title: Optically Pure Diphenoxy Derivatives as More Flexible Probes for β-Amyloid Plaques.
abstract: The highly rigid and planar scaffold with π-conjugated systems has been widely considered to be indispensable for Aβ binding probes. However, the flexible benzyloxybenzene derivative [(125)I]BOB-4 represents an excellent lead candidate for targeting Aβ in AD brains. Based on that, we designed two pairs of more flexible and optically pure diphenoxy derivatives with a chiral center as novel Aβ probes. These compounds possessed high affinity (Ki = 15.8-45.0 nM) for Aβ1-42 aggregates, and (R)-enantiomers showed slightly better binding ability than (S)-enantiomers. In addition, the competition binding assay implied that the optically pure diphenoxy derivatives with more flexible geometry shared the same binding site as IMPY, a classical rigid and planar Aβ probe. For (125)I-radiolabeled enantiomers, (S)-[(125)I]5 and (R)-[(125)I]5, specific plaque labeling on brain sections of Tg mice and AD patients were observed in in vitro autoradiography, persuasively proving the excellent affinity of the probes. In biodistribution, (S)-[(125)I]5 and (R)-[(125)I]5 with relatively low lipophilicity exhibited moderate initial brain uptake (4.37% and 3.72% ID/g at 2 min, respectively) and extremely fast washout from normal mice brain (brain2min/brain60min = 19.0 and 17.7, respectively). In summary, the separate enantiomers displayed similar properties in vitro and in vivo, and (S/R)-[(123)I]5 may be potential SPECT probes for recognizing Aβ plaques in AD brains.
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University , Beijing 100875, P. R. China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Jia
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University , Beijing 100875, P. R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Song
authors.affiliation: Wuhan Institute for Neuroscience and Neuroengineering, South-Central University for Nationalities , Wuhan 430074, P. R. China.
authors.forename: Jiapei
authors.initials: J
authors.lastname: Dai
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University , Beijing 100875, P. R. China.
authors.forename: Boli
authors.initials: B
authors.lastname: Liu
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University , Beijing 100875, P. R. China.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Cui
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics / Q000494:pharmacology; D000814:Aniline Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology; D013267:Stilbenes / Q000493:pharmacokinetics / Q000494:pharmacology; D013961:Thyroid Gland / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects / Q000235:genetics
chemical_list: C513504:1,4-bis(4'-aminostyryl)-2-dimethoxybenzene; C473191:6-iodo-2-(4'-dimethylamino-)phenyl-imidazo(1,2-a)pyridine; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D010446:Peptide Fragments; D011725:Pyridines; D013267:Stilbenes; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Aβ plaque; benzyloxybenzene; enantiopure; imaging probe