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J Nucl Med. 2008; 49 (Supplement 1):210P
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Neurosciences: Basic Science

Basic Science Posters

P-glycoprotein modulation at the rat blood-brain barrier studied with (R)-[11C]verapamil PET

Claudia Kuntner1, Jens Bankstahl2, Aiman Abrahim3, Rudolf Karch4, Johann Stanek1, Thomas Wanek1, Maria Zsebedics5, Wolfgang Wadsak6, Wolfgang Löscher2 and Oliver Langer1

1 Dep. of Radiopharmaceuticals, ARC, Seibersdorf, Austria; ; 2 Dep. of Pharmacology, Toxicology & Pharmacy, TIHO, Hannover, Germany; ; 3 Dep. of Clinical Pharmacology; ; 4 Dep. of Medical Computer Sciences, MUW, Vienna, Austria; ; 5 Dep. of Toxicology, ARC, Seibersdorf, Austria; ; 6 Dep. of Nuclear Medicine, MUW, Vienna, Austria

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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.





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