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 [ 125I] through direct radioiodination using sodium [ 125I] iodide in the presence of Chloramine T. The radioligand (4-[2,6′]dibenzothiazolyl-2′-yl-2-[ 125I]-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.