Wu Chunying, Wei Jingjun, Gao Kuanqiang, Wang Yanming
Department of Chemistry and Radiology, Case Western Reserve University, Cleveland, OH 44106, USA.
Bioorg Med Chem. 2007 Apr 1;15(7):2789-96. doi: 10.1016/j.bmc.2006.11.022. Epub 2006 Nov 16.
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.
合成了新型二苯并噻唑衍生物并将其作为淀粉样蛋白成像剂进行评估。使用阿尔茨海默病脑组织匀浆进行的体外定量结合研究表明，二苯并噻唑衍生物表现出高结合亲和力，其解离常数（Ki）值在纳摩尔范围内（6.8 - 36 nM）。这些衍生物具有相对亲脂性，分配系数（logP oct）在1.25 - 3.05范围内。初步的构效关系研究表明，带有供电子基团的二苯并噻唑衍生物比带有吸电子基团的衍生物表现出更高的结合亲和力。选择了一种具有高结合亲和力的先导化合物，并在氯胺T存在下，使用碘化钠[（125）I]通过直接放射性碘化将其用[（125）I]进行放射性标记。放射性配体（4 - [2,6']二苯并噻唑基 - 2'-基 - 2 - [（125）I] - 苯胺）表现出适度的亲脂性（logP oct，2.70），非常好的脑摄取（小鼠静脉注射后2分钟时为3.71±0.63% ID/g），以及从正常脑中快速清除（30分钟和60分钟时分别为0.78%和0.43% ID/g）。这些研究表明，亲脂性二苯并噻唑衍生物是开发用于阿尔茨海默病和相关神经退行性疾病潜在应用的新型淀粉样蛋白成像剂的有前景的药效基团。
