Development of a Bi-Labeled Pyridyl Benzofuran for Targeted α-Therapy of Amyloid-β Aggregates.

Alzheimer disease is a neurodegenerative disorder with limited treatment options. It is characterized by the presence of several biomarkers, including amyloid-β aggregates, which lead to oxidative stress and neuronal decay. Targeted α-therapy (TAT) has been shown to be efficacious against metastatic cancer. TAT takes advantage of tumor-localized α-particle emission to break disease-associated covalent bonds while minimizing radiation dose to healthy tissues due to the short, micrometer-level, distances traveled. We hypothesized that TAT could be used to break covalent bonds within amyloid-β aggregates and facilitate natural plaque clearance mechanisms. We synthesized a Bi-chelate-linked benzofuran pyridyl derivative (BiBPy) and generated [Bi]BiBPy, with a specific activity of 120.6 GBq/μg, dissociation constant of 11 ± 1.5 nM, and logP of 0.14 ± 0.03. As the first step toward the validation of [Bi]BiBPy as a TAT agent for the reduction of Alzheimer disease-associated amyloid-β, we showed that brain homogenates from APP/PS1 double-transgenic male mice (6-9 mo old) incubated with [Bi]BiBPy exhibited a marked reduction in amyloid-β plaque concentration as measured using both enzyme-linked immunosorbent and Western blotting assays, with a half-maximal effective concentration of 3.72 kBq/pg. This [Bi]BiBPy-concentration-dependent activity shows that TAT can reduce amyloid plaque concentration in vitro and supports the development of targeting systems for in vivo validations.