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Tariquidar-Induced P-Glycoprotein Inhibition at the Rat Blood–Brain Barrier Studied with (R)-¹¹C-Verapamil and PET

¹ Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany; ² Department of Radiopharmaceuticals and microPET Imaging, Austrian Research Centers GmbH–ARC, Seibersdorf, Austria; ³ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; ⁴ Department of Medical Computer Sciences, Medical University of Vienna, Vienna, Austria; and ⁵ Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

Correspondence: For correspondence or reprints contact: Oliver Langer, Department of Radiopharmaceuticals and microPET Imaging, Austrian Research Centers GmbH–ARC, A-2444 Seibersdorf, Austria. E-mail: oliver.langer{at}arcs.ac.at

The multidrug efflux transporter P-glycoprotein (P-gp) is expressed in high concentrations at the blood–brain barrier (BBB) and is believed to be implicated in resistance to central nervous system drugs. We used small-animal PET and (R)-¹¹C-verapamil together with tariquidar, a new-generation P-gp modulator, to study the functional activity of P-gp at the BBB of rats. To enable a comparison with human PET data, we performed kinetic modeling to estimate the rate constants of radiotracer transport across the rat BBB. Methods: A group of 7 Wistar Unilever rats underwent paired (R)-¹¹C-verapamil PET scans at an interval of 3 h: 1 baseline scan and 1 scan after intravenous injection of tariquidar (15 mg/kg, n = 5) or vehicle (n = 2). Results: After tariquidar administration, the distribution volume (DV) of (R)-¹¹C-verapamil was 12-fold higher than baseline (3.68 ± 0.81 vs. 0.30 ± 0.08; P = 0.0007, paired t test), whereas the DVs were essentially the same when only vehicle was administered. The increase in DV could be attributed mainly to an increased influx rate constant (K₁) of (R)-¹¹C-verapamil into the brain, which was about 8-fold higher after tariquidar. A dose–response assessment with tariquidar provided an estimated half-maximum effect dose of 8.4 ± 9.5 mg/kg. Conclusion: Our data demonstrate that (R)-¹¹C-verapamil PET combined with tariquidar administration is a promising approach to measure P-gp function at the BBB.

Key Words: small-animal PET • (R)-¹¹C-verapamil • tariquidar • P-glycoprotein • blood–brain barrier • drug resistance

^* Contributed equally to this work.

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

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