BMS-181101 is a novel antidepressant drug that is currently under clinical investigation. The goal of this study was to evaluate the pharmacokinetics and receptor binding of this agent in the brains of healthy human volunteers. BMS-181101 was radiolabeled with 11C by methylation with [11C]CH3I of the 5-hydroxypiperazine precursor and the product was purified by high-performance liquid chromatography. Cerebral pharmacokinetics of [11C]BMS-181101 were studied by dynamic positron emission tomography imaging in six healthy volunteers. Two studies were performed in each subject. For the first study the subject was injected with 10 mCl of high specific activity [11C]BMS-181101 (approximately 1700 mCi/mumol) and serial positron emission tomography images and arterial blood samples were collected over 90 min. Thirty minutes after acquiring the final image, each subject was coinjected with a second dose, 10 mCi of [11C]BMS-181101 plus 3 mg of unlabeled drug (final specific activity approximately 1.5 mCi/mumol), and imaging/blood collection was repeated. The data were analyzed by calculating regional tracer accumulation (percent injected dose/g) at 60 min after injection and compartmental modeling. Measurements of percent injected dose/g yielded similar values for all brain regions, independent of specific activity. Kinetic modeling of time activity curves for cerebellum, caudate, putamen, thalamus, pons and temporal, occipital and frontal cortex demonstrated that tissue distribution can be described by a simple two-compartment flow model. Statistical comparisons of the apparent distribution volumes for each region failed to reveal significant differences between the high and low specific activity studies. These results indicate that the central nervous system distribution of [11C]BMS-181101 is dominated by blood flow and significant receptor-specific localization does not occur in any brain region.