087235 describes pyrrolidine derivatives as dipeptidyl peptidase IV inhibitors to treat Type II diabetes. WO2018111989 describes conjugates comprising fibroblast activation protein (FAP) inhibitor, bivalent linker and e.g. near infrared (NIR) dye, useful for removing cancer-associated fibroblasts, imaging population of cells in vitro, and treating cancer.

Tsutsumi et al. (J Med Chem 1994) describe the preparation and in vitro prolyl endopeptidase (PEP) inhibitory activity of a series of a-keto heterocyclic compounds. Hu et al. (Bioorg Med Chem Lett 2005) describe the structure-activity relationship of various N-alkyl Gly-boro-Pro derivatives against FAP and other two dipeptidyl peptidases. Edosada et al. (J Biol Chem 2006) describe the dipeptide substrate specificity of FAP and the development of a Ac-Gly-BoroPro FAP-selective inhibitor. Gilmore et al. (Biochem Biophys Res Commun 2006) describe the design, synthesis, and kinetic testing of a series of dipeptide proline diphenyl phosphonates, against DPP-IV and FAP. Tran et al. (Bioorg Med Chem Lett 2007) describe the structure-activity relationship of various N-acyl-Gly-, N-acyl-Sar-, and N-blocked- boroPro derivatives against FAP. Tsai et al. (J Med Chem 2010) describe structure-activity relationship studies that resulted in a number of FAP inhibitors with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9. Ryabtsova et al. (Bioorg Med Chem Lett 2012) describe the synthesis and the evaluation of FAP inhibition properties of a series of N-acylated glycyl-(2-cyano)pyrrolidines. Poplawski et al. (J Med Chem 2013) describe N-(pyridine-4-carbonyl)-D-Ala-boroPro as a potent and selective FAP inhibitor. Jansen et al. (ACS Med Chem Lett 2013) describe FAP inhibitors based on the N-(4-quinolinoyl)-Gly-(2- cyanopyrrolidine) scaffold. Jansen et al. (Med Chem Commun 2014) the structure-activity relationship of FAP inhibitors based on the linagliptin scaffold. Jansen et al. (Med Chem Commun 2014) describe xanthine -based FAP inhibitors with low micromolar potency. Jansen et al. (J Med Chem 2014) describe the structure-activity relationship of FAP inhibitors based on the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold. Jackson et al. (Neoplasia 2015) describe the development of a pseudopeptide inhibitor of FAP. Meletta et al. (Molecules 2015) describe the use of a boronic-acid based FAP inhibitor as non-invasive imaging tracers of atherosclerotic plaques. Dvofakova et al. (J Med Chem 2017) describe the preparation of a polymer conjugate containing a FAP-specific inhibitor for targeting applications. Loktev et al. (J Nucl Med 2018) describe the development of an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor. Lindner et al. (J Nucl Med 2018) describe the modification and optimization of FAP inhibitors for use as theranostic tracers. Giesel et al. (J Nucl Med 2019) describe the clinical imaging performance of quinoline -based PET tracers that act as FAP inhibitors.

Nevertheless, developing potent FAP binders with superior targeting properties, and SMDCs and SMRCs based thereon, remains a challenging task. Particularly desirable would be SMRCs exhibiting advantageous tumor-to-organ biodistribution, high activity labelling, and/or good compound stability, especially with respect to chemical and radiolytic stability and stability in in vitro and in vivo biological systems.

PROBLEMS TO BE SOLVED BY THE INVENTION

The present invention aims at the problem of providing improved compounds for targeted delivery, in particular SMRCs, which bind the fibroblast activation protein (FAP). The compounds (“binders”) should be suitable for therapeutic and/or diagnostic applications, and be capable of reaching a site afflicted by or at risk of disease or disorder characterized by overexpression of FAP. Preferably, the compound should form a stable complex with FAP, display a prolonged residence at the site of disease, and a lower accumulation in healthy organs. SUMMARY OF THE INVENTION

The present inventors have found novel compounds (in particular: SMRCs) binding fibroblast activation protein (FAP) which are particularly suitable for targeting applications, and are suitable for addressing the above -described problems.

The present invention provides a compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or a pharmaceutically acceptable salt thereof, wherein the compound structure comprises: a moiety A represented by or comprising the following structure:

one or more diagnostic or therapeutic agent moieties C; and a moiety B covalently connecting A to C, and comprising a carbocyclic or heterocyclic group.

The present invention further provides a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient.

The present invention further provides said compound or pharmaceutical composition for use in a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; as well as a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject in need thereof.

The present invention further provides said compound or pharmaceutical composition for use in a method for therapy or prophylaxis of a subject suffering from or having risk for a disease or disorder; as well as a method for treatment therapy or prophylaxis of a disease or disorder comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or having risk for said disease or disorder.

The present invention further provides said compound or pharmaceutical composition for use in a method for guided surgery practiced on a subject suffering from or having risk for a disease or disorder; as well as a method for guided surgery comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or having risk for a disease or disorder.

The present invention further provides said compound or pharmaceutical composition for use in a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET); as well as a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET), and comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject in need thereof.

The present invention further provides said compound or pharmaceutical composition for use in a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder; as well as a method for targeted delivery of a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or having risk for a disease or disorder.

Preferably, the aforementioned disease or disorder is characterized by overexpression of FAP and is independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorder, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymus cancer, desmoid tumors, glioma, astrocytoma, cervix cancer, skin cancer, kidney cancer, breast cancer, and prostate cancer. More preferably, the disease or disorder is selected from melanoma, breast cancer, and renal cell carcinoma.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. ESV6-NODAGA-A1-F: Chromatographic purity of the labelling procedure measured by LC- UV-MS (Agilent 6100 Series Single Quadrupole MS System combined with Agilent 1200 Series LC System. Chromatographic method Water/ACN + 0.1% HCOOH 90:10 to 0:100 in 3 min) identified a single chemical species after labelling.

Figure 2. NanoHPLC chromatogram of ESV6-NODAGA-A1-F: By applying nanoHPLC, a chromatography with higher resolution, three different chemical species were identified: (i) ESV6- NODAGA-A1 (at 15.34 min 883.31254 m/z) corresponding to the compound with a loss of the fluorine anion (ii) ESV6-NODAGA-A1-OH (at 13.56 min 901.32311 m/z) corresponding to the compound with the fluorine anion substituted with a hydroxyl anion and (iii) ESV6-NODAGA-A1-F (at 16.42 min 903.31877 m/z). This figure indicates that ESV6-NODAGA labelling may results in a mixture of species.

Figure 3. ESV6-NOTA (Compound 1): Chromatographic purity of the labelling procedure measured by LC-UV-MS (Agilent 6100 Series Single Quadrupole MS System combined with Agilent 1200 Series LC System. Chromatographic method Water/ACN + 0.1% HCOOH 90:10 to 0:100 in 3 min) identified a single chemical species after labelling.

Figure 4. NanoHPLC chromatogram of ESV6-NOTA-A1-F (Compound A1F@1): By applying nanoHPLC, a chromatography with higher resolution, a single peak was identified (15.24 min and 857.31329 m/z) indicating a high degree of purity for the labelled version of ESV6-NOTA.

Figure 5. Schematic workflow of the ex-vivo biodistribution experiments: Mice were treated with either ESV6-NODAGA-A1-F (represented as a sum of the three species) or ESV6-NOTA-A1-F (Compound A1F@1) and euthanized after two hours. Tissues were harvested, deproteinized, cleaned up with two SPE in line, and analyzed with a nanoLC-HR-MS platform. As internal standard for the MS analysis, isotopically labelled derivative of the analytes at fixed concentrations were added to the samples prior to sample preparation.

Figure 6. Ex vivo biodistribution results: ESV6-NODAGA-A1-F (represented as a sum of the three species) and ESV6-NOTA-A1-F, are expressed as pmol/g in tumor and in selected organs 2 hours after injection. *** = p value < 0.001, Q = 0.003 with unpaired t test (95%). The preferential uptake of ESV6- NOTA-A1-F in the tumor is remarkable, and significantly superior compared to the tumor uptake presented by ESV6-NODAGA-A1-F.

Figure 7. Quantitative in vivo biodistribution results of ESV6-NOTA-[¹⁸F]A1-F in nude mice bearing subcutaneous HT-1080.hFAP tumors: results are expressed as the percentage of injected dose per gram of tissue (A) and as tumor to organs ratio (B). The preferential uptake of ESV6-NOTA-[¹⁸F]A1-F is remarkable while the uptake in normal organs is at negligible levels.

Figure 8. Coelution experiments with a) [⁶⁸Ga]GaESV6-NOTA, b) [⁶⁸Ga]GaESV6-NODAGA and c) ESV6-NOTA-[¹⁸F]A1-F and human FAP.In the presence of the human FAP the complexes are the only compounds present. Binding experiments demonstrate high affinity of all the radiolabelled ESV6 moieties towards human FAP. DETAILED DESCRIPTION OF THE INVENTION

The present inventors have identified compounds, and in particular small molecule radio conjugates (SMRCs), which bind to the fibroblast activation protein (FAP), and are suitable for targeting applications. The SMRCs according to the invention provide good inhibition of FAP, good affinity for FAP and/or are suitable for targeted delivery of a payload, such as a therapeutic or diagnostic agent, to a site afflicted by or at risk of disease or disorder characterized by overexpression of FAP.

