title: Styrylbenzoxazole derivatives for in vivo imaging of amyloid plaques in the brain.
abstract: Progressive deposition of senile plaques (SPs) is one of the major neuropathological features of Alzheimer's disease (AD) that precedes cognitive decline. Noninvasive detection of SPs could, therefore, be a potential diagnostic test for early detection of AD patients. For imaging SPs in the living brain, we have developed a series of styrylbenzoxazole derivatives that achieve high binding affinity for amyloid-beta (Abeta) fibrils. One of these compounds, 6-(2-Fluoroethoxy)-2-[2-(4-methylaminophenil) ethenyl]benzoxazole (BF-168), selectively binds SPs in AD brain sections and recognizes Abeta1-42-positive diffuse plaques as well as neuritic plaques in AD brain sections. Intravenous injection of BF-168 in PS1/APP and APP23 transgenic mice resulted in specific in vivo labeling to both compact and diffuse amyloid deposits in the brain. In addition, (18)F-radiolabeled BF-168 demonstrated abundant initial brain uptake (3.9% injected dose/gm at 2 min after injection) and fast clearance (t(1/2) = 24.7 min) after intravenous administration in normal mice. Furthermore, autoradiograms of brain sections from APP23 transgenic mice at 180 min after intravenous injection of [(18)F]BF-168 showed selective labeling of brain amyloid deposits with little nonspecific binding. These findings strongly suggest that styrylbenzoxazole derivatives are promising candidate probes for positron emission tomography and single-photon emission computed tomography imaging for early detection of amyloid plaque formation.
authors.affiliation: BF Research Institute, Suita 565-0873, Japan. oka@mail.tains.tohoku.ac.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suemoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimadzu
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shiomitsu
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Hidetada
authors.initials: H
authors.lastname: Sasaki
authors.forename: Yukitsuka
authors.initials: Y
authors.lastname: Kudo
authors.forename: Tohru
authors.initials: T
authors.lastname: Sawada
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000814:Aniline Compounds / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001583:Benzoxazoles / Q000378:metabolism / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D006801:Humans; D007275:Injections, Intravenous; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism; D012680:Sensitivity and Specificity; D014055:Tomography, Emission-Computed / Q000379:methods; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: C485711:6-(2-fluoroethoxy)-2-(2-(4-methylaminophenil)ethenyl)benzoxazole; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D001583:Benzoxazoles; D005462:Fluorine Radioisotopes; D046911:Macromolecular Substances; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)