The 5-HT1A ligands [ 18F]FPWAY and [ 18F]FCWAY are metabolized to [ 18F]fluorobenzoic acid (FB) and [ 18F]fluorocyclohexanecarboxylic acid (FC), respectively. To quantify the penetration of these acids into the brain, dynamic positron emission tomography studies were performed in rhesus monkeys with [ 18F]FB and [ 18F]FC. High-performance liquid chromatography analysis of arterial blood samples showed no metabolites for [ 18F]FB, whereas [ 18F]FC was rapidly metabolized to [ 18F]fluoride. A model with one tissue compartment and vascular radioactivity was used to analyze gray matter time-activity curves. For [ 18F]FC, an additional term was added to account for [ 18F]fluoride skull spillover into the brain; this term accounted for 70% to 90% of the measured radioactivity concentration at 90 minutes. For [ 18F]FB, mean gray matter parameters were as follows: K1, 10 +/- 3 micro L. min(-1). mL(-1); distribution volume, 0.052 +/- 0.006 (mL/mL). For [ 18F]FC, the values were as follows: K1, 15 +/- 4 micro L. min(-1). mL(-1); V, 0.29 +/- 0.06 mL/mL. The values were consistent with a physiologic model that included brain-to-blood pH difference and the plasma free fraction of the acid. Simulations based on [ 18F]FCWAY human data showed that [ 18F]FC uptake produces significant biases in estimates in regions with low specific binding. These results can be used to correct the tissue [ 18F]FCWAY time-activity data for brain uptake of [ 18F]FC using the measured [ 18F]FC input function.