Development of a 213Bi-Labeled Pyridyl Benzofuran for Targeted α-Therapy of Amyloid-ß Aggregates.
J Nucl Med
; 2024 Jul 25.
Article
en En
| MEDLINE
| ID: mdl-39054283
ABSTRACT
Alzheimer disease is a neurodegenerative disorder with limited treatment options. It is characterized by the presence of several biomarkers, including amyloid-ß 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-ß 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-ß, 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-ß 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.
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01-internacional
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MEDLINE
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En
Revista:
J Nucl Med
Año:
2024
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Article