[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-[C-11]verapamil display low brain concentrations with a distribution volume of around 1. [C-11]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 [C-11]phenytoin and to characterize its properties as a P-gp tracer. Methods: [C-11]CO was used to synthesize [C-11]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [C-11]phenytoin were studied in rats. Effects of P-gp function on [C-11]phenytoin uptake were assessed using predosing with tariquidar. Results: [C-11]phenytoin was synthesized via [C-11]CO in an overall decay-corrected yield of 22 +/- 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [C-11]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [C-11]phenytoin. Conclusions: Using [C-11]CO, the radiosynthesis of [C-11]phenytoin could be improved. [C-11]phenytoin appeared to be a rather weak P-gp substrate.