PET neuroimaging of [ 11C]mirtazapine enantiomers in pigs

Previously, we used positron emission tomography (PET) for studying the pharmacokinetics of rac-[ 11C]mirtazapine in living brain. Our findings showed that rac-[ 11C]mirtazapine has suitable properties for PET neuroimaging. However, separate studies of enantiomers are typically required for characterizing the pharmacokinetics of a racemic drug. Therefore, we have determined the whole-body distribution and brain pharmacokinetics of S- and R-[ 11C]mirtazapine in pigs. The enantiomers of [ 11C]mirtazapine produced similar effective doses of radioactivity in most body organs, except for the brain, in which the dose was ∼ 40% higher after injection of S-[ 11C]mirtazapine than the antipode. Kinetic analyses of dynamic brain PET recordings showed that values for regional accumulation of compound ( k 3) were significantly higher for S-[ 11C]mirtazapine than for the antipode, while the values for clearance of compounds from tissue to circulation ( k 2) were consistently lower for S-[ 11C]mirtazapine than for the R-form. No reliable difference occurred in the rate of metabolism of S- and R-[ 11C]mirtazapine in the bloodstream of the pigs. The present findings indicate that enantioselective processes affect the cerebral pharmacokinetics of rac-mirtazapine.