Using 14C-labeled alprazolam (1-[14C]APZ) as a model for 1-[11C]APZ, we evaluated the tissue distribution of total radioactivity and assessed the contribution of the polar metabolites of APZ (alpha-hydroxymethyl- and 4-hydroxy-APZ) to radioactivity levels in the plasma and brains of rats over the course of 1 h. The biodistribution data showed that the uptake of radioactivity by rat brain was 0.31% of the injected dose per gram of tissue weight at 10 min postinjection. Pretreating rats reduced the levels in brain to 0.21% of the injected dose at 10 min but had little effect on the distribution of radioactivity in plasma and other tissues studied. Analysis of the metabolites in plasma and brain homogenates by an extraction-thin-layer chromatography-liquid scintillation method revealed that greater than 94% of the radioactivity in the rat brain was due to 1-[14C]APZ over the course of 1 h. APZ, therefore, is stable to metabolic transformations in the rat brain, and the polar metabolites are readily conjugated and excreted so that their cerebral uptake is minimal.