Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for <i>in vivo</i> imaging of amyloid-β species
Daqing Fang, Xidan Wen, Yuqi Wang, Yidan Sun, Ruibing An, Yu Zhou, Deju Ye, Hong Liu
Abstract
Near-infrared (NIR) fluorescent imaging of both soluble and insoluble A species in the brain of Alzheimer's disease (AD) is crucial for the early diagnosis and intervention of AD. To date, a variety of NIR fluorescent probes have been reported for the detection of A species. Among these probes, CRANAD-58 was reported to have the capability to detect both soluble and insoluble A species, which is vital to monitor the changes of A species during the pathological course of the disease. Though CRANAD-58 has shown promise to noninvasively detect A species in transgenic AD mice, the emission wavelength (~670 nm) is still too short for further applications. Therefore, new probes with longer emission wavelength and improved physiological properties are in highly demand. Herein, we report the design and engineering of nine donor-acceptor-donor molecules as "off-on" near-infrared fluorescent probes for in vivo imaging of both soluble and insoluble A species in living AD mice owing to its improved in vitro properties and in vivo performance. Methods: We report a two-round strategy to develop nine "off-on" NIR fluorescence probes via structural modification of a curcumin analogue-based donor-acceptor-donor architecture. In round one, probes 1 and 2 were synthesized, and probe 2 was identified to be an optimum probe as it showed distinct "off-on" NIR fluorescence at > 690 nm upon binding to A monomers, oligomers and aggregates. To further improve the in vivo performance, further structural modification of probe 2 into probes 3-9 was then conducted. The fluorescence response with A species and histological staining in vitro and in vivo imaging of A species in APP/PS1 transgenic AD mice and age-matched wild-type mice were performed.