The [(18)F]fluoromethyl analog of the sigma(1) selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([(18)F]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma(1) receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma(1) receptor (K(i) for sigma(1) receptor, 6.4 nM; K(i) for sigma(2) receptor, 250 nM) that was compatible with the affinity of SA4503 (K(i) for sigma(1) receptor, 4.4 nM; K(i) for sigma(2) receptor, 242 nM). [(18)F]FM-SA4503 was synthesized by (18)F-fluoromethylation of O-demethyl SA4503 in the radiochemical yield of 2.9-16.6% at the end of bombardment with a specific activity of 37.8-283 TBq/mmol at the end of synthesis. In mice, the uptake of [(18)F]FM-SA4503 in the brain was gradually increased for 30 min after injection, and then decreased. In the blocking study, brain uptake was significantly decreased by co-injection of haloperidol to 32% of control, and FM-SA4503 to 52% of control. In PET study of the monkey brain, high uptake was found in the cerebral cortex, thalamus and striatum. The radioactivity level of [(18)F]FM-SA4503 in the brain regions gradually increased over a period of 120 min after injection, followed by a stable plateau phase until 180 min after injection. In pretreatment with haloperidol measurement of the monkey brain, the radioactivity level was 22-32% and 11-25% of the baseline at 60 and 180 min, respectively, after injection, suggesting high receptor-specific binding. [(18)F]FM-SA4503 showed specific binding to sigma(1) receptors in mice and monkeys; therefore, [(18)F]FM-SA4503 has the potential for mapping sigma(1) receptors in the brain.