title: In vitro characterisation of BF227 binding to alpha-synuclein/Lewy bodies.
abstract: Amyloid-beta (Abeta) plaques are a pathological hallmark of Alzheimer's disease and a current target for positron emission tomography (PET) imaging agents. Whilst [(11)C]-PiB is currently the most widely used PET ligand in clinic, a novel family of benzoxazole compounds have shown promise as Abeta imaging agents; particularly BF227. We characterised the in vitro binding of [(18)F]-BF227 toward alpha-synuclein to address its selectivity for Abeta pathology, to establish whether [(18)F]-BF227 binds to alpha-synuclein/Lewy bodies, in addition to Abeta plaques. In vitro [(18)F]-BF227 saturation studies were conducted with 200 nM alpha-synuclein or Abeta(1-42) fibrils or 100 microg of Alzheimer's disease, pure dementia with Lewy bodies or control brain homogenates. Non-specific binding was established with PiB (1 microM). In vitro binding studies indicated that [(18)F]-BF227 binds with high affinity to two binding sites on Abeta(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) = 9.63 nM). [(18)F]-BF227 bound to Abeta-containing Alzheimer's disease brain (K(D) = 25 +/- 0.5 nM), but failed to bind to Abeta-free dementia with Lewy bodies or age-matched control homogenates. Moreover, BF227 labelled both Abeta plaques and Lewy bodies in immunohistochemical/fluorescence analysis of human Alzheimer's disease and Parkinson's disease brain sections, respectively. This study suggests that [(18)F]-BF227 is not Abeta-selective. Evaluation of BF227 as a potential biomarker for Parkinson's disease is warranted.
authors: Department of Pathology, The University of Melbourne, VIC, Australia.
authors: Michelle T
authors: MT
authors: Fodero-Tavoletti
authors: Rachel S
authors: RS
authors: Mulligan
authors: Nobuyuki
authors: N
authors: Okamura
authors: Shozo
authors: S
authors: Furumoto
authors: Christopher C
authors: CC
authors: Rowe
authors: Yukitsuka
authors: Y
authors: Kudo
authors: Colin L
authors: CL
authors: Masters
authors: Roberto
authors: R
authors: Cappai
authors: Kazuhiko
authors: K
authors: Yanai
authors: Victor L
authors: VL
authors: Villemagne
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001583:Benzoxazoles / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism*; D020961:Lewy Body Disease / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C516779:2-(2-(2-dimethylaminothiazol-5-yl)ethenyl)-6-(2-(fluoro)ethoxy)benzoxazole; D016229:Amyloid beta-Peptides; D001583:Benzoxazoles; D005462:Fluorine Radioisotopes; D010446:Peptide Fragments; D013844:Thiazoles; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42)