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 [3H]M503-1619 has a suitable in vitro profile for detecting α-synuclein pathology in LBDs but not in MSA patients. We thank the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania for providing the human post-mortem brain samples used for the autoradiography and immunohistochemistry studies. This research was funded by NIH grant U19-NS110456 to R.H.M., P30AG072979, P01AG066597, P01AG084497 to University of Pennsylvania Brain Bank.

The Movement Disorders Brain Bank at Washington University, which provided the postmortem brain tissue used to produce amplified LBD fibrils, was supported by RF1NS075321 (NINDS/NIA), American Parkinson Disease Association (APDA), Missouri Chapter of the APDA, Barnes-Jewish Hospital Foundation (Elliot Stein Family Professorship and Parkinson Disease Research Fund), and the Bander-Jansky Fund to the Washington University Brain Bank. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Dinahlee Saturnino Guarino, John-Grey Crosby & Robert H. Mach Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Department of Neurology, Washington University School of Medicine, St Louis, MO, USA Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA John L.

Robinson, Theresa Schuck, Edward B. Lee The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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