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

作者：Liang, Steven H.; Southon, Adam G.; Fraser, Benjamin H.; Krause-Heuer, Anwen M.; Zhang, Bo; Shoup, Timothy M.; Lewis, Rebecca; Volitakis, Irene; Han, Yifeng; Greguric, Ivan; Bush, Ashley I.^*; Vasdev, Neil

来源：ACS Medicinal Chemistry Letters, 2015, 6(9): 1025-1029.

DOI：10.1021/acsmedchemlett.5b00281

• 8-Hydroxyquinoline
• metal ionophore
• positron emission tomography
• Alzheimer's disease

Zinc, copper, and iron ions are involved in amyloid-beta (A beta) deposition and stabilization in Alzheimer's disease (AD). Consequently, metal binding agents that prevent metal-A beta interaction and lead to the dissolution of A beta 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 15-17 and 28-30 showed exceptional metal ionophore ability (6-40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced A beta oligomerization (EC(50)s < similar to 5 mu M). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with F-18.

• 出版日期2015-9
• 单位浙江理工大学