title: Synthesis and evaluation of novel ¹⁸F labeled 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives as ligands for positron emission tomography (PET) imaging of β-amyloid plaques.
abstract: A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for (18)F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [(18)F]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([(18)F]32) (K(i) = 8.0 ± 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [(18)F]32 to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [(18)F]32 is a promising Aβ imaging agent for PET and merits further evaluation in human subjects.
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China. cmc@bnu.edu.cn
authors.forename: Mengchao
authors.initials: M
authors.lastname: Cui
authors.forename: Xuedan
authors.initials: X
authors.lastname: Wang
authors.forename: Pingrong
authors.initials: P
authors.lastname: Yu
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhang
authors.forename: Zijing
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Yang
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jia
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
authors.forename: Boli
authors.initials: B
authors.lastname: Liu
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C578490:5-(5-(2-fluoroethoxy)benzo(d)oxazol-2-yl)-N-methylpyridin-2-amine; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D001583:Benzoxazoles; D005462:Fluorine Radioisotopes; D008024:Ligands; D010446:Peptide Fragments; D011725:Pyridines; D019275:Radiopharmaceuticals; C075222:amyloid beta-protein (1-42); D011092:Polyethylene Glycols