The compounds according to the present invention form a stable complex with FAP, display an increased affinity, increased inhibitory activity, a slower rate of dissociation from the complex, and/or prolonged residence at a disease site. The compounds according to the invention further can have an increased tumor-to-liver, tumor-to-kidney and/or tumor-to-intestine uptake ratio; a more potent anti-tumor effect (e.g., measured by mean tumor volume increase), and/or lower toxicity (e.g., as assessed by the evaluation of changes (%) in body weight). The compounds according to the invention preferably attain FAP-specific cellular binding; FAP-selective accumulation on the cell membrane; FAP-selective accumulation inside the cytosol. Further, the compounds according to the invention preferably can rapidly and homogeneously localize at the tumor site in vivo with a high tumor-to-organs selectivity, in particular for melanoma and/or renal cell carcinoma. Compounds according to the invention comprising a radioactive payload (e.g., ¹⁸Fluorine) preferably attain dose-dependent response, e.g., with target saturation reached between 500 pmol/g and 1000 pmol/g reached and/or maintained at up to 12 h, more preferably 1 to 9 h, further more preferably 1 to 3 h after intravenous administration.

PET imaging is one of the preferred applications of the compounds described herein. Affinity for FAP, lipophilicity and stability of the compounds can be among the relevant factors determining the suitability of a SMRC for such applications. For instance, PET and gamma counting-based biodistribution can be used to assess tracer kinetics and uptake. Without wishing to be bound by theory, the compounds described herein, are believed to exhibit favourable biodistribution and kinetics with high and reliable uptake in cancer tissues, which is believed to result from the combination of the moiety A with a very high FAP binding affinity, the particular linking group B, and a radioactive therapeutic or diagnostic moiety C.

The present invention provides a compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or a pharmaceutically acceptable salt thereof, wherein the compound structure comprises a moiety A represented by or comprising the following structure:

A is a binding moiety (i.e., moiety binding to FAP), and is covalently connected to one or more one or more diagnostic or therapeutic agent moieties C (i.e., payload(s), such as a radioactive group comprising a radionuclide) through a moiety B.

B can be represented by the following structure:

wherein each b¹ and b³ is independently an integer from 0 to 4, preferably 0 or 1; each b² is independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; each B² is independently represented by wherein:

Y and Z are linking groups forming part of a carbocyclic or heterocyclic group, preferably a C3-13 carbocyclic or C2 12 heterocyclic group, wherein all valences are satisfied.

*-Y preferably represents *-C, *-CR, *-N, *-NR, *-NRC(O)C, *-NRC(O)CR,

*-NRC(O)CR₂C, *-NRC(O)CR₂CR, *-NRC(S)NRC, *-NRC(S)NRCR,*-NRC, *-NRCR, *— NRCR2C, or *— NRCR2CR;

Z— preferably represents C— , CR— , N— , NR—, CC(O)NRCRC(O)NR— , CCR₂C(O)NR— , CRCR₂C(O)NR-, CNRC(S)NR-, NRC(S)CRNR-, CNR-, CRNR-, CCR2NR-, or CRCR2NR— ;

Each * represents a point of attachment closer to moiety A than to a moiety C; and each • represents a point of attachment closer to a moiety C than to moiety A. Each B³ is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; and is preferably a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene. The shortest path between B² and C preferably comprises 10 or less, more preferably 7 or less, most preferably 6 or less covalently connected atoms or is a bond. Each of B¹, B² and B³ independently optionally substituted by one or more of R. Each R is independently selected from H, OH, SH, NH₂, halogen, cyano, oxo, carboxy, C(O)NH₂ C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C_{3– 6} cycloalkoxy, C_6–10 aryl, C_6–10 aryloxy, C_5–10 heteroaryl and C_5–10 heteroaryloxy, of which the SH, NH₂, C(O)NH₂, C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C_3–6 cycloalkoxy, C_6–10 aryl, C_6–10 aryloxy, C_5–10 heteroaryl and C_5–10 heteroaryloxy can be optionally substituted with one or more of OH, SH, NH₂, halogen, cyano, oxo, carboxy, C_1–6 alkyl, C_1–5 heteroalkyl, C_3–6 cycloalkyl, C_6–10 aryl and C_5–10 heteroaryl, and two or more of R can be bound together to form part of a carbocyclic or heterocyclic ring system. A compound according to the present invention may be represented by Formula I:

Therein, B is a covalent bond or a moiety comprising a chain of atoms covalently attaching A to C. C is a therapeutic or diagnostic agent, which may be, e.g., an atom, a molecule, a particle, or a radionuclide. Moiety A Without wishing to be bound by any theory, it is contemplated that some of the beneficial technical effects achieved by the compounds of the invention are associated with the particular structure of the binding moiety A wherein the quinoline ring is substituted at the 8-position by a nitrogen-containing group, such as an amino or amido group:

It has been previously shown that the higher target protein affinity of a compound results in longer tumor residence in vivo (Wichert et al., Nature Chemistry 7, 241-249 (2015)). The compounds of the present invention have an increased affinity, slower dissociation rate with respect to FAP as compared to prior art compounds, and therefore are also considered to as having a prolonged residence at the disease site at a therapeutically or diagnostically relevant level, preferably beyond 1 h, more preferably beyond 6 h post injection. Preferably, the highest enrichment is achieved after 5 min, 10 min, 20 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h or 6 h; and/or enrichment in the disease site is maintained at a therapeutically or diagnostically relevant level, over a period of or at least for 5 min, 10 min, 20 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h or 6 h, more preferably beyond 6 h post injection. Compounds according to the invention comprising a radioactive payload (e.g., ¹⁸Fluorine) may attain dose-dependent response, e.g., with target saturation reached between 500 pmol/g and 1000 pmol/g reached and/or maintained at up to 12 h, more preferably 1 to 9 h, further more preferably 1 to 3 h after intravenous administration.

Preferably, the binding moiety A has the following structure A¹, A² or A³, wherein m is 0, 1, 2, 3, 4, or 5, preferably 1; and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 2:

More preferably, moiety A has the structure A², most preferably wherein m is 1.

Moiety B

Moiety B is a covalent bond or a moiety comprising a chain of atoms that covalently attaches A to the payload(s) C, i.e., through one or more covalent bond(s). The moiety B links one or more payload and/or binder moieties to form the targeted conjugate of the invention. In some embodiments, the structure of the compound comprises one moiety A and more than one moieties C per molecule, e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 moieties C per molecule. In such embodiments, one moiety C can be attached to moiety B at the position indicated by • in any of the general formulae disclosed herein, and the remaining moieties C are attached as substituents at further positions on moiety B. Moiety B can be represented by the following structure:

wherein each b¹ and b³ is independently an integer from 0 to 4, preferably 0 or 1; each b² is independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; each B² is independently represented by wherein Y and Z are linking groups

forming part of a carbocyclic or heterocyclic group; each _* represents a point of attachment closer to moiety A than to a moiety C; each _• represents a point of attachment closer to a moiety C than to moiety A; each B¹ is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; each B³ is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; each of B¹, B² and B³ is independently optionally substituted by one or more of R; each R is independently selected from H, OH, SH, NH₂, halogen, cyano, oxo, carboxy, C(O)NH₂ C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C_{3– 6} cycloalkoxy, C_6–10 aryl, C_6–10 aryloxy, C_5–10 heteroaryl and C_5–10 heteroaryloxy, of which the SH, NH₂, C(O)NH₂, C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C_3–6 cycloalkoxy, C_6–10 aryl, C_6–10 aryloxy, C_5–10 heteroaryl and C_5–10 heteroaryloxy is optionally substituted with one or more of OH, SH, NH₂, halogen, cyano, oxo, carboxy, C_1–6 alkyl, C_1–5 heteroalkyl, C_3–6 cycloalkyl, C_6–10 aryl and C_5–10 heteroaryl, and two or more of R can be bound together to form part of a carbocyclic or heterocyclic ring system; and all valences are satisfied. In any of the embodiments described therein, * represents a point of attachment to moiety A or a point of attachment for which the shortest path to moiety A comprises less atoms than that for •, as the case may be; and • represents a point of attachment a point of attachment to moiety C or a point of attachment to moiety C for which the shortest path to moiety C comprises less atoms than that for *, as the case may be. The following notations and all have the meaning of a point of attachment of a certain group or atom (e.g., R) to a further moiety:

Each B¹ is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; and is preferably a bond, alkylene or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O. The shortest path between A and B² preferably comprises 6 or less, more preferably 3 or less, most preferably 2 or less covalently connected atoms or is a bond. In a preferred embodiment, b¹ is 0 or 1; b² is 1; b³ is 1; and z is 1. Preferably, B¹ is a bond, alkylene or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O. Preferably, the shortest path between A and B² preferably comprises 6 or less, more preferably 3 or less, most preferably 2 or less covalently connected atoms or is a bond. Preferably, B³ a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene; wherein the shortest path between B² and C preferably comprises 10 or less, more preferably 7 or less, most preferably 6 or less covalently connected atoms or is a bond. Preferably, is a C_3–13 carbocyclic or C_2–12 heterocyclic group.

