Evaluation of ( R)-[ 11C]verapamil as PET tracer of P-glycoprotein function in the blood–brain barrier: kinetics and metabolism in the rat

There is evidence that P-glycoprotein (P-gp) in the blood–brain barrier (BBB) may be involved in the aetiology of neurological disorders. For quantification of P-gp function in vivo, ( R)-[ 11C]verapamil can be used as a positron emission tomography (PET) tracer, provided that a mathematical model describing kinetics of uptake and clearance of verapamil is available. To develop and validate such a model, the kinetic profile and metabolism of ( R)-[ 11C]verapamil have to be known. The aim of this study was to investigate the presence of labeled metabolites of [ 11C]verapamil in the plasma and (brain) tissue of Wistar rats. For this purpose, extraction and high-performance liquid chromatography (HPLC) methods were developed. The radioactive metabolites of ( R)-[ 11C]verapamil in the liver were N-dealkylated compounds, O-demethylated compounds and a polar fraction formed from N-demethylation products of ( R)-[ 11C]verapamil. Apart from this [ 11C] polar fraction, other radioactive metabolites of [ 11C]verapamil were not detected in the brain tissue. Thirty minutes after injection, unmetabolized ( R)-[ 11C]verapamil accounted for 47% of radioactivity in the plasma and 69% in the brain. Sixty minutes after injection, unmetabolized ( R)-[ 11C] verapamil was 27% and 48% in the plasma and the brain, respectively.