Synthesis and evaluation of (S)-[¹⁸F]fesetron in the rat brain as a potential PET imaging agent for serotonin 5-HT₃ receptors

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• 作者：Neema K. Pithia ; Christopher Liang ; Xiang-Zuo Pan ; Min-Liang Pan ; Jogeshwar Mukherjee ; ^{mukherjj@uci.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Fesetron ; Serotonin 5-HT3 receptors ; PET ; Autoradiography ; Palonosetron ; Zacopride ; Cancer chemotherapy
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：26
• 期：8
• 页码：1919-1924
• 全文大小：1445 K

文摘

Serotonin 5-HT₃ receptors are involved in various brain functions including as an emesis target during cancer chemotherapy. We report here the development of (S)-2,3-dimethoxy-5-(3′-[¹⁸F]fluoropropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide ([¹⁸F]fesetron) as a potential PET imaging agent for serotonin 5-HT₃ receptors. By radiolabeling((S)-2,3-dimethoxy-5-(3′-tosyloxypropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide) with fluorine-18, (S)-[¹⁸F]fesetron was obtained in 5 to 10% decay-corrected yields and with specific activities >74 GBq/μmol at the end of radiosynthesis. PET imaging in rats showed low uptake of [¹⁸F]fesetron in the brain with retention of binding in the striatal and cerebellar regions. Using colliculi as a reference region, ratios were 3.4 for striata and 2.5 for cerebellum. Ex vivo brain PET analysis displayed binding of [¹⁸F]fesetron in the hippocampus, striatum and cerebellar regions. Cerebellar regions corresponded to area postrema and nucleus tract solitaris known to contain 5-HT₃ receptors. Dorsal hippocampus showed the highest uptake with ratio of >17 with respect to colliculi, while area postrema and striata had ratios of >10. Thus, [¹⁸F]fesetron exhibited a unique binding profile to rat brain regions known to contain significant amounts of serotonin 5-HT₃ receptors. However, the very low brain uptake limits its usefulness as a PET radiotracer in this animal model.