EVALUATION OF CEREBRAL PHARMACOKINETICS OF THE NOVEL ANTIDEPRESSANT DRUG, BMS-181101, BY POSITRON EMISSION TOMOGRAPHY

BMS-181101 is a novel antidepressant drug that is currently under clin ical investigation. The goal of this study was to evaluate the pharmac okinetics and receptor binding of this agent in the brains of healthy human volunteers. BMS-181101 was radiolabeled with C-11 by methylation with [C-11]CH3I of the 5-hydroxypiperazine precursor and the product was purified by high-performance liquid chromatography. Cerebral pharm acokinetics of [C-11]BMS-181101 were studied by dynamic positron emiss ion tomography imaging in six healthy volunteers. Two studies were per formed in each subject. For the first study the subject was injected w ith 10 mCi of high specific activity [C-11]BMS-181101 (similar to 1700 mCi/mu mol) and serial positron emission tomography images and arteri al blood samples were collected over 90 min. Thirty minutes after acqu iring the final image, each subject was coinjected with a second dose, 10 mCi of [C-11]BMS-181101 plus 3 mg of unlabeled drug (final specifi c activity similar to 1.5 mCi/mu mol), and imaging/blood collection wa s repeated. The data were analyzed by calculating regional tracer accu mulation (percent injected dose/g) at 60 min after injection and compa rtmental modeling. Measurements of percent injected dose/g yielded sim ilar values for all brain regions, independent of specific activity. K inetic modeling of time activity curves for cerebellum, caudate, putam en, thalamus, pens and temporal, occipital and frontal cortex demonstr ated that tissue distribution can be described by a simple two-compart ment flow model. Statistical comparisons of the apparent distribution volumes for each region failed to reveal significant differences betwe en the high and low specific activity studies. These results indicate that the central nervous system distribution of [C-11]BMS-181101 is do minated by blood flow and significant receptor-specific localization d oes not occur in any brain region.