Styrylbenzoxazole derivatives for in vivo imaging of amyloid plaques in the brain.
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.
Okamura
Nobuyuki
N
BF Research Institute, Suita 565-0873, Japan. oka@mail.tains.tohoku.ac.jp
Suemoto
Takahiro
T
Shimadzu
Hiroshi
H
Suzuki
Masako
M
Shiomitsu
Tsuyoshi
T
Akatsu
Hiroyasu
H
Yamamoto
Takayuki
T
Staufenbiel
Matthias
M
Yanai
Kazuhiko
K
Arai
Hiroyuki
H
Sasaki
Hidetada
H
Kudo
Yukitsuka
Y
Sawada
Tohru
T
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
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)