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EP-4735443-A1 - CUCURBITURIL DERIVATIVES FOR RADIOLABELING, PROCESSES OF PRODUCTION AND USES THEREOF

EP4735443A1EP 4735443 A1EP4735443 A1EP 4735443A1EP-4735443-A1

Abstract

The present invention concerns cucurbituril derivatives for radiolabeling, processes of production and uses thereof. Said invention also concerns the corresponding radiolabeled cucurbituril derivatives of formula (I), processes of production and uses thereof to obtain conjugates by supramolecular chemistry, in particular with targeting agents, more particularly labelled biomolecules, notably in nuclear medicine.

Inventors

  • GONCALVES, Victor
  • VIZIER, Romane

Assignees

  • Université de Bourgogne Europe
  • Centre National de la Recherche Scientifique

Dates

Publication Date
20260506
Application Date
20240628

Claims (16)

  1. 1. A compound of following formula (I): wherein: W is of following formula (A): -X-L-(Y)i-Z (A), Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11 and R12 are identical and are: H; OH; or a methyl group; R13 is: H; OH; a (Ci-Ce) alkyl group a aryl group, in particular a phenyl; a O-(Ci-Ci2)-alkyl, O-(C2-Ci2)-alkenyl, or O-(C2-Ci2)-alkynyl group, said group being optionally interrupted by at least one atom or group chosen from -O-, -NR-, -S- , and/or substituted, notably terminally substituted, by a T group chosen from halogens, in particular -Cl; OR a ; and NR a Rb; R a and Rb being independently chosen from H and (C1-C12)- alkyl groups; i is at each occurrence independently chosen from 0 and 1; X is chosen from O, CH2, NHC(=O), and NH; L is a linear or branched (Ci-C24)-alcane diyl group, optionally interrupted by at least one atom or group chosen from -O-, -NR-, -S-, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -NR- C(=O)-, -C(=O)-NR-, -NR-C(=O)-NR’-, -NR-C(=S)-NR’-, -NR-C(=O)-O-, -O-C(=O)- NR’-; -C(R)=C(R’)-, -C=C-, and arene diyl, in particular benzene diyl, or by a group of the following formula: Y is chosen from -O-, -NR-, -S-, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -NR-C(=O)-, - C(=O)-NR-, -NR-C(=O)-NR’-, -NR-C(=O)-O-, -O-C(=O)-NR’-; -C(R)=C(R’)-, and -C=C-; -NR-C(=S)-NR’- , and groups of one of the following formulae: R and R’ are at each occurrence independently chosen from H and Ci-Ce-alkyl groups; Z is a chelator.
  2. 2. The compound according to claim 1, wherein: all of the R1-R13 groups are H; or R13 group is not H, R13 being in particular OH or a (Ci-Ce) alkyl group, the R1-R12 groups being H.
  3. 3. The compound according to any one of the preceding claims, wherein W is of following formula (Ai): wherein: X, Y, Z, and i are as defined in claim 1 ; j is at each occurrence independently chosen from 0 and 1; Li and L2 are at each occurrence independently a linear or branched (Ci-Ci2)-alcane diyl group, optionally interrupted by at least one atom or group chosen from -O-, -NR-, -S-, -C(R)=C(R’)-, and -C=C-: Y’ is chosen from -C(=O)-, -O-C(=O)-, -C(=O)-O-, -NR-C(=O)-, -C(=O)-NR-, -NR- C(=O)-NR’-, -NR-C(=S)-NR’-, -NR-C(=O)-O-, -O-C(=O)-NR’-; -C(R)=C(R’)-, -C=C-, and by groups of one of the following formulae: R and R’ are at each occurrence independently chosen from H and linear or branched Ci-Ce-alkyl groups.
  4. 4. The compound according to any one of the preceding claims, being of the following formula (la):
  5. 5. The compound according to any one of the preceding claims, wherein W is of one of the following formulae: --X-L 1 Y'-L 2 4Y-Z --x-L 1 -Y’-L 2 -Y-z (A4) -X-LI-Z (AJ) -x- Ll -Y-z (A6) wherein X, Y, Y’, Z, Li, L2 and j are as defined in claim 1 and 3.
  6. 6. The compound according to any one of claims 3 to 5, wherein Li and/or L2 are at each occurrence independently: a linear (Ci-Ci2)-alcane diyl group, in particular a linear (Ci-Ce)-alcane diyl group, optionally interrupted by at least one atom -O-; a linear (Ci-Ci2)-alcane diyl group, in particular a linear (Ci-Ce)-alcane diyl group, more particularly a C2-alcane diyl group; -a (CH2-CH2-O)n-CH2-CH 2 - group, wherein n ranges from 1 to 7, notably from 1 to 5; i is 1 and Y is NH, NHC(=O) or -C(=O)-NH; j is 1 and Y’ is NHC(=O) or -C(=O)-NH; Li is a (Ci-Ce)-alcane diyl group, in particular a C2-alcane diyl group, i is 1, j is 0, and Y is NH or NH-C(=O) or Li is a (Ci-Ce)-alcane diyl group, in particular a C2-alcane diyl group, i is 0, j is 1, Y’ is NHC(=O) or -C(=O)-NH, and L2 is a (Ci-Ce)-alcane diyl group, in particular a C2-alcane diyl group.
