Synthesis and evaluation of novel radioiodinated phenylbenzofuranone derivatives as α-synuclein imaging probes

Abstract

α-Synuclein (α-syn) aggregates are major components of pathological hallmarks observed in the human brain affected by neurodegenerative diseases such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. It is known that α-syn aggregates are involved in the pathogenesis of these neurodegenerative diseases. However, detailed mechanisms have not been fully elucidated. Therefore, the development of radiolabeled imaging probes to detect α-syn aggregates in vivo may contribute to early diagnosis and pathophysiological elucidation of neurodegenerative diseases affected by α-syn aggregates. In the present study, we designed and synthesized four radioiodinated phenylbenzofuranone (PBF) derivatives: [123/125I]IDPBF-2, [123/125I]INPBF-2, [123/125I]IDPBF-3, and [123/125I]INPBF-3, as candidates for α-syn imaging probes. All four compounds exhibited high binding affinity for recombinant α-syn aggregates in an inhibition assay. However, brain uptake of all four compounds was insufficient to achieve α-syn imaging in vivo. Considering the results of this study, while further structural modifications are required to improve brain uptake, it is suggested that PBF derivatives show fundamental characteristics as α-syn imaging probes.