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

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