| Literature DB >> 26396692 |
Steven H Liang1, Adam G Southon2, Benjamin H Fraser3, Anwen M Krause-Heuer3, Bo Zhang3, Timothy M Shoup1, Rebecca Lewis4, Irene Volitakis2, Yifeng Han5, Ivan Greguric3, Ashley I Bush2, Neil Vasdev1.
Abstract
Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer's disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ 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 Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with (18)F.Entities:
Keywords: 8-Hydroxyquinoline; Alzheimer’s disease; metal ionophore; positron emission tomography
Year: 2015 PMID： 26396692 PMCID： PMC4569883 DOI： 10.1021/acsmedchemlett.5b00281
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345