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.
