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


ABSTRACT: The development of 64Cu-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 [64Cu]Cu-15-5 complex prompted us to investigate its potential for the 64Cu-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 64Cu, obtaining excellent radiochemical yields, under mild conditions. Although all the radioimmunoconjugates showed excellent stability in PBS or mouse serum, [64Cu]Cu-15-5- and [64Cu]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.

SUBMITTER: Maisonial-Besset A 

PROVIDER: S-EPMC9822305 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Maisonial-Besset Aurélie A   Witkowski Tiffany T   Quintana Mercedes M   Besse Sophie S   Gaumet Vincent V   Cordonnier Axel A   Alliot Cyrille C   Vidal Aurélien A   Denevault-Sabourin Caroline C   Tarrit Sébastien S   Levesque Sophie S   Miot-Noirault Elisabeth E   Chezal Jean-Michel JM  

Molecules (Basel, Switzerland) 20221222 1


The development of <sup>64</sup>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 [<sup>64</sup>Cu]Cu-15-5 complex prompted us to investigate its potential for the <sup>64</sup>Cu-labelling of monoclonal antibodies  ...[more]

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