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

The development of (64)Cu-based immuno-PET radiotracers requires the use of copper-specific 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 exce...

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Detalles Bibliográficos
Autores principales: Maisonial-Besset, Aurélie, Witkowski, Tiffany, Quintana, Mercedes, Besse, Sophie, Gaumet, Vincent, Cordonnier, Axel, Alliot, Cyrille, Vidal, Aurélien, Denevault-Sabourin, Caroline, Tarrit, Sébastien, Levesque, Sophie, Miot-Noirault, Elisabeth, Chezal, Jean-Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9822305/
https://www.ncbi.nlm.nih.gov/pubmed/36615280
http://dx.doi.org/10.3390/molecules28010075
Descripción
Sumario:The development of (64)Cu-based immuno-PET radiotracers requires the use of copper-specific 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.