New PET ligand 3H-M503-1619 captures α-synuclein in human postmortem LBDs but not in MSA tissue

Alpha synuclein (a-syn) is an intracellular protein that is normally present as an alpha helix. Misfolding to form a beta pleated sheet leads to intracellular aggregates having strain diversity, which has presented a challenge to those trying to design a PET imaging agent for this purpose. Here, we describe the in vitro binding properties of a new compound, M503-1619, characterized through radioligand binding studies in amplified Lewy body disease fibrils and in vitro autoradiography using human post-mortem samples from neurodegenerative diseases and mouse models of seeded α-synucleinopathy in conjunction with immunohistochemistry. Potential off-target binding towards monoamine oxidase-B (MAO-B) was also evaluated. Results suggest high affinity and target engagement with a-synuclein inclusions in LBDs but not in MSA brains. Off-target binding to MAO-B was minimal. Overall, these results indicate that the novel radioligand [ 3 H]M503-1619 has a suitable in vitro profile for detecting α-synuclein pathology in LBDs but not in MSA patients.