Discovery of styrylaniline derivatives as novel alpha-synuclein aggregates ligands

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Early diagnosis is the key to treatment but is still a great challenge in the clinic now. The discovery of alpha-synuclein (alpha-syn) aggregates ligands has become an attractive strategy to meet the early diagnosis of PD. Herein, we designed and synthesized a series of styrylaniline derivatives as novel alpha-syn aggregates ligands. Several compounds displayed good potency to alpha-syn aggregates with K-d values less than 0.1 mu M. The docking study revealed that the hydrogen bonds and cation-pi interaction between ligands and a-syn aggregates would be crucial for the activity. The representative compound 7-16 not only detected alpha-syn aggregates in both SH-SY5Y cells and brain tissues prepared from two kinds of alpha-syn preformed- fibrils-injected mice models but also showed good blood-brain barrier penetration characteristics in vivo with a brain/plasma ratio over 1.0, which demonstrates its potential as a lead compound for further development of in vivo imaging agents. (C) 2021 Elsevier Masson SAS. All rights reserved.