A Novel Probe with a Chlorinated α-Cyanoacetophenone Acceptor Moiety Shows Near-Infrared Fluorescence Specific for Tau Fibrils.

Development of a novel, tau-selective near-infrared fluorescence (NIRF) probe was attempted by combining the 3,5-dimethoxy-N,N-dimethylaniline-4-yl moiety with an α-cyanoacetophenone via hexatrienyl π-linker. In particular, for structure-activity relationship study of the α-cyanoacetophenones, a chlorine substituent was introduced to the aromatic ring to give a series of compounds (2a-2d). Among those, compound 2c with meta-chloro aryl substituent was identified as a tau-selective NIRF probe: selectivity for tau over amyloid β (Aβ) and bovine serum albumin (BSA) was estimated to be 10.3 and 19.5 fold, respectively. The mechanism for tau-selectivity of 2c was found to be based on the specific recognition of the microenviroment of tau fibrils, which was endowed by its molecular rotor-like properties. The tau-selective NIRF probe 2c was also able to stain tau fibrils in tau-green fluorescent protein (GFP)-transgenic human neuroblastoma cells (SH-SY5Y cells).