  7. 7. The compound according to any one of the preceding claims, wherein Z is chosen from DOTA, NOD AGA, DOTAGA, DTP A, DFO, NOTA, RESCA, NODA-MPAA, HBED, TETA, CB-TE2A, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NET A, H4octapa, Pycup, N x S 4 -x (N4, N2S2, N3S), Hynic, and 99m Tc(CO) 3 -chelators.
  8. 8. The compound according to any one of the preceding claims, being chosen from the following formulae:
  9. 9. A compound of following formula (II): wherein: W is of following formula (B): — X-L-(Y)i-ZM (B), Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11 and R12 are identical and are: H; OH; or a methyl group; R13 is: H; OH; a (Ci-Ce) alkyl group a aryl group, in particular a phenyl; a O-(Ci-Ci2)-alkyl, O-(C2-Ci2)-alkenyl, or O-(C2-Ci2)-alkynyl group, said group being optionally interrupted by at least one atom or group chosen from -O-, -NR-, -S- , and/or substituted, notably terminally substituted, by a T group chosen from halogens, in particular -Cl; OR a ; and NR a Rb; R a and Rb being independently chosen from H and (C1-C12)- alkyl groups; i is at each occurrence independently chosen from 0 and 1; X is chosen from O, CH2, NHC(=O), and NH; L is a linear or branched (Ci-C24)-alcane diyl group, optionally interrupted by at least one atom or group chosen from -O-, -NR-, -S-, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -NR- C(=O)-, -C(=O)-NR-, -NR-C(=O)-NR’-, -NR-C(=S)-NR’-, -NR-C(=O)-O-, -O-C(=O)- NR’-; -C(R)=C(R’)-, -C=C-, and arene diyl, in particular benzene diyl, or by a group of the following formula: Y is chosen from -O-, -NR-, -S-, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -NR-C(=O)-, - C(=O)-NR-, -NR-C(=O)-NR’-, -NR-C(=O)-O-, -O-C(=O)-NR’-; -C(R)=C(R’)-, and -C=C-; -NR-C(=S)-NR’- , and by groups of one of the following formulae: R and R’ are at each occurrence independently chosen from H and Ci-Ce-alkyl groups; Z is a chelator; M is a radiometal.
  10. 10. The compound according to claim 9, wherein M is chosen from 43 Sc, 44 Sc, 47 Sc, 51 Cr, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 81m Kr, 82 Rb, 89 Zr, 90 Y, " m Tc, m In, 117m Sn, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 2O1 T1, 203 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, 227 Th.
  11. 11. A conjugate between at least one compound of following formula (II) as defined in claim 9 or 10 and at least one compound (III) comprising a targeting agent, in particular a biomolecule residue, linked, optionally through a linker L’, to a binder of cucurbit[7]urils.
  12. 12. The conjugate according to claim 11, wherein: the targeting agent is a biomolecule, in particular an antibody, more particularly a monoclonal antibody; the binder of cucurbit[7]urils is a ferrocene or a polycycloalkane, in particular an adamantane, bicyclo[2.2.2]octane, or a diamantane, said ferrocene or polycycloalkane substituted by at least one amine -NRcRa, ammonium -N + RcRdRe, linear or branched (Ci- C2)-alkyl-NRcRd, or linear or branched (Ci-C2)-alkyl-N + R c RdRe, wherein Re, Rd and Re are independently chosen from H and (Ci-Ce)-alkyl groups, and optionally further substituted by at least one hydroxyl, linear or branched (Ci-Ce)-alkyl, linear or branched (Ci-Ce)-alkyl- OH; and/or - the linker L’ is a linear or branched (Ci-C24)-alcane diyl group, optionally interrupted by at least one atom or group chosen from -O-, -NR-, -S-, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -NR-C(=O)-, -C(=O)-NR-, -NR-C(=O)-NR’-, -NR-C(=S)-NR’-, -NR-C(=O)- O-, -O-C(=O)-NR’-; -C(R)=C(R’)-, -C=C-, and arene diyl, in particular benzene diyl, or by a group of the following formula: - said linker L’ may be linked to said targeting agent by a Y” group chosen from - O-, -NR-, -S-, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -NR-C(=O)-, -C(=O)-NR-, -NR-C(=O)- NR -, -NR-C(=S)-NR’-, -NR-C(=O)-O-, -O-C(=O)-NR’-; -C(R)=C(R’)-, and -C=C-, or by a group of one of the following formulae: R and R’ are at each occurrence independently chosen from H and Ci-Ce-alkyl groups, L’ being for example a PEG.
