Synthesis and In Vitro Comparison of DOTA, NODAGA and 15-5 Macrocycles as Chelators for the 64Cu-Labelling of Immunoconjugates - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecules Année : 2022

Synthesis and In Vitro Comparison of DOTA, NODAGA and 15-5 Macrocycles as Chelators for the 64Cu-Labelling of Immunoconjugates

Résumé

The development of 64 Cu-based immuno-PET radiotracers requires the use of copperspecific bifunctional chelators (BFCs) that contain functional groups allowing both convenient bioconjugation and stable copper complexes to limit in vivo bioreduction, transmetallation and/or transchelation. The excellent in vivo kinetic inertness of the pentaazamacrocyclic [ 64 Cu]Cu-15-5 complex prompted us to investigate its potential for the 64 Cu-labelling of monoclonal antibodies (mAbs), compared with the well-known NODAGA and DOTA chelators. To this end, three NODAGA, DOTA and 15-5-derived BFCs, containing a pendant azadibenzocyclooctyne moiety, were synthesised and a robust methodology was determined to form covalent bonds between them and azide-functionalised trastuzumab, an anti-HER2 mAb, using strain-promoted azide-alkyne cycloaddition. Unlike the DOTA derivative, the NODAGA-and 15-5-mAb conjugates were radiolabelled with 64 Cu, obtaining excellent radiochemical yields, under mild conditions. Although all the radioimmunoconjugates showed excellent stability in PBS or mouse serum, [ 64 Cu]Cu-15-5-and [ 64 Cu]Cu-NODAGA-trastuzumab presented higher resistance to transchelation when challenged by EDTA. Finally, the immunoreactive fraction of the radioimmunoconjugates (88-94%) was determined in HER-2 positive BT474 human breast cancer cells, confirming that the bioconjugation and radiolabelling processes implemented had no significant impact on antigen recognition.
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hal-03911093 , version 1 (22-12-2022)

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Aurélie Maisonial-Besset, Tiffany Witkowski, Mercedes Quintana, Sophie Besse, Vincent Gaumet, et al.. Synthesis and In Vitro Comparison of DOTA, NODAGA and 15-5 Macrocycles as Chelators for the 64Cu-Labelling of Immunoconjugates. Molecules, 2022, 28 (1), pp.75. ⟨10.3390/molecules28010075⟩. ⟨hal-03911093⟩
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