Synthesis of a 11C-Isotopologue of the B-Raf-Selective Inhibitor Encorafenib Using In-Loop [11C]CO2 Fixation

Mark H Dornan; Daniil Petrenyov; José-Mathieu Simard; Mehdi Boudjemeline; Roxana Mititelu; Jean N DaSilva; Anthony P Belanger

doi:10.1021/acsomega.0c02419

Synthesis of a ¹¹C-Isotopologue of the B-Raf-Selective Inhibitor Encorafenib Using In-Loop [¹¹C]CO₂ Fixation

ACS Omega. 2020 Aug 16;5(33):20960-20966. doi: 10.1021/acsomega.0c02419. eCollection 2020 Aug 25.

Authors

Mark H Dornan^{1

2}, Daniil Petrenyov², José-Mathieu Simard², Mehdi Boudjemeline², Roxana Mititelu³, Jean N DaSilva², Anthony P Belanger¹

Affiliations

¹ Department of Imaging, Dana-Farber Cancer Institute & Department of Radiology, Harvard Medical School, Boston, Massachusetts 02115, United States.
² Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du Centre Hospitalier de l'Université de Montréal & Département de Radiologie, radiooncologie et médecine nucléaire, Faculté de médecine, Université de Montréal, Montréal, Quebec H3T 1J4, Canada.
³ Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.

Abstract

The serine/threonine kinase B-Raf is an essential regulator of cellular growth, differentiation, and survival. B-Raf protein expression is elevated throughout melanoma progression, making it an attractive target for noninvasive imaging using positron-emission tomography. Encorafenib is a potent and highly selective inhibitor of B-Raf used in the clinical management of melanoma. In this study, the radiosynthesis of a ¹¹C-isotopologue of encorafenib was developed using an in-loop [¹¹C]CO₂ fixation reaction. Optimization of reaction conditions reduced the formation of a radiolabeled side product and improved the isolated yields of [¹¹C]encorafenib (14.5 ± 2.4% radiochemical yield). The process was fully automated using a commercial radiosynthesizer for the production of 6845 ± 888 MBq of [¹¹C]encorafenib in high molar activity (177 ± 5 GBq μmol^-1), in high radiochemical purity (99%), and in a formulation suitable for animal injection. An in vitro cellular binding experiment demonstrated saturable binding of the radiotracer to A375 melanoma cells.