^Preferably, _* ^{–Y represents} _* ^–C, _* ^–CR, _* ^–N, _* ^–NR, _* ^–NRC(O)C, _* ^–NRC(O)CR, _* ^–NRC(O)CR ₂ ^C, _* ^–NRC(O)CR ₂ ^CR, _* ^{–NRC(S)NRC,} _* ^{–NRC(S)NRCR,} _* ^–NRC, _* ^–NRCR, _* ^–NRCR ₂ ^{C, or} _* ^–NRCR ₂ ^{CR; and Z–} _• ^{represents C–} _• ^{, CR–} _• ^{, N–} _• ^{, NR–} _• ^{, CC(O)NRCRC(O)NR–} _• ^{, CCR} ₂ ^C(O)NR– _• ^{, CRCR} ₂ ^C(O)NR– _• ^{, CNRC(S)NR–} _• ^{, NRC(S)CRNR–} _• ^{, CNR–} _• ^{, CRNR–} _• ^{, CCR} ₂ ^NR– _• ^{, or CRCR} ₂ ^NR– _• ^. In a preferred embodiment, each B¹ is independently selected from bond; C_1–10, preferably C_1–4, more preferably C_1–2 alkylene; C_1–10, preferably C_1–4, more preferably C_1–2 heteroalkylene group comprising one or two N atoms; NR(C_1–10, C_1–4, or C_1–2 alkylene)NR; (C_1–10, C_1–4, or C_1–2 alkylene)NR; NR(C_1–10, C_1–4, or C_1–2 alkylene); C(O); C(O)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_1–10 alkylene)C(O); C(O)(C_1–10 alkyl)C(O)NR; C(O)(C_5–10 heteroaryl)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_5–10 heteroaryl)CR₂; C(S)NR; C(S)NR(C_6–10 aryl)CR₂; and C(S)NR(C_5–10 heteroaryl)CR_2. More preferably, B¹ is bond, C(O)CH₂CH₂C(O), NHCH₂CH₂NH, CH₂CH₂NH, NHCH₂CH₂,

most preferably bond or NHCH2CH2NH. In a preferred embodiment, each B³ is independently selected from bond; C_1–10, preferably C_1–4, more _{preferably C1–2 alkylene; C1–10, preferably C1–4, more preferably C1–2 heteroalkylene group comprising one} or two N atoms; NR(C_1–10, C_1–4, or C_1–2 alkylene)NR; (C_1–10, C_1–4, or C_1–2 alkylene)NR; NR(C_1–10, C_1–4, or C_1–2 alkylene); C(O); C(O)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_5–10 heteroaryl)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_5–10 heteroaryl)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_5–10 heteroaryl)CR₂; C(S)NR; C(S)NR(C_6–10 aryl)CR₂; and C(S)NR(C_5–10 heteroaryl)CR_2. More preferably, B³ is bond, C(O)CH₂CH₂C(O), NHCH₂CH₂NH, CH₂CH₂NH, NHCH₂CH_2,

In a preferred embodiment, moiety A has the structure A²; m is 1; b¹ is 0 or 1; b² is 1; b³ is 1; and z is 1; and each of s, u, t, and v, if present, is 1, and w is 0 or 1. In an embodiment, B² is independently selected from:

wherein each s, u, t, and v is independently 0, 1, or 2; each w is independently 0, 1, 2, or 3; and each X is independently N, NH, NR, S, S(O), SO2, O, C, CR, CH, CR2 or CH2; preferably N.

In a preferred embodiment, each of s, u, t, and v, if present, is 1, and w is 0 or 1.

In a preferred embodiment, B² is selected from:

In a more preferred embodiment, B² is selected from:

In a most preferred embodiment, B² is selected from:

In one particular embodiment, B² is

most preferably

In another particular embodiment,

In another particular embodiment, B² is B² is

; more preferably

most preferably

Moiety B preferably comprises, more preferably consists of a unit from the following list:

C

Moiety C in the present invention represents a pay load, which can be generally any atom (including H), molecule or particle, and can function as a therapeutic or diagnostic agent. Preferably, moiety C is not a hydrogen atom, and may be selected from: a chelating agent group suitable for radiolabelling; a radioactive group comprising a radioisotope; a chelate of a radioactive isotope with a chelating agent; a fluorophore group; a cytotoxic and/or cytostatic agent; immunomodulator agent; or a protein

Payload moiety C may comprise of consist of a chelating agent (chelator) for radiolabeling.

Payload moiety C may be a radioactive group comprising or consisting of radioisotope including isotopes such as ²²³Ra, ⁸⁹Sr, ^94mTc, "^mTc, ¹⁸⁶Re, ¹⁸⁸Re, ²⁰³Pb, ⁶⁶Ga ⁶⁷Ga, ⁶⁸Ga, ⁴³Sc, ^Sc ⁴⁷Sc, ¹¹ ‘in, ⁹⁷Ru, ⁶²Cu, ^MCu. ⁸⁶ _Y, ⁸⁸Y, ⁹⁰Y, ¹²¹Sn, ¹⁶¹Tb, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁰⁵Rh, ¹⁷⁷Lu, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁸F, ²¹¹At, ²²⁵ Ac, ⁸⁹Sr, ^117mSn and ¹⁶⁹E. Preferably, In one preferred embodiment the radioisotopes are ⁶⁸Ga ⁶²Cu, ^MCu, ^{1 H}In, ¹⁸F.

In a preferred embodiment, ¹⁸F is bound to a cation; more preferably, the cation is aluminium (Al) in any of its oxidation states.

The payload may be a chelate of an isotope, preferably of a radioactive isotope, listed under above.

Particularly preferred embodiments for the moiety C as well as the compound according to the present invention are shown in the appended claims.

The chelating agent group suitable for radiolabelling may be derived from 1,4,7-triazacyclononane- N,N',N"-triacetic acid (NOTA), 2,2',2"-(l,4,7-triazonane-l,4-diyl)diacetic acid (NODA), 2,2'-((2-((4-(2- amino-2-oxoethyl)benzyl)(carboxymethyl)amino)cyclohexyl)azanediyl)diacetic acid] (RESCA), sulfur colloid, diethylenetriaminepentaacetic acid (DTP A), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10- tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOT A), [2,2',2"-(10-(4-((2-aminoethyl)amino)-l- carboxy-4-oxobutyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid DOTA-GA), [1,4,8,11- tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA), iminodiacetic acid, bis(carboxymethylimidazole)glycine, 6-Hydrazinopyridine-3 -carboxylic acid (HYNIC).

The chelating agent group may have a structure according to one of the following formulae C¹, C², C³, C⁴, and C⁵:

wherein: each q is independently 0, 1, 2, 3, 4 or 5; preferably 0; _R ^1e _{, R} ^1f _{, R} ^1g _{, R} ^1h _{, and R} ¹ⁱ _{are each independently H, COOH, aryl-COOH or heteroaryl-COOH;} preferably COOH; _R ^2e, _R ^2f _{, R} ^2g _{, R} ^2h _{, and R} ²ⁱ _{are each independently H, COOH, aryl-COOH or heteroaryl-COOH;} preferably COOH; _R ^3e, _R ^3f _{, R} ^3g _{, R} ^3h _{, R} ^4h _{, and R} ³ⁱ _{are each independently H, COOH, aryl-COOH or heteroaryl-COOH;} preferably COOH; and _{and R} ^4e _{is independently H, COOH, aryl-COOH or heteroaryl-COOH, with the proviso that when q is 0, R} ^4e _{is H;} each X is independently NH, NR, S, O, CR₂, or H,H; preferably O; each Q is N or O, preferably N; _{wherein when Q is O, CH2R} ^2e, _CH2R ^2f _{, CH2R} ^2g _{, CH2R} ^2h _{, and CH2R} ²ⁱ _{is absent; and} L is –CH₂C(O)– or –NHC(S)–. _{In a preferred embodiment, q is 0, R} ^1e _{, R} ^1f _{, R} ^1g _{, R} ^1h _{, R} ¹ⁱ _{, R} ^2e, _R ^2f _{, R} ^2g _{, R} ^2h _{, and R} ²ⁱ _{are each} independently COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; _R ^3e, _R ^3f _{, R} ^3g _{, R} ^3h _{, R} ^4h _{, and R} ³ⁱ _{are each independently H, COOH, aryl-COOH or heteroaryl-COOH;} preferably COOH; and _R ^4e _{is H; and} Q is N. The chelating agent group may have a structure selected from the following:

The radioactive group, in general, may comprise a radioisotope is selected from ²²³Ra, ⁸⁹Sr, ^94mTc, ^99mTc, 1⁸⁶Re, ¹⁸⁸Re, ²⁰³Pb, ⁶⁷Ga, ⁶⁸Ga, ⁴⁷Sc, ¹¹¹In, ⁹⁷Ru, ⁶²Cu, ⁶⁴Cu, ⁸⁶Y, ⁸⁸Y, ⁹⁰Y, ¹²¹Sn, ¹⁶¹Tb, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁰⁵Rh, 1⁷⁷Lu, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁸F, ²¹¹At, ²²⁵Ac, ⁸⁹Sr, ^117mSn and ¹⁶⁹Er. In the radioactive groups useful in the present invention, e.g., chelate complexes with one or more of the chelators described herein, ¹⁸F, when present, is preferably bound to chelated Al, Zr, Si, Ga, or In, more preferably ¹⁸F is bound to Al chelated by the chelator. In the context of the present disclosure, also complexes of the chelators described herein are contemplated wherein F is present, which is preferably bound to chelated Al, Zr, Si, Ga, or In, wherein F can contain any isotope of fluorine, e.g., ¹⁸F and/or ¹⁹F. Particularly useful diagnostic or therapeutic agents C for use in the present invention are chelates of a radioactive isotope listed under above with any of the chelating agents listed under (a) above. Alternatively, diagnostic or therapeutic agents C is a group selected from any of the following structures comprising covalently bound radioactive nuclides:

wherein X is as defined further above, and can be, e.g., N, S, S(O), SO₂, O, CR, CH; preferably CH or N. For instance, a preferred structure comprising covalently a bound radioactive nuclide is

In the context of the present disclosure, compounds are also contemplated wherein any isotope of F or I can be present instead of ¹⁸F, ¹²³I, ¹²⁴I, ¹²⁵I or ¹³¹I, as the case may be. Most preferably, moiety C is a chelator selected from:

and even more preferably wherein ¹⁸F is bound to Al chelated by the chelator.

