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

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 beta-sheet structures shared with A beta fibrils. Herein, three new donor-pi-acceptor fluorophores (T1 -T3) composed of 3,5-dimethoxy-N,N-dimethylani-line-4-yl and quinoxaline, bridged by 1-3 C--C bond are rationally designed for selectively imaging tau ag-gregates. For the first time, we demonstrated the side substitution on D-pi-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-A beta 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-pi-A skeleton in increasing the selectivity of tau probes, which provides a rational strategy to design novel tau probes with high selectivity in future.

Automated summary

The aggregation of Tau proteins is closely related to the progression and severity of Alzheimer's disease. Developing selective imaging probes for Tau aggregates is challenging. This study designed three new fluorescent dyes and demonstrated the importance of side chain substitution in improving the selectivity of Tau probes.