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

Journal of Nuclear Medicine

Johann Stanek¹  Claudia Kuntner¹  Thomas Wanek¹  Oliver Langer¹  Rudolf Karch¹  Jens P. Bankstahl¹  Aiman Abrahim¹  Wolfgang Wadsak¹  Kurt Kletter¹  Wolfgang Löscher¹  Markus Müller¹ 

关键词: small-animal PET;    (R)-¹¹C-verapamil;    tariquidar;    P-glycoprotein;    blood–brain barrier;    drug resistance;   

DOI  :  10.2967/jnumed.108.051235

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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.

【 授权许可】

Unknown