These chelators are derived from derived from:

Without wishing to be bound by theory, it is believed that these chelators and their Al-F complexes are particularly advantageous from the viewpoint of activity labelling, stability, especially with respect to chemical and radiolytic stability and stability. Preferred compounds are listed in the appended claims, especially claim 14, as well as chelate complexes of thereof with ions or radionuclides as listed above, such as A1F (containing, e.g., ¹⁸F and/or ¹⁹F bound to

Al), or Ga (e.g., ⁶⁷Ga and/or ⁶⁸Ga in any oxidation state). Particularly preferred compounds are 1 and its

A1F complex A1F@1, which can contain ¹⁸F and/or ¹⁹F, even more preferably ¹⁸F, bound to Al.

1 A1F@1 Alternatively, moiety C can be a fluorophore group. Preferably, the fluorophore group is selected from a xanthene dye, acridine dye, oxazine dye, cyanine dye, styryl dye, coumarine dye, porphine dye, fluorescent metal-ligand-complex, fluorescent protein, nanocrystals, perylene dye, boron-dipyrromethene dye and phtalocyanine dye. Preferred structures may be selected from the following:

Alternatively, moiety C can be a cytotoxic and/or cytostatic agent, e.g., a chemotherapeutic agent. Preferably, such therapeutic agents are selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disrupters, DNA intercalating agents, DNA synthesis inhibitors, DNA-RNA transcription regulator, enzyme inhibitors, gene regulators, hormone response modifiers, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, anti-vascular agents and a combination of two or more thereof. Such agents can inhibit or prevent the function of cells and/or cause destruction of cells. Examples of cytotoxic agents include radioactive isotopes, chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogues and derivatives thereof. The cytotoxic agent may be selected from the group consisting of an auristatin, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a lexitropsin, a duocarmycin, a taxane, a puromycin, a dolastatin, a maytansinoid and a vinca alkaloid or a combination of two or more thereof. Preferred cytotoxic and/or cytostatic payload moieties are listed in claim 8 (e).

In one embodiment, the payload is a chemotherapeutic agent selected from the group consisting of a topoisomerase inhibitor, an alkylating agent (e.g., nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas), an antimetabolite (e.g., mercaptopurine, thioguanine, 5- fluorouracil), an antibiotics (e.g., anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin. dactinomycin) a mitotic disrupter (e.g., plant alkaloids - such as vincristine and/or microtubule antagonists - such as paclitaxel), a DNA methylating agent, a DNA intercalating agent (e.g., carboplatin and/or cisplatin, daunomycin and/or doxorubicin and/or bleomycin and/or thalidomide), a DNA synthesis inhibitor, a DNA-RNA transcription regulator, an enzyme inhibitor, a gene regulator, a hormone response modifier, a hypoxia-selective cytotoxin (e.g., tirapazamine), an epidermal growth factor inhibitor, an anti- vascular agent (e.g., xanthenone 5,6-dimethylxanthenone-4-acetic acid), a radiation-activated prodrug (e.g., nitroarylmethyl quaternary (NMQ) salts) or a bioreductive drug or a combination of two or more thereof. In some embodiments, the payload (i.e., moiety C) is not derived from an anthracycline, preferably not derived from PNU 159682.

The chemotherapeutic agent may selected from the group consisting of Erlotinib (TARCEVA®), Bortezomib (VELCADE®), Fulvestrant (FASLODEX®), Sutent (SU11248), Letrozole (FEMARA®), Imatinib mesylate (GLEEVEC®), PTK787/ZK 222584, Oxaliplatin (Eloxatin®.), 5-FU (5 -fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®.), Lapatinib (GSK572016), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006), and Gefitinib (IRESSA®.), AG1478, AG1571 (SU 5271; Sugen) or a combination of two or more thereof.

The chemotherapeutic agent may be an alkylating agent - such as thiotepa, CYTOXAN® and/or cyclosphosphamide; an alkyl sulfonate - such as busulfan, improsulfan and/or piposulfan; an aziridine - such as benzodopa, carboquone, meturedopa and/or uredopa; ethylenimines and/or methylamelamines - such as altretamine, triethylenemelamine, triethylenepbosphor amide, triethylenethiophosphoramide and/or trimethylomelamine; acetogenin - such as bullatacin and/or bullatacinone; camptothecin; bryostatin; callystatin; cryptophycins; dolastatin; duocarmycin; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards - such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide and/or uracil mustard; nitrosureas - such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and/or ranimnustine; dynemicin; bisphosphonates - such as clodronate; an esperamicin; a neocarzinostatin chromophore; aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®. doxorubicin - such as morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and/or deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins - such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites - such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues - such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues - such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues - such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens - such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals - such as aminoglutethimide, mitotane, trilostane; folic acid replenisher - such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; def of amine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; macrocyclic depsipeptides such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes - such as verracurin A, roridin A and/or anguidine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; taxoids - such as TAXOL®. paclitaxel, abraxane, and/or TAXOTERE®, doxetaxel; chlor anbucil; GEMZAR®. gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues - such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; NAVELBINE®, vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids - such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.

The pay load may be a tubulin disruptor including but are not limited to: taxanes - such as paclitaxel and docetaxel, vinca alkaloids, discodermolide, epothilones A and B, desoxyepothilone, cryptophycins, curacin A, combretastatin A-4-phosphate, BMS 247550, BMS 184476, BMS 188791; LEP, RPR 109881A, EPO 906, TXD 258, ZD 6126, vinflunine, LU 103793, dolastatin 10, E7010, T138067 and T900607, colchicine, phenstatin, chaicones, indanocine, T138067, oncocidin, vincristine, vinblastine, vinorelbine, vinflunine, halichondrin B, isohomohalichondrin B, ER-86526, pironetin, spongistatin 1, spiket P, cryptophycin 1, LU103793 (cematodin or cemadotin), rhizoxin, sarcodictyin, eleutherobin, laulilamide, VP-16 and D-24851 and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.

The payload may be a DNA intercalator including but are not limited to: acridines, actinomycins, anthracyclines, benzothiopyranoindazoles, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin (adriamycin), actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cisplatin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan and topotecan and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.

The payload may be an anti-hormonal agent that acts to regulate or inhibit hormone action on tumours - such as anti-estrogens and selective estrogen receptor modulators, including, but not limited to, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and/or fareston toremifene and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above. The payload may be an aromatase inhibitor that inhibits the enzyme aromatase, which regulates estrogen production in the adrenal glands - such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, AROMASIN®. exemestane, formestanie, fadrozole, RIVISOR®. vorozole, FEMARA®. letrozole, and ARIMIDEX® and/or anastrozole and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.

The payload may be an anti-androgen such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and/or troxacitabine and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.

In a preferred embodiment, moiety C is an auristatin (i.e., having a structure derived from an auristatin compound family member) or an auristatin derivative. More preferably, moiety C has a structure according to the following formula:

wherein:

Rid is independently H or C | -Cg alkyl; preferably H or CH3;

R^d is independently C | -Cg alkyl; preferably CH3 or iPr;

R^d is independently H or C | -Cg alkyl; preferably H or CH3; ^{R4d is independently H, C} ₁ ^-C ₆ ^{alkyl, COO(C} ₁ ^-C ₆ ^{alkyl), CON(H or C} ₁ ^-C ₆ ^{alkyl), C} ₃ ^-C ₁₀ ^{aryl or C} ₃- ^C ₁₀ ^{heteroaryl; preferably H, CH} ₃ ^{, COOH, COOCH} ₃ ^{or thiazolyl;} R^5d is independently H, OH, C₁-C₆ alkyl; preferably H or OH; and ^{R6d is independently C} ₃ ^-C ₁ ^{0 aryl or C} ₃ ^-C ₁ ^{0 heteroaryl; preferably optionally substituted phenyl or} pyridyl. In a further preferred embodiment, moiety C is selected from the following structures:

5

Camptothecin derivative Uncialamycin

Alternatively, moiety C can be a immunomodulator agent. The immunomodulator agent is preferably selected from molecules known to be able to modulate the immune system, such as ligands of CD3, CD25, TLRs, STING, 4-1BBL, 4-1BB, PD-1, mTor, PDL-1, NKG-2D IMiDs, wherein ligands can be agonists and/or antagonists. Alternatively, moiety C can be a protein or an antibody. Preferably, the payload is a cytokine (e.g., an interleukin such as IL2, IL 10, IL 12, IL15; a member of the TNF superfamily; or an interferon such as interferon gamma.).

Any payload may be used in unmodified or modified form. Combinations of payloads in which some are unmodified and some are modified may be used. For example, the payload may be chemically modified. One form of chemical modification is the derivatisation of a carbonyl group - such as an aldehyde.

Treatment

The compounds described herein may be used to treat disease. The treatment may be therapeutic and/or prophylactic treatment, with the aim being to prevent, reduce or stop an undesired physiological change or disorder. The treatment may prolong survival as compared to expected survival if not receiving treatment.

