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

Abstract

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 BRAFV600E 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 (BRAFV600E) and MeWo (BRAFwt) 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 BRAFV600E mutations in vivo using PET with [11C]vemurafenib will be challenging.

Preclinical evaluation of [18F]cabozantinib as a PET imaging agent in a prostate cancer mouse model

“…Tracer concentration in heart tissue was significantly higher than in blood at all studied time points, indicating that the heart uptake is not solely due to a well-perfused heart. The heart uptake observed with [ 18 F]cabozantinib is notably higher than what has been observed with other TKI PET tracers [6,33,34].…”

Effects of Macrofungal Polysaccharides Combined with Vemurafenib on Melanoma and Its Associated Mechanism

“…3 × 10 6 human melanoma MeWo cells in a logarithmic growth phase were injected subcutaneously into the right ankle of nude mice. When the tumor grows to at least 100-300 mm 3 , the mice were used for in vivo experiments [17].…”

Carbon-11: Radiochemistry and Target-Based PET Molecular Imaging Applications in Oncology, Cardiology, and Neurology

“…The achieved radiochemical yield was 21%. 64 The S-[ 11 C]methylated mercaptoimidazole piperazinyl derivatives as PET radiotracers have been reported as 5-HT 1A receptor imaging agents. In the radiochemical synthesis, the [ 11 C]methyl group was introduced at the C-2 position of an imidazole ring.…”

“…64) PET radioligand which has specificity for DAT showed a 50% reduction of DAT availability in the striatum of Huntington's disease (HD) patients compared to control subjects 246. [ 11 C]PE2I(65) showed high affinity, specificity, and selectivity binding to central DAT by displacement experiments in the monkey brain in vivo 247.…”