Discovery of benzoxazole derivatives as novel α-synuclein aggregate ligands with potential for PET tracer development

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, and the abnormal aggregation of α-synuclein (α-Syn) constitutes its core pathological hallmark. Positron emission tomography (PET) imaging of cerebral α-Syn aggregates holds great promise for the early diagnosis of PD. However, the imaging quality critically depends on the ligands with high binding affinity and selectivity for α-Syn aggregates. In this work, we developed a new type of benzoxazole-based α-Syn aggregate ligands via an SPR-based screening. Among them, candidates D15 (K_D = 0.12 μM) and D16 (K_D = 0.08 μM) exhibited high binding affinities for α-Syn aggregates in vitro and good potency in the SH-SY5Y cellular model and brain tissues from α-Syn PFF-injected PD mouse models, as well as excellent selectivity for tau and Aβ aggregates in rTg4510 and APP23 transgenic mouse brain sections. Thanks to their favorable blood-brain barrier permeability and suitable structures for radiolabeling for PET imaging, these new ligands represent promising candidates for the development of α-Syn PET radiotracers, offering a valuable foundation for the early diagnosis of PD and related synucleinopathies.