Discovery of Diphenoxy Derivatives with Flexible Linkers as Ligands for β-Amyloid Plaques

The highly rigid and planar scaffolds with pi-conjugated systems have been widely considered to be indispensable for beta-amyloid (A beta) binding ligands. In this study, a library of diphenoxy compounds with different types of more flexible linkers as A beta ligands were synthesized and evaluated. Most of them displayed good affinity (K-i < 100 nM) for A beta(1-42) aggregates, and some ligands even showed values of K-i less than 10 nM. Structure-activity relationship analysis revealed that modification on the linkers or substituents tolerated great flexibility, which challenged the long-held belief that rigid and planar structures are exclusively favored for A beta binding. Three ligands were labeled by iodine-125, and they exhibited good properties in vitro and in vivo, which further supported that this flexible scaffold was potential and promising for the development of A beta imaging agents.