In vitro characterisation of BF227 binding to α-synuclein/Lewy bodies

Amyloid-beta (A beta) plaques are a pathological hallmark of Alzheimer's disease and a current target for positron emission tomography (PET) imaging agents. Whilst [C-11]-PiB is currently the most widely used PET ligand in clinic, a novel family of benzoxazole compounds have shown promise as A beta imaging agents; particularly BF227. We characterised the in vitro binding of [F-18]-BF227 toward alpha-synuclein to address its selectivity for A beta pathology, to establish whether [F-18]-BF227 binds to alpha-synuclein/Lewy bodies, in addition to A beta plaques. In vitro [F-18]-BF227 saturation studies were conducted with 200 nM alpha-synuclein or A beta(1-42) fibrils or 100 mu g of Alzheimer's disease, pure dementia with Lewy bodies or control brain homogenates. Non-specific binding was established with PiB (1 mu M). In vitro binding studies indicated that [F-18]-BF227 binds with high affinity to two binding sites on A beta(1-42) fibrils (K-D1 = 1.31 and K-D2 = 80 nM, respectively) and to one class of binding sites on alpha-synuclein fibrils (K-D = 9.63nM). [F-18]-BF227 bound to A beta-containing Alzheimer's disease brain (K-D = 25 +/- 0.5 nM), but failed to bind to A beta-free dementia with Lewy bodies or age-matched control homogenates. Moreover, BF227 labelled both A beta plaques and Lewy bodies in immunohistochemical/fluorescence analysis of human Alzheimer's disease and Parkinson's disease brain sections, respectively. This study suggests that [F-18]-BF227 is not A beta-selective. Evaluation of BF227 as a potential biomarker for Parkinson's disease is warranted. (C) 2009 Elsevier B.V. All rights reserved.