Structure鈥揂ctivity Relationship Study of Heterocyclic Phenylethenyl and Pyridinylethenyl Derivatives as Tau-Imaging Agents That Selectively Detect Neurofibrillary Tangles in Alzheimer鈥檚 Disease Brains

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• 作者：Kenji Matsumura ; Masahiro Ono ; Ayane Kitada ; Hiroyuki Watanabe ; Masashi Yoshimura ; Shimpei Iikuni ; Hiroyuki Kimura ; Yoko Okamoto ; Masafumi Ihara ; Hideo Saji
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7241-7257
• 全文大小：776K
• ISSN：1520-4804

文摘

In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimer鈥檚 disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)ethenyl derivatives with or without a dimethyl amino group. In in vitro autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to A尾 deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([¹²⁵I]64) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [¹²⁵I]64 also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [¹²³I]64 may be a new candidate tau-imaging agent.