Abstract

P-glycoprotein (P-gp) is a major efflux transporter contributing to the efflux of a range of xenobiotic compounds at the blood-brain barrier (BBB). In the present study, we evaluated the P-gp function at the BBB using positron emission tomography (PET) in nonhuman primates. Serial brain PET scans were obtained in three rhesus monkeys after intravenous administration of [¹¹C]verapamil under control and P-gp inhibition conditions ([PSC833 ([3′-keto-Me-Bmt¹]-[Val²]-cyclosporin) 20 mg/kg/2 h]). The parent [¹¹C]verapamil and its metabolites in plasma were determined by HPLC with a positron detector. The initial brain uptake clearance calculated from the integration plot was used for the quantitative analysis. After intravenous administration, [¹¹C]verapamil was taken up rapidly into the brain (time to reach the peak, 0.58 min). The blood level of [¹¹C]verapamil decreased rapidly, and it underwent metabolism with time. The inhibition of P-gp by PSC833 increased the brain uptake of [¹¹C]verapamil 4.61-fold (0.141 versus 0.651 ml/g brain/min, p < 0.05). These results suggest that PET measurement with [¹¹C]verapamil can be used for the evaluation of P-gp function at the BBB in the living brain.