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

[11C]CO was used to synthesize [11C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [11C]phenytoin were studied in rats. Effects of P-gp function on [11C]phenytoin uptake were assessed using predosing with tariquidar.[11C]phenytoin was synthesized via [11C]CO in an overall decay-corrected yield of 22？±？4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [11C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [11C]phenytoin.Using [11C]CO, the radiosynthesis of [11C]phenytoin could be improved. [11C]phenytoin appeared to be a rather weak P-gp substrate.The blood–brain barrier (BBB) is a tightly connected cell layer that protects the brain from harmful substances and regulates transfer of various compounds between the brain and blood. The tight junctions between endothelial cells of the BBB force drugs to penetrate through rather than between these cells, either by passive diffusion, active influx or active efflux [1,2]. Active influx and efflux are processes that can transport molecules against a concentration gradient, hence requiring ATP-provided energy. P-glycoprotein (P-gp) is an ATP-dependent 170- to 180-kDa transmembrane glycoprotein present at the luminal side of the BBB where it prevents its substrates from entering the brain. This phenomenon may, however, also be associated with drug-resistance in several diseases, such as temporal lobe epilepsy [3-5], depression [6] and HIV [7]. In addition, a change in P-gp function at the BBB has been proposed as a possible link in the etiology of several neurological diseases [6-8].A number of positron emission tomography (PET) tracers [9,10] for imaging P-gp function in man have been described, and they are all strong substrates of P-gp. Strong substrate tracers such as 11C]verapamil [11-13], 11C]desmethyl loperamide [14], 11C]laniqu