Novel Fluorinated 8-Hydroxyquinoline Based Metal Ionophores for Exploring the Metal Hypothesis of Alzheimer鈥檚 Disease

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• 作者：Steven H. Liang ; Adam G. Southon ; Benjamin H. Fraser ; Anwen M. Krause-Heuer ; Bo Zhang ; Timothy M. Shoup ; Rebecca Lewis ; Irene Volitakis ; Yifeng Han ; Ivan Greguric ; Ashley I. Bush ; Neil Vasdev
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：6
• 期：9
• 页码：1025-1029
• 全文大小：332K
• ISSN：1948-5875

文摘

Zinc, copper, and iron ions are involved in amyloid-beta (A尾) deposition and stabilization in Alzheimer鈥檚 disease (AD). Consequently, metal binding agents that prevent metal-A尾 interaction and lead to the dissolution of A尾 deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, clioquinol, and PBT2. Compounds 15鈥?b>17 and 28鈥?b>30 showed exceptional metal ionophore ability (6鈥?0-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced A尾 oligomerization (EC₅₀s < 鈭? 渭M). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with ¹⁸F.