The disease that is treated by the compound may be any disease that might benefit from treatment. This includes chronic and acute disorders or diseases including those pathological conditions which predispose to the disorder.

The term "cancer" and "cancerous" is used in its broadest sense as meaning the physiological condition in mammals that is typically characterized by unregulated cell growth. A tumor comprises one or more cancerous cells.

When treating cancer, the therapeutically effect that is observed may be a reduction in the number of cancer cells; a reduction in tumor size; inhibition or retardation of cancer cell infiltration into peripheral organs; inhibition of tumor growth; and/or relief of one or more of the symptoms associated with the cancer.

In animal models, efficacy may be assessed by physical measurements of the tumor during the treatment, and/or by determining partial and complete remission of the cancer. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).

Particularly preferred embodiments for the methods of treatment related to the present invention are shown in the appended claims.

Herein disclosed are also methods for treatment of the human or animal body, e.g., by surgery or therapy, or diagnostic method practiced on the human or animal body, the methods involving a step of administering a therapeutically or diagnostically effective amount of a compound or a pharmaceutical composition as described herein to a subject in need thereof. More specifically, herein disclosed are methods for treatment, e.g., by therapy or prophylaxis, of a subject suffering from or having risk for a disease or disorder; or by guided surgery practiced on a subject suffering from or having risk for a disease or disorder; method for diagnosis of a disease or disorder, e.g., diagnostic method practiced on the human or animal body and/or involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT); method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder. In the aforementioned methods, said disease or disorder may be independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorder, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymus cancer, desmoid tumors, glioma, astrocytoma, cervix cancer, skin cancer, kidney cancer and prostate cancer. When used in the methods disclosed herein, the compound has a prolonged residence at the disease site at a therapeutically or diagnostically relevant level, preferably beyond 1 h, more preferably beyond 6 h post injection.

Pharmaceutical

Also disclosed is a pharmaceutical composition comprising the compound according to any of the preceding aspects, and a pharmaceutically acceptable excipient. Such pharmaceutical composition is also disclosed for use in: (a) a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; or (b) a method for therapy or prophylaxis of a subject suffering from or having risk for a disease or disorder; or (c) a method for guided surgery practiced on a subject suffering from or having risk for a disease or disorder; or (d) a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT); or (e) a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder, wherein in each of the preceding (b)-(e), said disease or disorder is independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorder, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multidrug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymus cancer, desmoid tumors, glioma, astrocytoma, cervix cancer and prostate cancer; preferably wherein the compound has a prolonged residence at the disease site at a therapeutically or diagnostically relevant level, preferably beyond 1 h, more preferably beyond 6 h post injection.

The compounds described herein may be in the form of pharmaceutical compositions which may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s).

Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

There may be different composition/formulation requirements dependent on the different delivery systems. By way of example, the pharmaceutical composition may be formulated to be administered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be administered by a number of routes.

If the agent is to be administered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.

Where appropriate, the pharmaceutical compositions may be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents, or the pharmaceutical compositions can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration, the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. The compound of the present invention may be administered in the form of a pharmaceutically acceptable or active salt. Pharmaceutically-acceptable salts are well known to those skilled in the art, and for example, include those mentioned by Berge et al, in J.Pharm.Sci., 66, 1-19 (1977). Salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The routes for administration (delivery) may include, but are not limited to, one or more of oral (e.g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e.g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, sublingual. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for administration. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Exemplary unit dosage formulations contain a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of the active ingredient. Chemical synthesis The compounds described herein may be prepared by chemical synthesis techniques. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound. This may be achieved by conventional techniques, for example as described in "Protective Groups in Organic Synthesis" by T W Greene and P G M Wuts, John Wiley and Sons Inc. (1991), and by P.J.Kocienski, in "Protecting Groups", Georg Thieme Verlag (1994). It is possible during some of the reactions that any stereocenters present could, under certain conditions, be epimerized, for example if a base is used in a reaction with a substrate having an optical center comprising a base-sensitive group. It should be possible to circumvent potential problems such as this by choice of reaction sequence, conditions, reagents, protection/deprotection regimes, etc. as is well-known in the art.

Definitions

Derivative. A derivative includes the chemical modification of a compound. Examples of such modifications include the replacement of a hydrogen by a halo group, an alkyl group, an acyl group or an amino group and the like. The modification may increase or decrease one or more hydrogen bonding interactions, charge interactions, hydrophobic interactions, van der Waals interactions and/or dipole interactions.

Analog. This term encompasses any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts and hydrates of such compounds.

Unless otherwise stated, the following definitions apply to chemical terms used in connection of compounds of the invention and compositions containing such compounds.

Alkyl refers to a branched or unbranched saturated hydrocarbyl radical. Suitably, the alkyl group comprises from 1 to 100, preferably 3 to 30, carbon atoms, more preferably from 5 to 25 carbon atoms. Preferably, alkyl refers to methyl, ethyl, propyl, butyl, pentyl, or hexyl.

Alkenyl refers to a branched or unbranched hydrocarbyl radical containing one or more carbon-carbon double bonds. Suitably, the alkenyl group comprises from 2 to 30 carbon atoms, preferably from 5 to about 25 carbon atoms.

Alkynyl refers to a branched or unbranched hydrocarbyl radical containing one or more carbon-carbon triple bonds. Suitably, the alkynyl group comprises from about 3 to about 30 carbon atoms, for example from about 5 to about 25 carbon atoms.

Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Cycloalkyl refers to an alicyclic moiety, suitably having 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.

Aryl refers to an aromatic carbocyclic ring system, suitably comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or

16 ring carbon atoms. Aryl may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl fluorenyl, azulenyl, indenyl, anthryl and the like.

The prefix “hetero”, unless specified otherwise, signifies that one or more of the carbon atoms of the group may be substituted by nitrogen, oxygen, phosphorus, silicon or sulfur. Heteroalkyl groups include for example, alkyloxy groups and alky thio groups. Heterocycloalkyl or heteroaryl groups herein may have from 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulfur. In particular, a 3- to 10-membered ring or ring system and more particularly a 5- or 6-membered ring, which may be saturated or unsaturated. For example, selected from oxiranyl, azirinyl, 1 ,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl, 1,3-Dioxo-1,3- dihydro-isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, [beta]- carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl, 3,4-dihydro-2H-isoquinolin-l-one, 3,4-dihydro-2H-isoquinolinyl, and the like.

“Substituted”, unless specified otherwise, signifies that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of substituents. The term "optionally substituted" as used herein includes substituted or unsubstituted. It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds. Preferably, the term “substituted” signifies one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of substituents selected from OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl. Additionally, the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognized by the skilled person. Preferably, any of the aforementioned substituents may be further substituted by any of the aforementioned substituents, each of which may be further substituted by any of the aforementioned substituents. Substituents may suitably include halogen atoms and halomethyl groups such as CF₃ and CCl₃; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitrogen containing groups such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulfur containing groups such as thiol, alkylthiol, sulfonyl and sulfoxide; heterocyclic groups which may themselves be substituted; alkyl groups, which may themselves be substituted; and aryl groups, which may themselves be substituted, such as phenyl and substituted phenyl. Alkyl includes substituted and unsubstituted benzyl. More preferably, “substituted” signifies substitution by one or more groups selected from OH, SH, NH₂, halogen, cyano, oxo, carboxy, C(O)NH₂ C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C_3–6 cycloalkoxy, C_6–10 aryl, C_6–10 aryloxy, C_5–10 heteroaryl and C_5–10 heteroaryloxy, of which the SH, NH₂, C(O)NH₂, C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C_3–6 cycloalkoxy, C_6–10 aryl, C_{6– 10} aryloxy, C_5–10 heteroaryl and C_5–10 heteroaryloxy is optionally substituted with one or more of OH, SH, NH₂, halogen, cyano, oxo, carboxy, C_1–6 alkyl, C_1–5 heteroalkyl, C_3–6 cycloalkyl, C_6–10 aryl and C_5–10 heteroaryl; two or more of the aforementioned groups can be bound together to form part of a carbocyclic or heterocyclic ring system. Where two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties. MATERIAL & METHODS General remarks and procedures Yields refer to chromatographically purified compounds. Mass

: spectra were recorded on an Agilent 6100 Series Single Quadrupole MS System combined with an Agilent 1200 Series LC System, using an InfinityLab Poroshell 120 EC- C18 column, 4.6 mm ✕ 56 mm at a flow rate of 0.8 mL min^-1 with linear gradients of solvents A and B (A = Millipore water with 0.1% formic acid [FA], B = MeCN with 0.1% formic acid [FA]). NanoHPLC-HR-MS: chromatographic separation was carried out on an Acclaim PepMap RSLC column (50 µm x 15 cm, particle size 2 µm, pore size, 100 Å, Thermo Scientific) with a gradient program from 95% A (0.1% FA), 5 % B (ACN 0.1 % FA) to 5 % A, 95 % B in 45 minutes on an Easy nanoLC 1000 (Thermo Scientific). Sample clean up and concentration was carried out with a pre column Acclaim PepMAP 100 (75 µm x 2 cm, particle size 3 µm, pore size 100 Å; Thermo Scientific) mounted on the system. The LC system was coupled to a Q-Exactive mass spectrometer (Thermo Fisher) via a Nano Flex ion source (Thermo Scientific). Ionization was carried out with 2 kV of spray voltage, 250 °C of capillary temperature, 60 S-lens RF level. Mass spectrometry was working in Single ion Monitoring mode (SIM) following the mass range reported in Table 1. The detector was working in positive ion mode with the following parameters: resolution 70000 (FWHM at 400 m/z), AGC target 5 x 10⁴, and maximum injection time 200 ms. Data analysis was carried out with Thermo Xcalibur Qual Broswer v2.2 (Thermo Scientific) and Prism8 (GrapPhad). Preparative reversed-phase high-pressure liquid chromatography (RP-HPLC) was performed on an Agilent 1200 Series System, using a Phenomenex Gemini® 5 μm NX-C18 semipreparative column, 110 Å, 150 mm ✕ 10 mm at a flow rate of 5 mL min^-1 with linear gradients of solvents A and B (A = Millipore water with 0.1% trifluoroacetic acid [TFA], B = MeCN with 0.1% trifluoroacetic acid [TFA]). Example 1: Preparation of “ESV6-NODAGA” and labelling Synthesis Synthesis of Intermediate I-1

