Synthesis and evaluation of 1-[2-(4-[¹¹C]methoxyphenyl)phenyl]piperazine for imaging of the serotonin 5-HT₇ receptor in the rat brain

详细信息    查看全文

• 作者：Yoko Shimoda ; Joji Yui ; Lin Xie ; Masayuki Fujinaga ; Tomoteru Yamasaki ; Masanao Ogawa ; Nobuki Nengaki ; Katsushi Kumata ; Akiko Hatori ; Kazunori Kawamura ; Ming-Rong Zhang
• 关键词：5-HT7 receptor ; Carbon-11 ; PET ; Autoradiography
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 September, 2013
• 年：2013
• 卷：21
• 期：17
• 页码：5316-5322
• 全文大小：997 K

文摘

1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT₇ receptor antagonist (K_i = 2.6 nM) with a low binding affinity for the 5-HT_1A receptor (K_i = 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¡ä-(piperazin-1-yl)-[1,1¡ä-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.