Synthesis and Evaluation of Novel 18F-Labeled Spirocyclic Piperidine Derivatives as 蟽1 Receptor Ligands for Positron Emission Tomography Imaging

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• 作者：Yan Li ; Xia Wang ; Jinming Zhang ; Winnie Deuther-Conrad ; Fang Xie ; Xiaojun Zhang ; Jian Liu ; Jinping Qiao ; Mengchao Cui ; J枚rg Steinbach ; Peter Brust ; Boli Liu ; Hongmei Jia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：56
• 期：9
• 页码：3478-3491
• 全文大小：546K
• 年卷期：v.56,no.9(May 9, 2013)
• ISSN：1520-4804

文摘

A series of spirocyclic piperidine derivatives were designed and synthesized as 蟽₁ receptor ligands. In vitro competition binding assays showed that 1鈥?(4-(2-fluoroethoxy)benzyl)-3H-spiro[2-benzofuran-1,4鈥?piperidine] (19) possessed high 蟽₁ receptor affinity (K_i = 0.79 nM) and excellent 蟽₁/蟽₂ subtype selectivity (350-fold) as well as high 蟽₁/VAChT selectivity (799-fold). The radiolabeled compound [¹⁸F]19 was synthesized by substitution of the tosylate precursor 24 with [¹⁸F]fluoride, with an isolated radiochemical yield of 35鈥?0%, a radiochemical purity of >99%, and a specific activity of 30鈥?5 GBq/渭mol. Biodistribution studies in imprinting control region mice indicated that [¹⁸F]19 displayed excellent initial brain uptake and slow washout. Ex vivo autoradiography in Sprague鈥揇awley rats demonstrated high accumulation of the radiotracer in brain areas known to express high levels of 蟽₁ receptors. Micro positron emission tomography imaging and blocking studies confirmed the specific binding of [¹⁸F]19 to 蟽₁ receptors in vivo.