M503-1619 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 in silico ultrahigh throughput screening campaign was conducted using a 42 million compound library. Secondary in silico methods followed by visual inspection were used to select 6 compounds as candidates for in vitro binding studies. M503-1619 was found to have a high binding affinity (K _i = 6.5 nM versus the site 9 radioligand [³H]BF-2846) to α-Syn fibrils and low affinity for beta amyloid (K _i = 390 nM versus [³H]PiB) in competition binding assays. Saturation binding assays of [³H]M503-1619 in human tissues confirmed its high affinity to α-Syn (PD tissue, K _D = 2.5 nM; Alzheimer’s disease tissue, K _D = 37 nM; progressive supranuclear palsy tissue, K _D = 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 [¹¹C]M503-1619 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 [¹¹C]M503-1619 is a lead compound for radiotracer development imaging α-Syn with PET.