The World Health Organization estimates that ca. 11 million people worldwide have Alzheimer's disease (AD) and this population is expected to nearly double by 2030.1 This disease, which manifests in progressive neurodegeneration, is characterized by the presence of amyloid-β (Aβ) peptide aggregates.2 -4 The mechanism for the formation of Aβ aggregates is not entirely understood, though metal ions such as Cu II and Zn II have been shown to facilitate Aβ aggregation.2 -4 In particular, redox-active Cu II is implicated in the generation of reactive oxygen species (ROS), leading to an increase in oxidative stress, which is one proposed neuropathology of AD.2 -8 To elucidate Cu-mediated events in AD pathogenesis, Cu coordination to Aβ has been explored as well as effects on the removal of Cu from Cu-Aβ species using chelating agents.2 -13 These studies have demonstrated that the extent of metal-induced Aβ aggregation and ROS production can be modulated by metal chelators, which highlights metal-ion chelation therapy as a promising AD treatment.Many orthodox metal chelators show inhibition of metal-induced Aβ aggregation and ROS formation,2 -4 , 9 , 13 but they may not be suitable for AD therapeutics. Most of these chelators cannot cross the blood brain barrier (BBB) and are not able to specifically target metal ions in various Aβ forms without removing vital metals from other biological systems due to lack of an Aβ recognition ability. The metal chelator clioquinol (CQ) reveals decreased Aβ aggregate deposits and improved cognition in early clinical trials.14 The long-term use is, however, limited by an adverse side effect, subacute myelo-optic neuropathy.15 , 16 Our recent studies suggest that CQ assists, in part, in the disaggregation of Aβ aggregates, but could not completely prevent Aβ aggregation.17 Therefore, rational design of chelating agents capable of targeting metal ions in Aβ species followed by modulation of Aβ aggregation in the brain is essential toward metal-ion chelation therapy for AD. Only limited efforts have been made toward this goal.3 , 10 -12 Herein we present the preparation of bifunctional metal chelators (1 and 2) and their interaction with Cu-induced Aβ aggregates. Both chelators exhibit modulation of Cu-associated Aβ aggregation, which is more effective than that by the well-known metal chelating agents CQ, EDTA, and phen in this study.18Our strategy for developing metal chelators as potential AD therapeutics is to create bifunctional molecules that contain structural moieties for metal ion chelation and Aβ recognition (Figure 1). For the latter purpose, the basic frameworks of 1 and 2 are based on the Aβ aggregate-imaging probes 125 IMPY and p-125 I-stilbene,18 respectively, which show strong binding affinity to Aβ aggregates.19 These compounds are small, neutral, lipophilic, and thus able to penetrate the BBB. Furthermore, they are easily removed from normal brain mhlim@umich.edu . Supporting Information Available: Experimental procedures, preparation and characterization of 1 and 2, Ta...

Amyloid-beta (Abeta) plaques are largely associated with the neuropathogenesis of Alzheimer's disease (AD). Metal ions such as Cu(II) and Zn(II) have been implicated as contributors to their formation and deposition. Metal chelators have been used to modulate metal-induced Abeta aggregation. The bidentate ligand clioquinol (CQ) presents an effective influence on metal-involved Abeta aggregation, which has been explained through its metal chelation and is generally monitored by fluorescence and turbidity assays in vitro. The studies herein, however, suggest that the effects of CQ on metal-driven Abeta aggregation may not be visualized accurately by both assays. Subsequently, the present work demonstrates that CQ is able to chelate metal ions from metal-Abeta species and to assist, in part, in the disaggregation of Abeta aggregates, but it could not completely hinder the progression of Abeta aggregation.