The Binding of BF-227-Like Benzoxazoles to Human ?-Synuclein and Amyloid ? Peptide Fibrils.

ABSTRACT: Development of an ?-synuclein (?-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 ?-Syn binder and hence was employed as a lead to generate a library of ?-Syn-binding compounds. [³H]BF-227 bound to ?-Syn and amyloid ? peptide (A?) fibrils with affinities (K_D) of 46.0 nM and 15.7 nM, respectively. Affinities of BF-227-like compounds (expressed as K_i) for ?-Syn and A? fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for ?-Syn binding, defined as the K_i(A?)/K_i(?-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 ?-Syn selectivity. However, BF-227-like fluorobenzoxazoles had improved ?-Syn selectively having K_i(A?)/K_i(?-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 ?-Syn imaging agent with an appropriate affinity and selectivity.

SUBMITTER: Josephson L 

PROVIDER: S-EPMC6144582 | biostudies-literature | 2018 Jan-Dec

REPOSITORIES: biostudies-literature