[(18)F]FCWAY (N-{2-[4-(2-methoxyphenyl)piperazino]}-N-(2-pyridinyl)trans-4-fluorocyclohexanecarboxamide) has been prepared routinely as a serotonin 5-HT(1A) receptor ligand for clinical human studies. We have developed an automated one-step radiosynthesis using a modified Nuclear Interface C-11 Methylation System. The chemical synthesis of an appropriate methanesulfonate precursor for single-step nucleophilic substitution with [(18)F]fluoride ion and the adaptation of radiochemical synthesis to an automated production module were accomplished. Following purification of a substrate using countercurrent chromatography, radiochemical yield increased from 18.9+/-0.3% to 21.9+/-2.2%. In addition, reduction of chemical impurities from about 40% to about 20% of total mass was observed. Further improvements in chemical purity were achieved by minimization of side reactions by modification of reaction conditions and optimization of the high-performance liquid chromatography method for the purification of the final radiopharmaceutical. Optimized automated synthesis produced [(18)F]FCWAY in a radiochemical yield of 28+/-6% at a chemical purity of 99.3% based on the absorbance of FCWAY at 254 nm and with a specific activity of 3433+/-1015 mCi/micromol at the end of bombardment, all calculated from the same 50 runs.