We previously synthesized [O-methyl-C-11]WAY-100635. However, recent literature reports indicated that this compound is metabolized in vivo to [O-methyl-C-11]WAY-100634 (decyclohexylcarbonyl)WAY100635, which is also taken up into the brain in significant amounts. The synthesis of [C-11-carbonyl]WAY-100635 was recently report&L Metabolism of this compound in the brain leads to unlabeled WAY- 100634 and [C-11]cyclohexanecarboxylic acid, which is not taken up into the brain. Therefore, we synthesized [C-11-carbonyl]WAY-100635 by an adaptation of the method of Pike et al. Med Chem Res 5:208 and determined its uptake in rat brain. We also synthesized the F-18 4- fluorobenzoyl analog of WAY-100634 by the procedure of Shiue et al. JNucl Med 35:252P and compared it with [C-11-carbonyl]WAY-1O0635 in rat brain. In addition, we prepared the F-18 4-fluoro-3-methyl- benzoyl analog of WAY-100634 and determined its uptake in rat brain. Rats were injected with the radioactive compounds with or without 50 nmol of unlabeled WAY-I 00635 and sacrificed at peak uptake (30 min) to obtain %ID/g. The F-18 4-fluorobenzol analogs of WAY-100634 were 5HT1A subtype specific but had relatively low brain uptake compared to [C-11- carbonyl]WAY-100635. The brain uptake does not appear to be related to the lipophilicity as measured by reversed phase HPLC. Other F-18 fluorobenzoyl WAY-100634 derivatives are being synthesized based on log P considerations.
