Feasibility of Targeted Alpha Therapy for Alzheimer's Disease Using 211At-labeled Agent Targeting Amyloid-β Aggregates

Amyloid-β (Aβ) aggregates are one of the pathological hallmarks and also an important therapeutic target of Alzheimer's disease (AD). Although targeted alpha therapy (TAT) has been established primarily for cancer treatments, it has potential application as a novel treatment approach for AD by reducing Aβ aggregates. However, no TAT agents targeting Aβ aggregates have demonstrated usefulness in vivo. In this study, we newly synthesized and evaluated [211At]APBF-2, a pyridyl benzofuran (PBF) derivative labeled with astatine-211 (211At, t1/2 = 7.2 h), as a small molecule-based TAT agent targeting Aβ aggregates. In an in vitro thioflavin T (ThT) assay, [211At]APBF-2 significantly reduced the quantity of Aβ1-42 aggregates. Additionally, in an in vivo biodistribution study using normal mice, [211At]APBF-2 demonstrated favorable blood-brain barrier (BBB) permeability (2.95% injected dose (ID)/g at 2 min after intravenous injection). These results suggest that [211At]APBF-2 may be a TAT agent demonstrating therapeutic efficacy against AD in vivo.