The development of a PET radiotracer for imaging alpha synuclein aggregates in Parkinson's disease.

was identified as a promising ligand for positron emission tomography (PET) imaging of α-synuclein (α-Syn) pathology in Parkinson's disease (PD). An exemplar for binding site 9 (residues GLY-86, ILE-88, PHE-94 and LYS-96) of α-Syn fibrils was generated. An ultrahigh throughput screening campaign was conducted using a 42 million compound library. Secondary methods followed by visual inspection were used to select 6 compounds as candidates for binding studies. was found to have a high binding affinity ( = 6.5 nM the site 9 radioligand [H]BF-2846) to α-Syn fibrils and low affinity for beta amyloid ( = 390 nM [H]PiB) in competition binding assays. Saturation binding assays of in human tissues confirmed its high affinity to α-Syn (PD tissue, = 2.5 nM; Alzheimer's disease tissue, = 37 nM; progressive supranuclear palsy tissue, = 55 nM). Autoradiography studies demonstrated a higher binding of this radioligand in PD brain sections than in multiple system atrophy brain sections. PET studies with showed high brain uptake and rapid washout (whole brain peak to 60 min ratio = 3.2) in non-human primates. The results of this study suggest that is a lead compound for radiotracer development imaging α-Syn with PET.