In a 25 mL round bottom flask, 8-aminoquinoline-4-carboxylic acid (100 mg, 0.531 mmol, 1 eq), (S)-1- (2-aminoacetyl)-4.4-difluoropyrrolidine-2-carbonitrile hydrochloride (132 mg, 0.585 mmol, 1.1 eq) and HATU (202 mg, 0.531 mmol, 1 eq) were suspended in 900 μL of DMF and 4 mL of DCM. DIPEA (371 μL, 2.127 mmol, 4 eq) was added dropwise and the reaction was stirred until completion (checked via LC/MS with the method 90:10 Water/Acetonitrile 0.1% FA to 100% Acetonitrile 0.1% FA in 3min, Positive). The crude was diluted with DCM, washed with water, dried over Na₂SO₄, filtered and the solvent evaporated under vacuum. The dried crude was purified via CombiFlash Nextgen 300+ (parameters: flow 50 ml/min, 40 gr silica column, 100% DCM to 85:15 DCM/MeOH in 5 min) to obtain an amber oil (172 mg, 90% yield). MS (ESI+) m/z 360.1 [M+H]⁺ Synthesis of Intermediate I-2

In a 25 mL round bottom flask, Intermediate A (48 mg, 0.134 mmol, 1 eq), succinic anhydride (669 mg, 6.683 mmol, 50 eq) and DMAP (8 mg, 0.067 mmol, 0.5 eq) were dissolved in 3 mL of THF. The reaction was heated at 60 °C for 6h and checked via LC/MS (method 90:10 Water/Acetonitrile 0.1% FA to 100% Acetonitrile 0.1% FA in 3min, Positive). The reaction was dried under vacuum, diluted with water, extracted with DCM, dried over Na₂SO₄, filtered, and concentrated under. The dried crude was purified via CombiFlash Nextgen 300+ (parameters: flow 30 ml/min, 24 gr silica column, DMC/MeOH 90:10 to _{70:30 in 4 minutes) to obtain an amber oil (58 mg, 95% yield).} MS (ESI+) m/z 460.1 [M+H]⁺ From (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4- oxobutanoic acid (I-2) to ESV6-NODAGA

(S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4 oxobutanoic acid (15 mg, 0.032 mmol, 1.0 eq) was dissolved in dry DMSO (400 μL). Dicyclohexylcarbodiimide (9 mg, 0.042 mmol, 1.3 eq) and N-hydroxysuccinimide (4.5 mg, 0.039 mmol, 1.3 eq) were added and the reaction was stirred overnight at room temperature, protected from light. 100 μL of PBS solution containing 2,2'-(7-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7-triazonane- l,4-diyl)diacetic acid (16.2 mg, 0.039 mmol, 1.2 eq) were added and the reaction was stirred for 2h. The crude product was purified by reversed phase HPLC (95:5 to 20:80 water/ ACN + 0.1%TFA in 20 min) and lyophilized, to obtain a white solid. (21 mg, 75%).

MS (ESI+) m/z 859.9 [M+H]⁺ Labelling: from ESV6-NODAGA to ESV6-NODAGA-A1-F

ESV6-NODAGA (1 mg, 1.16 pmol, 1 eq) was dissolved in a mixture of DMSO (0.05 mL) and acetate buffer pH=4 (0.2 mL). AIF3 (1 mg, 11.6 pmol, 10 eq.) was added and the mixture was heated at 95°C for 15 min. Then the mixture was purified via RP-HPLC (95:5 to 0:100 water/ACN + 0.1% TFA in 20 min) the desired fractions were collected and lyophilized to afford a white solid. (0.8 mg, 80%).

MS (ESI+) m/z 903.4 [M+H]⁺

Example 2: Preparation of “ESV6-NOTA” and labelling

Synthesis From (S)-4-((4-((2-(2-cyano-4,4-difhioropyrrolidin-l-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4- oxobutanoic acid (1-2) to tert-butyl (S)-4-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2- oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)piperazine-l -carboxylate (1-3)

Intermediate I-2 (50 mg, 0.11 mmol, 1 eq), N-Boc-piperazine (24 mg, 0.13 mmol, 1.2 eq) and HATU (49 mg, 0.13 mmol, 1.2 eq) was dissolved in DMF (1 mL). DIPEA (0.08 mL, 0.44 mmol, 4 eq) was added dropwise and the mixture was stirred for 30 min at room temperature. The mixture was purified via RP flash chromatography (2:98 to 100:0 ACN/water + 0.1% HCOOH in 40 min). The desired fractions were collected and lyophilized to afford a white solid. (40 mg, 58%). MS (ESI+) m/z 627.9 [M+H]⁺ From tert-butyl (S)-4-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutanoyl)piperazine-1-carboxylate (I-3) to (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)-8-(4-oxo-4-(piperazin-1-yl)butanamido)quinoline-4-carboxamide (I-4)

Intermediate I-3 (40 mg, 0,06 mmol, 1 eq.) was dissolved in DCM (1 mL) and TFA (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 3h then solvent was evaporated, and the crude was purified via RP flash chromatography (2:98 to 100:0 ACN/water + 0.1% HCOOH in 40 min). The desired fractions were collected and lyophilized to afford a colorless oil. (17 mg, 51%). MS (ESI+) m/z 527.9 [M+H]⁺ From (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4-oxo-4-(piperazin-1- yl)butanamido)quinoline-4-carboxamide (I-4) to (S)-2,2'-(7-(2-(4-(4-((4-((2-(2-cyano-4,4- difluoropyrrolidin-l-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)piperazin-l-yl)-2- oxoethyl)-!, 4, 7-triazonane-l,4-diyl)diacetic acid (ESV6-NOTA; 1).

Intermediate 1-4 (8 mg, 0.02 mmol, 1 eq) and NOTA-NHS (19 mg, 0.04 mmol, 2 eq) was dissolved in DMF (0.2 mL). DIPEA (0.01 mL, 0.08 mmol, 4 eq) was added to the mixture and stirred for Ih at room temperature. The mixture was purified via RP-HPLC (90:10 to 0:100 water/ ACN + 0.1% TFA in 12 min). The desired fractions were collected and lyophilized to afford a white solid. (4 mg, 25%).

MS (ESI+) m/z 812.7 [M+H]⁺

Labelling: from ESV6-NOTA (1) to ESV6-NOTA-A1-F (A1F@1)

From (S)-2,2'-(7-(2-(4-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2-oxoethyl)carbamoyl)quinolin-8- yl)amino)-4-oxobutanoyl)piperazin-l -yl)-2-oxoethyl)-l ,4,7-triazonane-l ,4-diyl)diacetic acid (1) to

ESV6-NOTA-A1-F (A1F@1)

Compound 1 (1 mg, 1.16 µmol, 1 eq) was dissolved in a mixture of DMSO (0.05 mL) and acetate buffer pH=4 (0.2 mL). AlF₃ (1 mg, 11.6 µmol, 10 eq.) was added and the mixture was heated at 95°C for 15 min. Then the mixture was purified via RP-HPLC (95:5 to 0:100 water/ACN + 0.1% TFA in 20 min) the desired fractions were collected and lyophilized to afford a white solid. (0.8 mg, 80%). ¹³ _{C4-ESV6-NODAGA-Al-F was generated following the same procedure described for ESV6-} NODAGA-Al-F, using ¹³C₄ succinic anhydride as isotopically labelled building block for the synthesis of 1. 13C4-ESV6-NOTA-Al-F was generated following the same procedure described for ESV6-NOTA-Al-F, _using ¹³ _{C4 succinic anhydride as isotopically labelled building block for the synthesis of 1.} Example 3: Ex vivo characterization of “ESV6-NODAGA-Al-F” and of “ESV6-NOTA-Al- F” All animal experiments were conducted in accordance with Swiss animal welfare laws and regulations under the license number ZH06 / 2021 granted by the Veterinäramt des Kantons Zürich. Implantation of subcutaneous tumors Tumor cells were grown to 80% confluence and detached with Trypsin-EDTA 0.05%. SK-RC-52.hFAP, cells (FAP positive cells) were resuspended in Hanks’ Balanced Salt Solution medium. Aliquots of 5 to 10 × 10⁶ cells (100 to 150 μL of suspension) were injected subcutaneously in the right or left flanks of female athymic Balb/c AnNRj-Foxn1 mice (6 to 8 wk of age, Janvier). Ex Vivo biodistribution experiments. Mice bearing subcutaneous SK-RC-52.hFAP tumors were injected intravenously with ESV6-NODAGA- Al-F and ESV6-NOTA-Al-F (10 nmol dissolved in sterile PBS, pH 7.4). Animals were sacrificed 2 h after intravenous injection, organs and tumor were subsequently excised, snap frozen at such, and stored at −80 °C. Sample Preparation 50 mg of mice tissues were resuspended in 600 µL of a solution containing 95 % ACN and 0.1 % FA to induce protein precipitation. In parallel 50 µL of a solution 600 nM of internal standard (¹³C₄-ESV6- NODAGA-Al-F or ¹³C₄-ESV6-NOTA-Al-F) were also added to the solution. Samples were then homogenized with a tissue lyser (TissueLyser II, QIAGEN) for 15 minutes at 30 Hz. After homogenization, samples were centrifugated at 14000 g for 10 minutes and supernatants were dried at room temperature with a vacuum centrifuge.

