title: Synthesis and evaluation of fluorine-18-labeled SA4503 as a selective sigma1 receptor ligand for positron emission tomography.
abstract: 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.
authors.affiliation: Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0022, Japan. kawamurak@bri.niigata-u.ac.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.forename: Chieko
authors.initials: C
authors.lastname: Tsuji
authors.forename: Norihiro
authors.initials: N
authors.lastname: Harada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kimura
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; C101789:SA 4503