Synthesis and evaluation of novel tropane derivatives as potential PET imaging agents for the dopamine transporter

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• 作者：Hongwen Qiao^a ; ^b ; Lin Zhu^a ; ^b ; Brian P. Lieberman^b ; Zhihao Zha^b ; Karl Plö ; ssl^b ; Hank F. Kung^a ; ^b ; ^c ; ^{kunghf@sunmac.spect.upenn.edu}
• 关键词：Dopamine transporter ; Tropane ; Fluorine-18 ; Imaging tracers ; PET
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 July, 2012
• 卷：22
• 期：13
• 页码：4303-4306
• 文件大小：231 K

摘要

A novel series of tropane derivatives containing a fluorinated tertiary amino or amide at the 2尾 position was synthesized, labeled with the positron-emitter fluorine-18 (t_1/2 = 109.8 min), and tested as potential in vivo dopamine transporter (DAT) imaging agents. The corresponding chlorinated analogs were prepared and employed as precursors for radiolabeling leading to the fluorine-18-labeled derivatives via a one-step nucleophilic aliphatic substitution reaction. In vitro binding results showed that the 2尾-amino compounds 6b, 6d and 7b displayed moderately high affinities to DAT (K_i <10 nM). Biodistribution studies of [¹⁸F]6b and [¹⁸F]6d showed that the brain uptakes in rats were low. This is likely due to their low lipophilicities. Further structural modifications of these tropane derivatives will be needed to improve their in vivo properties as DAT imaging agents.