Synthesis and evaluation of fluorine-18-labeled SA4503 as a selective sigma1 receptor ligand for positron emission tomography

The [18F]fluoromethyl analog of the sigma1 selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([18F]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma1 receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma1 receptor (Ki for sigma1 receptor, 6.4 nM; Ki for sigma2 receptor, 250 nM) that was compatible with the affinity of SA4503 (Ki for sigma1 receptor, 4.4 nM; Ki for sigma2 receptor, 242 nM). [18F]FM-SA4503 was synthesized by 18F-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 [18F]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 [18F]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. [18F]FM-SA4503 showed specific binding to sigma1 receptors in mice and monkeys; therefore, [18F]FM-SA4503 has the potential for mapping sigma1 receptors in the brain.