Samples were then resuspended in 1 mF solution containing 3% ACN and 0.1 % of TFA and subsequently cleaned up using Oasis HLB SPE columns (Waters). Eluted samples were again dried under vacuum at room temperature, resuspended in 1 mL 3% ACN and 0.1 % of TFA and cleaned up using Sep-Pak SPE columns (Waters). Eluted samples were then dried under vacuum at room temperature.

Dry samples were finally resuspended in 30 pF of a solution containing 3 % of ACN and 0.1 % of FA. 3 pl of each sample (10% of the total) were then injected in the nanoLC-HR-MS system (as depicted in Figure 5). nanoLC-HR-MS analysis

Chromatographic separation was carried out on an Acclaim PepMap RSLC column (50 pm x 15 cm, particle size 2 pm, pore size, 100 A) with a gradient program from 95% A (0.1% FA), 5 % B (ACN 0.1 % FA) to 5 % A, 95 % B in 45 minutes on an Easy nanoEC 1000. Sample clean up and concentration was carried out with a pre column Acclaim PepMAP 100 (75 pm x 2 cm, particle size 3 pm, pore size 100 A) mounted on the system. The EC system was coupled to a Q-Exactive mass spectrometer via a Nano Flex ion source. Ionization was carried out with 2 kV of spray voltage, 250 °C of capillary temperature, 60 S- lens RF level. Mass spectrometry was working in Single ion Monitoring mode (SIM) following the mass range reported in Table 1. The detector was working in positive ion mode with the following parameters: resolution 70000 (FWHM at 400 m/z), AGC target 5 x 10⁴, and maximum injection time 200 ms. Data analysis was carried out with Thermo Xcalibur Qual Broswer v2.2 and Prism8.

Table 1: Mass range windows for the SIM mode of the mass spectrometer.

The results shown in Figure 6 indicate a remarkable tumor-to-organ ratio for ESV6-NOTA-A1-F.

Example 4: Quantitative in vivo biodistribution of “ESV6-NOTA-[¹⁸F]A1-F”

Animal studies

All animal experiments were conducted in accordance with Swiss animal welfare laws and regulations under the license number ZH06/2021 granted by the Veterinaramt des Kantons Zurich. Implantation of subcutaneous tumors

HT-1080.hFAP cells (FAP positive tumor cells) were grown to 80% confluence in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% Fetal Bovine Serum and 1% antibiotic-antimycotic and detached with Trypsin-EDTA 0.05%. Cells were resuspended in Hanks’ Balanced Salt Solution medium. Aliquots of 5 x 10⁶ cells (100 pL of suspension) were injected subcutaneously in the right flanks of female athymic Balb/c AnNRj-Foxnl mice (6 to 8 wk of age).

Biodistribution studies in tumour bearing mice

Female athymic Balb/c AnNRj-Foxnl mice (6 to 8 wk of age) implanted in the right flank with HT- 1080.hFAP tumors as described above were allowed to grow to an average tumor volume of 250 mm³. Mice were randomized (n = 5 per group) and injected intravenously with radiolabeled preparations of ESV6-NOTA-[¹⁸F]A1-F (10 nmol/mice; 77 KBq). Mice were euthanized Ih after the injection by CO2 asphyxiation. Organs were extracted, weighted, and radioactivity was measured with a Gamma Counter. Values are expressed as percent ID/g + SD. Results are reported in Figure 7.

Radiolabelling of ESV6-NOTA

Radiolabelling of ESV6-NOTA (200-300 pg) with ¹⁸F was performed via aluminium (Al³⁺) fluoride complex using FASTlab 2 synthesis module and the cassette. During the placement of vials and reagents on the cassette, the 5 mL reactor vessel was prefilled with 25 pL of 2mM aluminium chloride (Aids, anhydrous, powder, 99.999% trace metals basis) in sodium acetate buffer (0.1 M, pH=4.1). [¹⁸F] -fluoride was transferred to the module and trapped on a Sep-Pak light Accel plus QMA cartridge (Cl- form:). The cartridge was washed with 6 mL of water (HPCE grade). [¹⁸F] -fluoride was eluted from the QMA cartridge into reactor vessel with 500 pL of the eluent solution (250 pL NaCl 0.9%; 99.999% trace metals basis NaCl;) in water for injection and 250 pL absolute ethanol). The solution was stirred for 5 min at room temperature under gentle nitrogen flow to form [¹⁸F]A1F. The precursor solution (600 pL of 350 pg/mL ESV6-NOTA in sodium acetate 0.1M pH 4.5) was added to the reactor which was sealed and heated for 10 min at 95°C. Next, the reactor was cooled to 40°C and the reaction mixture was diluted with 3.5 mL of NaCl 0.9% and sent through the preactivated Cl 8 cartridge, Cl 8 was washed with 5 mL of NaCl 0.9% and eluted with 1.5 mL of absolute EtOH. The product was diluted with NaCl 0.9% to obtain the final formulation. The radiochemical purity for each batch of ESV6-NOTA-[¹⁸F]A1-F was determined by radio-HPLC and reported in Table 2.

TABLE 2

Example 5: Radiosynthesis of [⁶⁸Ga]GaESV6-NODAGA and of [⁶⁸Ga]GaESV6-NOTA

[⁶⁸Ga]GaESV6-NODAGA/NOTA (15-25 pg) were synthesized in an FASTlab 2 synthesis module using the cassette. The synthesis is carried out using ⁶⁸Ga (ti/2 = 68 min, P⁺= 89%, and EC=11%) obtained by a Eckert & Ziegler generator (1850 MBq, GalliaPharm), eluted with HC1 (4.5ml, 0.1M TRASIS ALLinONE reagent kit). 4 ml of [⁶⁸Ga]GaC13 was transferred to the reactor vessel, the precursor dissolved in sodium acetate (750 pL, 0.7M TRASIS ALLinONE reagent kit) is aspirated into the reactor, the solution was stirred for 5 min at room temperature under gentle nitrogen flow. Next, the reaction mixture is sent through the preactivated Cl 8 cartridge, washed with NaCl 0.9% (5ml, TRASIS ALLinONE reagent kit) and eluted with eluent solution (700 pL of absolute ethanol and 800 pL of water for injection). The product is diluted with NaCl 0.9% to obtain the final formulation. The radiochemical purity for each batch of [⁶⁸Ga]GaESV6-NODAGA/NOTA is determined by radio-HPLC and reported in Table 3 and 4 respectively.

TABLE 3

TABLE 4

The acceptance criteria and the average results of synthesis are reported in Table 5

Example 6: Characterization of r⁶⁸Ga1GaESV6-NODAGA, [⁶⁸Ga1GaESV6-NOTA and of ESV6- NOTA-[¹⁸F1A1-F binding to human FAP

Radiolabelled ESV6-derivatives binding to hFAP were tested by loading a solution of preincubated of either 68Ga/[18F]AlF/-ESV6 derivatives (500KBq) and human FAP (2 pM, lOOpl) on PD-10 columns preequilibrated with running buffer (50 mM Tris, 100 mM NaCl, and 1 mM ethylenediaminetetraacetic acid [EDTA], pH = 7.4), and flushed with running buffer. Fractions of the flow through (500 pF) were collected in 3ml test tube, and the radioactivity intensity associated with the concentration of radiocompounds was measured immediately on a gamma counter (7=51 I KeV for 68Ga and 18F).

For all the radiolabelled compounds the coelution experiments of the radiopharmaceutical in the absence and in the presence of the human FAP protein show an excellent affinity towards their biological target as can be seen from Figure 8.

