title: Synthesis and in vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand.
abstract: The potential of a 11C-labeled selective sigma1 receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([11C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma, receptors in the central nervous system and peripheral organs. [11C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [11C]CH3I, with the decay-corrected radiochemical yield of 39 +/- 5% based on [11C]CH3I and with the specific activity of 53 +/- 17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [11C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [11C]SA6298 by these organs except for the small intestine, but significant displacement of [11C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (-)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma1 receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [11C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [11C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma1 receptors. The saturable brain uptake of [11C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a relatively high uptake was found in the cortex, thalamus, striatum, and cerebellum. These results have indicated a receptor-mediated uptake of the tracer to some extent in the brain and peripheral organs. However, the tracer has a limited potential for the PET study of the brain receptors because of a relatively high nonspecific binding.
authors.affiliation: Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: K
authors.initials: K
authors.lastname: Ishiwata
authors.forename: H
authors.initials: H
authors.lastname: Tajima
authors.forename: S
authors.initials: S
authors.lastname: Ishii
authors.forename: Y
authors.initials: Y
authors.lastname: Shimada
authors.forename: K
authors.initials: K
authors.lastname: Matsuno
authors.forename: Y
authors.initials: Y
authors.lastname: Homma
authors.forename: M
authors.initials: M
authors.lastname: Senda
mesh_terms: D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry; D002415:Cats; D005260:Female; D006168:Guinea Pigs; D007202:Indicators and Reagents; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000187:drug effects*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D002250:Carbon Radioisotopes; D007202:Indicators and Reagents; D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; C406247:SA 6298