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