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.