[11C]phenytoin revisited: synthesis by [11C]CO carbonylation and first evaluation as a P-gp tracer in rats

Background At present, several positron emission tomography (PET) tracers are in use for imaging P-glycoprotein (P-gp) function in man. At baseline, substrate tracers such as R -[ 11 C]verapamil display low brain concentrations with a distribution volume of around 1. [ 11 C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline. This could facilitate assessment of P-gp function when P-gp is upregulated. The purpose of this study was to synthesize [ 11 C]phenytoin and to characterize its properties as a P-gp tracer. Methods [ 11 C]CO was used to synthesize [ 11 C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [ 11 C]phenytoin were studied in rats. Effects of P-gp function on [ 11 C]phenytoin uptake were assessed using predosing with tariquidar. Results [ 11 C]phenytoin was synthesized via [ 11 C]CO in an overall decay-corrected yield of 22 ± 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [ 11 C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [ 11 C]phenytoin. Conclusions Using [ 11 C]CO, the radiosynthesis of [ 11 C]phenytoin could be improved. [ 11 C]phenytoin appeared to be a rather weak P-gp substrate.