Structural insight into binding of novel PET tracer MODAG-005 to lipidic ????-Synuclein fibrils

Accumulation of -synuclein (Syn) aggregates in the human brain is the major hallmark of synucleinopathies such as Parkinsons Disease, Multiple System Atrophy, and Dementia with Lewy bodies. Positron Emission Tomography (PET) plays a vital role in diagnosing these diseases and monitoring their progression by enabling the non-invasive and sensitive detection of Syn aggregates in the brain. However, developing PET tracers with specific target binding, as well as identifying the binding site and complex structure present significant challenges. Here, we investigated the interaction between lipidic Syn aggregates and MODAG-005, a new Syn PET tracer candidate, using nuclear magnetic resonance spectroscopy, cryogenic electron microscopy and molecular dynamics (MD) simulations. Two binding sites of MODAG-005 were found, one on the surface and one in a tubular cavity of the fibril, of which the occupancies were found to depend on the preparation protocols. The cavity binding site is thermodynamically more stable than the external binding site and is the only site occupied when MODAG-005 is applied with liposome as carriers to the aggregates. This is corroborated by MD simulations in which stable interactions between MODAG-005 and glycine containing backbone motifs of the tubular cavity of the aggregates are observed.