The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid ß Peptide Fibrils.
Mol Imaging
; 17: 1536012118796297, 2018.
Article
em En
| MEDLINE
| ID: mdl-30213230
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 ß peptide (Aß) 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 Aß fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for α-Syn binding, defined as the Ki(Aß)/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(Aß)/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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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
/
Benzoxazóis
/
Peptídeos beta-Amiloides
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Alfa-Sinucleína
Limite:
Humans
Idioma:
En
Revista:
Mol Imaging
Assunto da revista:
DIAGNOSTICO POR IMAGEM
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos