RT Journal Article SR Electronic T1 Development of a 213Bi-Labeled Pyridyl Benzofuran for Targeted α-Therapy of Amyloid-β Aggregates JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1467 OP 1472 DO 10.2967/jnumed.124.267482 VO 65 IS 9 A1 Bender, Aidan A. A1 Kirkeby, Emily K. A1 Cross, Donna J. A1 Minoshima, Satoshi A1 Roberts, Andrew G. A1 Mastren, Tara E. YR 2024 UL http://jnm.snmjournals.org/content/65/9/1467.abstract AB 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. Methods: We synthesized a 213Bi-chelate–linked benzofuran pyridyl derivative (BiBPy) and generated [213Bi]BiBPy, with a specific activity of 120.6 GBq/μg, dissociation constant of 11 ± 1.5 nM, and logP of 0.14 ± 0.03. Results: As the first step toward the validation of [213Bi]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 [213Bi]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. Conclusion: This [213Bi]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.