A rational design to improve selective imaging of tau aggregates by constructing side substitution on N,N-dimethylaniline/quinoxaline D-π-A fluorescent probe

Abstract

Tau aggregation correlates rigorously with the progression and severity of Alzheimer’s disease (AD). However, it is extremely challenging to develop tau-selective imaging probes due to similar β-sheet structures shared with Aβ fibrils. Herein, three new donor-π-acceptor fluorophores (T1-T3) composed of 3,5-dimethoxy-N,N-dimethylaniline-4-yl and quinoxaline, bridged by 1–3 CC bond are rationally designed for selectively imaging tau aggregates. For the first time, we demonstrated the side substitution on D-π-A skeleton is significant for improving the selectivity of tau probes. Molecular docking results revealed that the lateral methoxy groups on molecular rotors could act as antennas to interact with surrounding tau hydrophilic residues via hydrogen-bond and other kinds of intermolecular interactions, improving selective recognition for tau aggregates. Compared with its non-side-substitution precursor T02, T2 exhibited 4.7 times higher tau-over-Aβ selectivity after introducing methoxy substituents. Owing to the improved selectivity, T2 was successfully applied to detect tau aggregates in cells and pathologically relevant regions of AD mice model. This work verifies the pivotal role of side substitution on D-π-A skeleton in increasing the selectivity of tau probes, which provides a rational strategy to design novel tau probes with high selectivity in future.