Development of [¹¹C]vemurafenib employing a carbon-11 carbonylative Stille coupling and preliminary evaluation in mice bearing melanoma tumor xenografts

Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAF^V600E mutation. The aim of this study was to develop vemurafenib as PET tracer to determine its potential for identification of tumors sensitive to vemurafenib treatment. Therefore, vemurafenib was labeled with carbon-11 and analyzed for its tumor targeting potential in melanoma xenografts Colo829 (BRAF^V600E) and MeWo (BRAF^wt) using autoradiography on tissue sections, in vitro tumor cell uptake studies and biodistribution studies in xenografted athymic nu/nu mice. [¹¹C]vemurafenib was synthesized in 21 ± 4% yield (decay corrected, calculated from [¹¹C]CO) in > 99% radiochemical purity and a specific activity of 55 ± 18 GBq/μmol. Similar binding of [¹¹C]vemurafenib was shown during autoradiography and cellular uptake studies in both cell lines. Plasma metabolite analysis demonstrated > 95% intact [¹¹C]vemurafenib in vivo at 45 minutes after injection, indicating excellent stability. Biodistribution studies confirmed the in vitro results, showing similar tumor-to-background ratios in both xenografts models. These preliminary results suggest that identification of BRAF^V600E mutations in vivo using PET with [¹¹C]vemurafenib will be challenging.