title: Dibenzothiazoles as novel amyloid-imaging agents.
abstract: Novel dibenzothiazole derivatives were synthesized and evaluated as amyloid-imaging agents. In vitro quantitative binding studies using AD brain tissue homogenates showed that the dibenzothiazole derivatives displayed high binding affinities with K(i) values in the nanomolar range (6.8-36 nM). These derivatives are relatively lipophilic with partition coefficients (logP oct) in the range of 1.25-3.05. Preliminary structure-activity relationship studies indicated dibenzothiazole derivatives bearing electron-donating groups exhibited higher binding affinities than those bearing electron-withdrawing groups. A lead compound was selected for its high binding affinity and radiolabeled with [(125)I] through direct radioiodination using sodium [(125)I] iodide in the presence of Chloramine T. The radioligand (4-[2,6']dibenzothiazolyl-2'-yl-2-[(125)I]-phenylamine) displayed moderate lipophilicity (logP oct, 2.70), very good brain uptake (3.71+/-0.63% ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.78% and 0.43% ID/g at 30 and 60 min, respectively). These studies indicated that lipophilic dibenzothiazole derivatives represent a promising pharmacophore for the development of novel amyloid-imaging agents for potential application in Alzheimer's disease and related neurodegenerative disorders.
authors.affiliation: Department of Chemistry and Radiology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Wu
authors.forename: Jingjun
authors.initials: J
authors.lastname: Wei
authors.forename: Kuanqiang
authors.initials: K
authors.lastname: Gao
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism; D017772:Amyloid Neuropathies / Q000000981:diagnostic imaging* / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010539:Permeability; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
chemical_list: D052160:Benzothiazoles; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals