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 (α-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 α-syn aggregates ligands. Several compounds displayed good potency to α-syn aggregates with K d values less than 0.1 μM. The docking study revealed that the hydrogen bonds and cation-pi interaction between ligands and α-syn aggregates would be crucial for the activity. The representative compound 7–16 not only detected α-syn aggregates in both SH-SY5Y cells and brain tissues prepared from two kinds of α-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. • Styrylaniline derivatives was firstly developed as novel α-syn aggregates ligands. • Candidate 7–16 displayed strong binding affinity to α-syn aggregates. • Candidate 7–16 detected α-syn aggregates in SH-SY5Y cell and PFFs-injected mice. • Candidate 7–16 showed good blood-brain barrier permeability in vivo .