18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a 蟽1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

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• 作者：Fang Xie ; Ralf Bergmann ; Torsten Kniess ; Winnie Deuther-Conrad ; Constantin Mamat ; Christin Neuber ; Boli Liu ; J枚rg Steinbach ; Peter Brust ; Jens Pietzsch ; Hongmei Jia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5395-5407
• 全文大小：649K
• ISSN：1520-4804

文摘

We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as 蟽₁ receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (K_i = 5.4 卤 0.4 nM) for 蟽₁ receptors and selectivity for 蟽₂ receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [¹⁸F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25鈥?5 GBq/渭mol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [¹⁸F]5a to 蟽₁ receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for 蟽₁ receptors could be used for tumor imaging.