  13. 13. A diagnostic and/or therapeutic composition, comprising a compound of formula (II) as defined in claim 9 or 10, and a pharmaceutically acceptable excipient.
  14. 14. The compound of formula (II) as defined in claim 9 or 10 for use as diagnostic or therapeutic agent for detecting, diagnosing or treating cancer, in particular thyroid cancer, neuroendocrine tumour, lung cancer, notably small-cell lung cancer, breast cancer, prostate cancer, notably castration-resistant prostate cancer, bone cancer, in particular bone metastases, non-Hodgkin lymphoma, notably large-cell lymphoma such as low-grade non-Hodgkin lymphoma, transformed low-grade non-Hodgkin lymphoma, diffuse large B-cell non-Hodgkin lymphoma, follicular lymphoma, notably follicular largecell lymphoma, relapsed non-Hodgkin lymphoma, refractory low-grade non-Hodgkin lymphoma, transformed B-cell non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, pheochromocytoma, paraganglioma, neuroblastoma, CNS cancer, in particular CNS metastases, small -round-cell tumour, pancreatic cancer, in particular pancreatic ductal adenocarcinoma, colorectal cancer, gastric cancer, head and neck cancer, multiple myeloma, lymphoma, liver cancer, in particular hepatocellular carcinoma, liver metastases, visceral metastases, gastroenteropancreatic neuroendocrine tumours.
  15. 15. A combination of a compound of formula (II) as defined in claim 9 or 10, with a compound (III) as defined in claim 11 or 12, for use in the diagnosis or treatment of cancer, in particular thyroid cancer, neuroendocrine tumour, lung cancer, notably small-cell lung cancer, breast cancer, prostate cancer, notably castration-resistant prostate cancer, bone cancer, in particular bone metastases, non-Hodgkin lymphoma, notably large-cell lymphoma such as low-grade non-Hodgkin lymphoma, transformed low-grade non-Hodgkin lymphoma, diffuse large B-cell non-Hodgkin lymphoma, follicular lymphoma, notably follicular large-cell lymphoma, relapsed non-Hodgkin lymphoma, refractory low-grade non- Hodgkin lymphoma, transformed B-cell non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, pheochromocytoma, paraganglioma, neuroblastoma, CNS cancer, in particular CNS metastases, small-round-cell tumour, pancreatic cancer, in particular pancreatic ductal adenocarcinoma, colorectal cancer, gastric cancer, head and neck cancer, multiple myeloma, lymphoma, liver cancer, in particular hepatocellular carcinoma, liver metastases, visceral metastases, gastroenteropancreatic neuroendocrine tumours, with simultaneous, separate or spread out administration over time
  16. 16. A conjugated compound as defined in claim 11 or 12, for use in the diagnosis or treatment of cancer, in particular thyroid cancer, neuroendocrine tumour, lung cancer, notably small-cell lung cancer, breast cancer, prostate cancer, notably castration-resistant prostate cancer, bone cancer, in particular bone metastases, non-Hodgkin lymphoma, notably large-cell lymphoma such as low-grade non-Hodgkin lymphoma, transformed low- grade non-Hodgkin lymphoma, diffuse large B-cell non-Hodgkin lymphoma, follicular lymphoma, notably follicular large-cell lymphoma, relapsed non-Hodgkin lymphoma, refractory low-grade non-Hodgkin lymphoma, transformed B-cell non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, pheochromocytoma, paraganglioma, neuroblastoma, CNS cancer, in particular CNS metastases, small-round-cell tumour, pancreatic cancer, in particular pancreatic ductal adenocarcinoma, colorectal cancer, gastric cancer, head and neck cancer, multiple myeloma, lymphoma, liver cancer, in particular hepatocellular carcinoma, liver metastases, visceral metastases, gastroenteropancreatic neuroendocrine tumours.

