Synthesis and evaluation of 1-[2-(4-[11C]methoxyphenyl)phenyl]piperazine for imaging of the serotonin 5-HT7 receptor in the rat brain |
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Authors: | Yoko Shimoda Joji Yui Lin Xie Masayuki Fujinaga Tomoteru Yamasaki Masanao Ogawa Nobuki Nengaki Katsushi Kumata Akiko Hatori Kazunori Kawamura Ming-Rong Zhang |
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Institution: | 1. Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan;2. SHI Accelerator Service Co. Ltd., 5-9-11 Kitashinagawa, Shinagawa-ku, Tokyo 141-8686, Japan |
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Abstract: | 1-2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki = 2.6 nM) with a low binding affinity for the 5-HT1A receptor (Ki = 476 nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, 11C]4 was synthesized at high radiochemical yield and specific activity, by O-11C]methylation of 2′-(piperazin-1-yl)-1,1′-biphenyl]-4-ol (6) with 11C]methyl iodide. Autoradiography revealed that 11C]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 11C]4 in the brain exceeded 90% of the radioactive components at 15 min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of 11C]4 in the brain (1.2 SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of 11C]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. |
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Keywords: | Carbon-11 PET Autoradiography |
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