Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid- β plaques in Alzheimer's disease

Eur J Med Chem. 2022 Aug 30;243:114715. doi: 10.1016/j.ejmech.2022.114715. Online ahead of print.ABSTRACTThe presence of Aβ plaques in the brain is a hallmark of Alzheimer's disease. Here, we designed and synthesized a series of molecular rotors with various bi-aromatic rings and investigated their applications as near-infrared (NIR) probes for Aβ plaques. We found that the interaction with Aβ aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity. Among them, probe 4b (Kd = 8.5 nM) with a phenyl-pyridine ring showed a 98-fold increase in fluorescence intensity upon binding with Aβ aggregates. In addition, 4b could identify Aβ plaques in brain sections of both a transgenic (Tg) mouse and AD patients. Furthermore, 4b could readily penetrate the mouse blood-brain barrier (brain2min = 10.11% ID/g) and washed out rapidly. Finally, the NIR imaging with Tg mice confirmed the practical application of 4b in detecting Aβ plaques in vivo. Altogether, our work widens the landscape of Aβ NIR probes and offers a new tool for Aβ detection.PMID:36070630 | DOI:10.1016/j.ejmech.2022.114715
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research