title: Synthesis and evaluation of 1-[2-(4-[(11)C]methoxyphenyl)phenyl]piperazine for imaging of the serotonin 5-HT7 receptor in the rat brain.
abstract: 1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki=2.6nM) with a low binding affinity for the 5-HT1A receptor (Ki=476nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, [(11)C]4 was synthesized at high radiochemical yield and specific activity, by O-[(11)C]methylation of 2'-(piperazin-1-yl)-[1,1'-biphenyl]-4-ol (6) with [(11)C]methyl iodide. Autoradiography revealed that [(11)C]4 showed in vitro specific binding with 5-HT7 in the rat brain regions, such as the thalamus which is a region with high 5-HT7 expression. Metabolite analysis indicated that intact [(11)C]4 in the brain exceeded 90% of the radioactive components at 15min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [(11)C]4 in the brain (1.2SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of [(11)C]4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT7 and higher in vivo stability in brain than 4.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001927:Brain Diseases / Q000175:diagnosis; D002250:Carbon Radioisotopes / Q000737:chemistry; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: C586729:1-(2-(4-methoxyphenyl)phenyl)piperazine; D002250:Carbon Radioisotopes; D010879:Piperazines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D000077489:Piperazine
keywords: 5-HT(7) receptor; Autoradiography; Carbon-11; PET