The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils:

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, ...