RT Journal Article SR Electronic T1 P-glycoprotein modulation at the rat blood-brain barrier studied with (R)-[11C]verapamil PET JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 210P OP 210P VO 49 IS supplement 1 A1 Claudia Kuntner A1 Jens Bankstahl A1 Aiman Abrahim A1 Rudolf Karch A1 Johann Stanek A1 Thomas Wanek A1 Maria Zsebedics A1 Wolfgang Wadsak A1 Wolfgang Löscher A1 Oliver Langer YR 2008 UL http://jnm.snmjournals.org/content/49/supplement_1/210P.4.abstract AB 909 Objectives: To study modulation of the multidrug efflux transporter P-glycoprotein (P-gp) at the rat blood-brain barrier (BBB) by the new-generation P-gp inhibitor tariquidar (TQD) with small-animal PET and (R)-[11C]verapamil (VPM). Methods: 5 Wistar Unilever rats underwent paired VPM PET scans and arterial blood sampling at an interval of 3 hours. At 2 hours before the 2nd PET scan, TQD (15 mg/kg) was administered by i.v. injection. 2 animals underwent test-retest examinations without TQD administration. An additional group of animals underwent single VPM PET scans after administration of 1, 3, 5, and 7.5 mg/kg of TQD. The PET data were analyzed with a 4-rate-constant-2-tissue compartment model. Results: Following TQD administration, the distribution volume DV of VPM was 12-fold higher than at baseline (3.68±0.81 vs. 0.30±0.08; p=0.0007, paired t-test), whereas the DVs were essentially the same in the test-retest examinations. The increase in DV could mainly be attributed to an increased influx rate constant K1 of radioactivity into the brain, which was about 8-fold higher after TQD. The dose-response assessment provided an estimated half-maximum effect dose of 6.5 mg/kg (95% confidence interval, 4.9-8.2) for TQD. VPM metabolism and plasma protein binding were unchanged after TQD administration. Conclusions: Our data suggest that TQD is a potent inhibitor of P-gp at the BBB that enhances intracerebral uptake of P-gp substrates.