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Our objectives were to determine if any of the second-generation antipsychotics studied could be detected in rat brain by magnetic resonance imaging (MRI) and if any of them could be estimated by simple kinetic models. Radioligand binding assays and in vivo uptake studies were used to estimate brain occupancy by 14 antipsychotics. (2)H-magnetic resonance imaging data was acquired from rats (n=9-24) and (18)F-fluorodeoxyglucose data was acquired from patients (n=20-29) over 0-180 min. Antipsychotics with a high affinity for dopamine (D(2)) receptors generally had the highest estimated brain occupancy. The estimated occupancies of the eight compounds with high affinity for both D(2) and serotonin (5-HT(2)) receptors were significantly correlated. The estimated occupancy of five of the 12 compounds with high affinity for D(2) receptors were significantly correlated with the radioactivity in the forebrain at 40 min. This provided a simple, semi-quantitative prediction of the brain occupancy. However, many of the compounds were rapidly cleared from the brain. This study demonstrates the