Brain uptake of the acid metabolites of F-18-labeled WAY 100635 analogs

The 5-HT1A ligands [F-18]FPWAY and [F-18]FCWAY are metabolized in vivo to [F-18]fluorobenzoic acid (FB) and [F-18]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 [F-18]FB and [F-18]FC. High-performance liquid chromatography analysis of arterial blood samples showed no metabolites for [F-18]FB, whereas [F-18]FC was rapidly metabolized to [F-18]fluoride. A model with one tissue compartment and vascular radioactivity was used to analyze gray matter time-activity curves. For [F-18]FC, an additional term was added to account for [F-18]fluoride skull spillover into the brain; this term accounted for 70% to 90% of the measured radioactivity concentration at 90 minutes. For [F-18]FB, mean gray matter parameters were as follows: K-1, 10 +/- 3 muL . min(-1) . mL(-1); distribution volume V, 0.052 +/- 0.006 (mL/mL). For [F-18]FC, the values were as follows: K-1, 15 +/- 4 muL . min(-1) . mL(-1); V, 0.29 +/- 0.06 mL/mL. The V 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 [F-18]FCWAY human data showed that [F-18]FC uptake produces significant biases in V estimates in regions with low specific binding. These results can be used to correct the tissue [F-18]FCWAY time-activity data for brain uptake of [F-18]FC using the measured [F-18]FC input function.