Description

CUCURBITURIL DERIVATIVES FOR RADIOLABELING, PROCESSES OF PRODUCTION AND USES THEREOF The present invention concerns cucurbituril derivatives for radiolabeling, processes of production and uses thereof. Said invention also concerns the corresponding radiolabeled cucurbituril derivatives, processes of production and uses thereof to obtain conjugates by supramol ecular chemistry, in particular with targeting agents, more particularly labelled biomolecules, notably in nuclear medicine. Antibodies, notably monoclonal antibodies, but also engineered affinity proteins, such as Affibody molecules and Affitins, and antibody fragments such as Fab, F(ab’)2, VHH fragments, and VNAR fragments, and constructs such as minibodies, diabodies, and singlechain variable region fragments (scFvs), owing to their outstanding affinity and selectivity for their target antigens, are vectors of choice for the targeting of cells and tissues of interest in vivo. They are successfully used, after radiolabeling, in nuclear medicine for nuclear imaging by positron emission tomography (PET) or single photon emission tomography (SPECT), or for targeted internal radiation therapy (TIR). Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Single-photon emission computed tomography (SPECT) is a nuclear medicine tomographic imaging technique using gamma rays. It is similar to conventional nuclear medicine planar imaging using a gamma camera (scintigraphy), but is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required. The technique generally needs delivery of a gamma-emitting radioisotope (a radionuclide) into the patient, normally through injection into the bloodstream. Targeted internal radiation therapy (TIR, also named Targeted Radionuclide Therapy, or Molecular Radionuclide Therapy) is a form of radiation therapy used in interventional radiology to treat cancer. It is generally for selected patients with surgically unresectable cancers, for example hepatocellular carcinoma or metastasis to the liver. Radiometalation of a biomolecule, such as a protein, traditionally involves two steps: first, the conjugation of a bifunctional chelator to the biomolecule, and second, the coordination of a radiometal by the biomolecule-chelator conjugate. The chelator ensures the rapid and stable formation of metal complexes. The chelators are often built around a polyamine system, more particularly polyazamacrocyclic motif, allowing the formation of complexes with good in vivo stability with a wide variety of clinically important radiometals. This is, for instance, the case of DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid). The radiometalation step frequently requires heating to achieve satisfactory complexation yields. While this is not usually a problem with small molecules or peptides, it becomes far more critical when it comes to labelling proteins. This issue motivated the development of a novel approach to protein radiolabeling: rather than trying to radiolabel chelator-antibody bioconjugates, one solution would be to first prepare the radiometal-chelator complex, under optimal conditions to obtain high radiochemical yields, and then to graft this radiolabeled complex to the protein under mild conditions, compatible with the stability of these biomolecules. This is classically achieved by creating covalent bonds between protein residues and the radiometal-chelator complex. Such approach requires the presence of a reactive function on the chelator, that will react with another function present on the biomolecule. For instance, the reaction between an N- hydroxysuccidimyl ester functionalized radiometal-chelator complex and the amine functions of lysine residues, creates an amide bond. Alternatively, bioorthogonal reactive functions, such as azide, trans-cyclooctenes, tetrazines or cycloctynes, can be used to perform so-called “click reactions”, which are high yielding, fast and selective, even in vivo. However, these reactive functions inherently exhibit a certain degree of instability. For example, N-hydroxysuccidimyl esters are slowly hydrolyzed in water. Similarly, tetrazines and trans-cyclooctenes have been shown to undergo degradation reactions resulting in loss of functionality. An alternative to covalent coupling is the implementation of non-covalent conjugation strategies, by supramolecular assembly. This type of approach has been used, for example, to label an antibody carrying a biotin, with [i nIn]In-DTPA-(strept)avidin. Biotin forms extremely stable interactions with (strept)avidin. Despite its exceptional affinity (K = 1015 M'1), the use of the biotin-(strept)avidin