Picomolar-sensitive beta-amyloid fibril fluorophores by tailoring the hydrophobicity of biannulated pi-elongated dioxaborine-dyes

Abstract

The pathological origin of Alzheimer's disease (AD) is still shrouded in mystery, despite intensive worldwide research efforts. The selective visualization of beta-amyloid (A beta), the most abundant proteinaceous deposit in AD, is pivotal to reveal AD pathology. To date, several small-molecule fluorophores for A beta species have been developed, with increasing binding affinities. In the current work, two organic small-molecule dioxaborine-derived fluo-rophores were rationally designed through tailoring the hydrophobicity with the aim to enhance the binding affinity for A beta 1-42 fibrils-while concurrently preventing poor aqueous solubility-via biannulate donor motifs in D-pi-A dyes. An unprecedented sub-nanomolar affinity was found (K-d = 0.62 +/- 0.33 nM) and applied to super-sensitive and red-emissive fluorescent staining of amyloid plaques in cortical brain tissue ex vivo. These fluo-rophores expand the dioxaborine-curcumin-based family of A beta-sensitive fluorophores with a promising new imaging agent.