Claims

CLAIMS 1. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or a pharmaceutically acceptable salt thereof, wherein the compound structure comprises: a moiety A represented by or comprising the following structure:

one or more diagnostic or therapeutic agent moieties C; and a moiety B covalently connecting A to C, which is represented by the following structure:

wherein each b¹ and b³ is independently an integer from 0 to 4, preferably 0 or 1; each b² is independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; each B² is independently represented by wherein:

Y and Z are linking groups forming part of a carbocyclic or heterocyclic group, preferably a C_3–13 carbocyclic or C_2–12 heterocyclic group; *^{–Y represents} _* ^–C, _* ^–CR, _* ^–N, _* ^–NR, _* ^–NRC(O)C, _* ^–NRC(O)CR, *^–NRC(O)CR ₂ ^C, _* ^–NRC(O)CR ₂ ^CR, _* ^{–NRC(S)NRC,} _* ^{–NRC(S)NRCR,} _* ^–NRC, _* ^–NRCR, *^–NRCR ₂ ^{C, or} _* ^–NRCR ₂ ^{CR; Z–} _• ^{represents C–} _• ^{, CR–} _• ^{, N–} _• ^{, NR–} _• ^{, CC(O)NRCRC(O)NR–} _• ^{, CCR} ₂ ^C(O)NR– _• ^{, CRCR} ₂ ^C(O)NR– _• ^{, CNRC(S)NR–} _• ^{, NRC(S)CRNR–} _• ^{, CNR–} _• ^{, CRNR–} _• ^{, CCR} ₂ ^NR– _• ^{, or CRCR} ₂ ^NR– _• ^; each _* represents a point of attachment closer to moiety A than to a moiety C; each _• represents a point of attachment closer to a moiety C than to moiety A; each B¹ is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; and is preferably a bond, alkylene or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O;. wherein the shortest path between A and B² preferably comprises 6 or less, more preferably 3 or less, most preferably 2 or less covalently connected atoms or is a bond; each B³ is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene comprising one or more heteroatoms selected from N and O; and is preferably a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene; wherein the shortest path between B² and C preferably comprises 10 or less, more preferably 7 or less, most preferably 6 or less covalently connected atoms or is a bond; each of B¹, B² and B³ can be independently substituted by one or more of R; each R is independently selected from H, OH, SH, NH₂, halogen, cyano, oxo, carboxy, C(O)NH₂ C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C3–6 cycloalkoxy, C6–10 aryl, C6–10 aryloxy, C5–10 heteroaryl and C5–10 heteroaryloxy, of which the SH, NH₂, C(O)NH₂, C_1–6 alkyl, C_1–6 alkoxy, C(O)C_1–6 alkyl, C_1–6 alkylthio, C_1–5 heteroalkyl, C_1–5 heteroalkoxy, C_3–6 cycloalkyl, C_3–6 cycloalkoxy, C_6–10 aryl, C_6–10 aryloxy, C_5–10 heteroaryl and C5–10 heteroaryloxy can be optionally substituted with one or more of OH, SH, NH₂, halogen, cyano, oxo, carboxy, C_1–6 alkyl, C_1–5 heteroalkyl, C_3–6 cycloalkyl, C_6–10 aryl and C_5–10 heteroaryl, and two or more of R can be bound together to form part of a carbocyclic or heterocyclic ring system; and all valences are satisfied. 2. The compound of claim 1, which is represented by the following Formula I:

3. The compound according to any one of the preceding claims, wherein moiety A has the following structure A¹, A² or A³, preferably A², wherein m is 0, 1, 2, 3, 4, or 5, preferably 1; and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 2:

. A¹ A² A³ 4. The compound of any one of the preceding claims, wherein each B² is independently selected from: ,

each s, u, t, and v is independently 0, 1, or 2; each w is independently 0, 1, 2, or 3; and each X is independently N, NH, NR, S, S(O), SO₂, O, C, CR, CH, CR₂ or CH₂; and preferably, B² is selected from:

more preferably, B² is selected from:

most preferably, B² is selected from:

5. The compound of any one of claims 1 to 4, wherein

6. The compound of any one of claims 1 to 4, wherein

p y The compound of any one of claims 1 to 4, wherein

The compound of any one of claims 1 to 4, wherein:

more preferably

most preferably

9. The compound of any one of claims 1 to 4, wherein

10. The compound of any one of claims 1 to 4, wherein

most preferably

11. The compound of any one of the preceding claims, wherein: each B¹ is independently selected from bond; C_1–10, preferably C_1–4, more preferably C_1–2 alkylene; C_1–10, preferably C_1–4, more preferably C_1–2 heteroalkylene group comprising one or two N atoms; NR(C_1–10, C_1–4, or C_1–2 alkylene)NR; (C_1–10, C_1–4, or C_1–2 alkylene)NR; NR(C_1–10, C_1–4, or C_1–2 alkylene); C(O); C(O)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_1–10 alkylene)C(O); C(O)(C_1–10 alkyl)C(O)NR; C(O)(C_5–10 heteroaryl)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_{5– 10} heteroaryl)CR₂; C(S)NR; C(S)NR(C_6–10 aryl)CR₂; and C(S)NR(C_5–10 heteroaryl)CR₂; and is CH₂CH₂NH, NHCH₂CH₂,

e_{ach B} ³ _{is independently selected from bond; C1–10, preferably C1–4, more preferably C1–2} alkylene; C1–10, preferably C1–4, more preferably C1–2 heteroalkylene group comprising one or two N atoms;n NR(C_1–10, C_1–4, or C_1–2 alkylene)NR; (C_1–10, C_1–4, or C_1–2 alkylene)NR; NR(C_1–10, C_1–4, or C_1–2 alkylene); C(O); C(O)CR₂;C(O)(C_6–10 aryl)CR₂; C(O)(C_5–10 heteroaryl)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_5–10 heteroaryl)CR₂; C(O)(C_6–10 aryl)CR₂; C(O)(C_5–10 heteroaryl)CR₂; C(S)NR; C(S)NR(C_6–10 aryl)CR₂; and C(S)NR(C_5–10 heteroaryl)CR₂; and is preferably bond,

12. The compound according to any one of the preceding claims, wherein the moiety C is selected from: a chelating agent group suitable for radiolabelling; a radioactive group comprising a radioisotope; a chelate of a radioactive isotope with a chelating agent; a fluorophore group; a cytotoxic and/or cytostatic agent; immunomodulator agent; or a protein, wherein preferably, C: (a) is chelating agent group suitable for radiolabelling: (i) derived from 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), 2,2',2''- (1,4,7-triazonane-1,4-diyl)diacetic acid (NODA), 2,2'-((2-((4-(2-amino-2- oxoethyl)benzyl)(carboxymethyl)amino)cyclohexyl)azanediyl)diacetic acid] (RESCA), sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane- N,N',N'',N'''-tetraacetic acid (DOTA), [2,2',2''-(10-(4-((2-aminoethyl)amino)-1- carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-GA), [1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA), iminodiacetic acid, bis(carboxymethylimidazole)glycine, 6- Hydrazinopyridine-3-carboxylic acid (HYNIC); or (ii) having a structure according to one of the following formulae C¹, C², C³, C⁴, and C⁵:

wherein: each q is independently 0, 1, 2, 3, 4 or 5; preferably 0; R^1e _{, R} ^1f _{, R} ^1g _{, R} ^1h _{, and R} ¹ⁱ _{are each independently H, COOH, aryl-COOH or} heteroaryl-COOH; preferably COOH; R^2e, _R ^2f _{, R} ^2g _{, R} ^2h _{, and R} ²ⁱ _{are each independently H, COOH, aryl-COOH or} heteroaryl-COOH; preferably COOH; R^3e, _R ^3f _{, R} ^3g _{, R} ^3h _{, R} ^4h _{, and R} ³ⁱ _{are each independently H, COOH, aryl-} COOH or heteroaryl-COOH; preferably COOH; and a_{nd R} ^4e _{is independently H, COOH, aryl-COOH or heteroaryl-COOH, with the proviso that when q is 0, R} ^4e _{is H;} each X is independently NH, NR, S, O, CR₂, or H,H; preferably O; each Q is N or O, preferably N; w_{herein when Q is O, CH2R} ^2e, _CH2R ^2f _{, CH2R} ^2g _{, CH2R} ^2h _{, and CH2R} ²ⁱ _is absent; and L is –CH₂C(O)– or –NHC(S)–; or (iii) having a structure selected from the following:

(b) radioactive group comprising a radioisotope is selected from ²²³Ra, ⁸⁹Sr, ^94mTc, "^mTc, 1⁸⁶Re, ¹⁸⁸Re, ²⁰³Pb, ⁶⁷Ga, ⁶⁸Ga, ⁴⁷Sc, ^{1 H}In, ⁹⁷Ru, ⁶²Cu, ^MCu, ⁸⁶Y, ⁸⁸Y, ⁹⁰Y, ¹²¹Sn, ¹⁶¹Tb, 1⁵³Sm, ¹⁶⁶HO, ¹⁰⁵Rh, ¹⁷⁷Fu, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁸F, ^{21 1}At, ²²⁵ Ac, ⁸⁹Sr, ^117mSn and ¹⁶⁹Er, wherein ¹⁸F is preferably bound to chelated Al, Zr, Si, Ga, or In, more preferably ¹⁸F is bound to Al chelated by the chelator;

(c) chelate of a radioactive isotope is a chelate of an isotope listed under (b) above and/or with a chelating agent listed under (a) above; or moiety C is a group selected from any of the following structures:

13. The compound of any one of claims 4 to 10, wherein C is a chelator selected from

preferably wherein ¹⁸F is bound to Al chelated by the chelator.

A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers, or a pharmaceutically acceptable salt thereof, having a structure selected from the following:

The compound according to any one of the preceding claims for use in:

(a) a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practised on the human or animal body; or

(b) a method for therapy or prophylaxis of a subject suffering from or having risk for a disease or disorder; or

(c) a method for guided surgery practised on a subject suffering from or having risk for a disease or disorder; or

(d) a method for diagnosis of a disease or disorder, the method being practised on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT); or

(e) a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder, wherein in each of the preceding (b)-(e), said disease or disorder is independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodelling and keloid disorder, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multi-drug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, oesophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumour, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymus cancer, desmoid tumours, glioma, astrocytoma, cervix cancer, skin cancer, kidney cancer, breast cancer, and prostate cancer; and wherein in each of the preceding uses or methods, the compound preferably has a prolonged residence at the disease site at a therapeutically or diagnostically relevant level, preferably beyond 1 h, more preferably beyond 6 h post injection.