title: (R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function: in vitro and in vivo evaluation.
abstract: The mdr1 gene product P-glycoprotein (P-gp) is involved in the bioavailability and pharmacokinetics of various drugs. Racemic [(11)C]verapamil has been used to image P-gp expression in vivo. A racemic tracer, however, is not suitable for quantification. The purpose of the present study was to identify the most appropriate enantiomer of [(11)C]verapamil as a potential PET-tracer for quantifying P-gp function. The two enantiomers, (R)- and (S)-[(11)C]verapamil, were synthesized and studied in vivo. For the in vivo model mdr1a/1b double gene knock-out and wild type mice were used. The in vitro study made use of the LLC-PK1 MDR cell line to examine the P-gp mediated transport of both enantiomers. The biodistribution of (R)- and (S)-[(11)C]verapamil in dKO and WT mice demonstrated no stereoselectivity of verapamil for P-gp in the blood-brain barrier and in the testes. In addition, no significant differences in P-gp transport for both enantiomers were observed in the in vitro experiments. Previous studies have shown that (R)-verapamil is metabolized less in man and that it has lower affinity for calcium channels. Since (R)- and (S)-verapamil have equal transport for P-gp, the (R)-enantiomer seems to be the best and safest candidate as PET-tracer for measuring P-gp function in vivo.
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000429:Alcohol Oxidoreductases; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*; D007536:Isomerism; D050540:Ketol-Acid Reductoisomerase; D018374:LLC-PK1 Cells; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D021381:Protein Transport / Q000502:physiology; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013552:Swine; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*; D014700:Verapamil / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D014700:Verapamil; D000429:Alcohol Oxidoreductases; D050540:Ketol-Acid Reductoisomerase