Turn-On Quinoline-Based Fluorescent Probe for Selective Imaging of Tau Aggregates in Alzheimer's Disease: Rational Design, Synthesis, and Molecular Docking

Tau aggregation is believed to have a strong association with the level of cognitive deficits in Alzheimer's disease (AD). Thus, optical brain imaging of tau aggregates has recently gained substantial attention as a promising tool for the early diagnosis of AD. However, selective imaging of tau aggregates is a major challenge due to sharing similar beta-sheet structures with homologous A beta fibrils. Herein, four quinoline-based fluorescent probes (Qtau) were judiciously designed using the donor-acceptor architecture for selective imaging of tau aggregates. In particular, probe Qtau 4 exhibited a strong intramolecular charge transfer and favorable photophysical profile, such as a large Stokes' shift and fluorescence emission wavelength of 630 nm in the presence of tau aggregates. The probe also displayed a turn-on fluorescence behavior toward tau fibrils with a 3.5-fold selectivity versus A beta fibrils. In addition, Qtau 4 exhibited nanomolar binding affinity to tau aggregates (K-d = 16.6 nM), which was 1.4 times higher than that for A beta fibrils. The mechanism of turn-on fluorescence was proposed to be an environment-sensitive molecular rotor-like response. Moreover, ex vivo labeling of human AD brain sections demonstrated favorable colocalization of Qtau 4 and the phosphorylated tau antibody, while comparable limited staining was observed with A beta fibrils. Molecular docking was conducted to obtain insights into the tau-binding mode of the probe. Collectively, Qtau 4 has successfully been used as a tau-specific fluorescent imaging agent with lower background interference.

Automated summary

The newly designed quinoline fluorescent probe, Qtau 4, shows selective imaging of tau aggregates with favorable photophysical properties and high binding affinity, exhibiting 3.5-fold selectivity towards tau fibrils and successfully used for fluorescence imaging of human AD brain tissues.