Design, synthesis and identification of N, N-dibenzylcinnamamide (DBC) derivatives as novel ligands for α-synuclein fibrils by SPR evaluation system

PET imaging of alpha-synuclein (alpha-syn) deposition in the brain will be an effective tool for earlier diagnosis of Parkinson's disease (PD) due to a-syn aggregation is the widely accepted biomarker for PD. However, the necessary PET radiotracer for imaging is clinically unavailable until now. The lead compound discovery is the first key step for the study. Herein, we initially established an efficient biologically evaluation system well in high throughput based on SPR technology, and identified a novel class of N, N-dibenzylcinnamamide (DBC) compounds as alpha-syn ligands through the assay. These compounds were proved to have high affinities against alpha-syn aggregates (K-D < 10 nM), which well met the requirement of binding activity for the PET probe. These DBC compounds were firstly reported as alpha-syn ligands herein and the preliminary obtained structure has been further modified into F-labeled ones. Among them, a high-affinity tracer (5-41) with 1.03 nM (K-D) has been acquired, indicating its potential as a new lead compound for developing PET radiotracer.