A Smart Near-Infrared Fluorescence Probe for Selective Detection of Tau Fibrils in Alzheimer’s Disease

Development of a novel, tau-selective smart near-infrared fluorescence (NIRF) probe was attempted by combining the previously identified core scaffold 3,5-dimethoxy-N,N-dimethylaniline-4-yl moiety, with the characteristic donor-π-acceptor architecture of the smart NIRF Aβ probes DANIR-2c and MCAAD-3. A series of compounds (2 and 3) were prepared, which were identified as “turn-on” NIRF probes for the visual detection of tau aggregates and Aβ fibrils (λem = 650 nm, Stokes shifts = 70–110 nm). In particular, combination of the 3,5-dimethoxy-N,N-dimethylanilin-4-yl moiety and the donor part of MCAAD-3 endowed the resulting probes, 3g and 3h, with significant selectivity toward tau aggregates (selectivity for tau over Aβ = 5.7 and 3.8); they showed much higher fluorescence intensities upon binding to tau aggregates (FItau = 49 and 108) than when bound to Aβ fibrils (FIAβ = 9 and 28). Quantitative analysis of binding affinities and fluorescence properties of 3g and 3h revealed that microenvironment-sensitive m...