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

• Published in: Nuclear medicine and biology 2003-10, Vol.30 (7), p.747-751
• Main Authors: Luurtsema, G, Molthoff, C.F.M, Windhorst, A.D, Smit, J.W, Keizer, H, Boellaard, R, Lammertsma, A.A, Franssen, E.J.F
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; BBB; Biological and medical sciences; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - metabolism; C-11 verapamil; Carbon Radioisotopes - blood; Carbon Radioisotopes - pharmacokinetics; Enantiomers; Isomerism; Ketol-Acid Reductoisomerase; LLC-PK1 Cells; Medical sciences; Metabolic Clearance Rate; Mice; Mice, Knockout; Organ Specificity; P-gp; Protein Transport - physiology; Radiopharmaceuticals - blood; Radiopharmaceuticals - pharmacokinetics; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Reproducibility of Results; Sensitivity and Specificity; Swine; Technology. Biomaterials. Equipments. Material. Instrumentation; Tissue Distribution; Tomography, Emission-Computed - methods; Verapamil - blood; Verapamil - pharmacokinetics
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/S0969-8051(03)00078-7

The mdr1 gene product P-glycoprotein (P-gp) is involved in the bioavailability and pharmacokinetics of various drugs. Racemic [ 11C]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 [ 11C]verapamil as a potential PET-tracer for quantifying P-gp function. The two enantiomers, (R)- and (S)-[ 11C]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)-[ 11C]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.