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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 11 C-isotopologue of encorafenib was developed using an in-loop [ 11 C]CO 2 fixation reaction. Optimization of reaction conditions reduced the formation of a radiolabeled side product and improved the isolated yields of [ 11 C]encorafenib (14.5 ± 2.4% radiochemical yield). The process was fully automated using a commercial radiosynthesizer for the production of 6845 ± 888 MBq of [ 11 C]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., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)