Novel ¹⁸F-labeled benzoxazole derivatives as potential positron emission tomography probes for imaging of cerebral β-amyloid plaques in Alzheimer's disease.
Two radiofluoro-pegylated phenylbenzoxazole derivatives, 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N-methylaniline ([(18)F]24) and 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N,N-dimethylaniline ([(18)F]32), were synthesized and evaluated as probes for imaging cerebral β-amyloid (Aβ) plaques in living brain tissue by PET. [(18)F]24 and [(18)F]32 displayed high affinity for Aβ(1-42) aggregates (K(i) = 9.3 and 3.9 nM, respectively). In vitro autoradiography with sections of post-mortem AD brain and transgenic mouse brain confirmed the affinity of these tracers. Initial high uptake into and rapid washout from the brain in normal mice were observed. [(18)F]24 also displayed excellent binding to Aβ plaques in ex vivo autoradiographic experiments with Tg2576 mice. Furthermore, small-animal PET studies demonstrated significant differences in the clearance profile after the administration of [(18)F]24 between Tg2576 and wild-type mice. The results suggest [(18)F]24 to be a useful PET agent for detecting Aβ plaques in the living human brain.
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Mengchao
M
Cui
Masahiro
M
Ono
Hiroyuki
H
Kimura
Masashi
M
Ueda
Yuji
Y
Nakamoto
Kaori
K
Togashi
Yoko
Y
Okamoto
Masafumi
M
Ihara
Ryosuke
R
Takahashi
Boli
B
Liu
Hideo
H
Saji
D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D001583:Benzoxazoles; D005462:Fluorine Radioisotopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C075222:amyloid beta-protein (1-42)