Abstract |
Development of an α- synuclein (α-Syn) positron emission tomography agent for the diagnosis and evaluation of Parkinson disease therapy is a key goal of neurodegenerative disease research. BF-227 has been described as an α-Syn binder and hence was employed as a lead to generate a library of α-Syn-binding compounds. [3H] BF-227 bound to α-Syn and amyloid β peptide (Aβ) fibrils with affinities (KD) of 46.0 nM and 15.7 nM, respectively. Affinities of BF-227-like compounds (expressed as Ki) for α-Syn and Aβ fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for α-Syn binding, defined as the Ki(Aβ)/Ki(α-Syn) ratio, was 0.23 for BF-227. A similar or lower ratio was measured for analogues decorated with alkyl or oxyethylene chains attached to the oxygen at the 6 position of BF-227, suggesting a lack of involvement of the side chain in fibril binding. BF-227-like iodobenzoxazoles had lower affinities and poor α-Syn selectivity. However, BF-227-like fluorobenzoxazoles had improved α-Syn selectively having Ki(Aβ)/Ki(α-Syn) ranging from 2.2 to 5.1 with appreciable fibril affinity, although not sufficient to warrant further investigation. Compounds based on fluorobenzoxazoles might offer an approach to obtaining an α-Syn imaging agent with an appropriate affinity and selectivity.
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Authors | Lee Josephson, Nancy Stratman, YuTing Liu, Fang Qian, Steven H Liang, Neil Vasdev, Shil Patel |
Journal | Molecular imaging
(Mol Imaging)
2018 Jan-Dec
Vol. 17
Pg. 1536012118796297
ISSN: 1536-0121 [Electronic] England |
PMID | 30213230
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2-(2-(2-dimethylaminothiazol-5-yl)ethenyl)-6-(2-(fluoro)ethoxy)benzoxazole
- Amyloid beta-Peptides
- Benzoxazoles
- SNCA protein, human
- Thiazoles
- alpha-Synuclein
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Topics |
- Amyloid beta-Peptides
(metabolism)
- Benzoxazoles
(chemistry, metabolism)
- Humans
- Protein Binding
- Reference Standards
- Thiazoles
(chemistry, metabolism)
- alpha-Synuclein
(metabolism)
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