(R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function:: in vitro and in vivo evaluation

The mdr1 gene product P-glycoprotein (P-gp) is involved in the bioavailability and pharmacokinetics of various drugs. Racemic [C-11]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 [C-11]verapamil as a potential PET-tracer for quantifying P-gp function. The two enantiomers, (R)- and (S)-[C-11]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)-[C-11]verapamil in dKO and WT mice demonstrated no stereo selectivity 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. (C) 2003 Elsevier Inc. All rights reserved.