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

The [F-18]fluoromethyl analog of the sigma, selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([F-18]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma, receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma, receptor (K-i for sigma, receptor, 6.4 nM; Ki for sigma(2) receptor, 250 nM) that was compatible with the affinity of SA4503 (K-i for sigma, receptor, 4.4 nM; Ki for sigma2 receptor, 242 nM). [F-18]FM-SA4503 was synthesized by F-18-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 [F-18]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 coinjection 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 [F-18]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. [F-18]FM-SA4503 showed specific binding to sigma, receptors in mice and monkeys;, therefore, [F-18]FMSA4503 has the potential for mapping sigma, receptors in the brain. (c) 2007 Elsevier Inc. All rights reserved.