Synthesis and Evaluation of Novel 18F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of 尾-Amyloid Plaques

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• 作者：Mengchao Cui ; Xuedan Wang ; Pingrong Yu ; Jinming Zhang ; Zijing Li ; Xiaojun Zhang ; Yanping Yang ; Masahiro Ono ; Hongmei Jia ; Hideo Saji ; Boli Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9283-9296
• 全文大小：574K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel 尾-amyloid (A尾) imaging probes for PET. They displayed binding affinities for A尾_1鈥?2 aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for ¹⁸F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [¹⁸F]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([¹⁸F]32) (K_i = 8.0 卤 3.2 nM) displayed a brain_2min/brain_60min ratio of 4.66, which is highly desirable for A尾 imaging agents. Target specific binding of [¹⁸F]32 to A尾 plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [¹⁸F]32 is a promising A尾 imaging agent for PET and merits further evaluation in human subjects.