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.
Mark H Dornan  1  2 ,  Daniil Petrenyov  2 ,  José-Mathieu Simard  2 ,  Mehdi Boudjemeline  2 ,  Roxana Mititelu  3 ,  Jean N DaSilva  2 ,  Anthony P Belanger  1
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.
PMID: 32875231 DOI: 10.1021/acsomega.0c02419
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.

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