Klinikum rechts der Isar, Department of Nuclear Medicine, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.
J Med Chem. 2011 Feb 24;54(4):949-56. doi: 10.1021/jm101129a. Epub 2011 Jan 28.
We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral β-amyloid (Aβ) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Aβ. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Aβ(1-40) (K(i) = 3.5 nM) and Aβ(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aβ-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aβ plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of Aβ plaques.
我们报告了一系列新型的 [(11)C] 标记的咪唑并[2,1-b]苯并噻唑（IBTs），可通过正电子发射断层扫描（PET）对阿尔茨海默病（AD）患者的脑β-淀粉样蛋白（Aβ）沉积进行成像。在一系列 11 种化合物中，确定了具有高 Aβ 结合亲和力的候选物。选择的化合物被制备为 O-或 N-[(11)C] 甲基衍生物，并显示在野生型小鼠中具有高初始脑摄取（5 分钟时范围为 1.9-9.2% ID/g）。基于高初始脑摄取、正常脑组织快速清除以及对 Aβ（1-40）（K(i) = 3.5 nM）和 Aβ（1-42）（5.8 nM）的高体外亲和力的综合有利特性，2-（对-[(11)C] 甲氨基苯基）-7-甲氧基咪唑并[2,1-b] 苯并噻唑（[(11)C]5）被确定为一种先导化合物，优于匹兹堡化合物 B（1a）。在 AD（Tg）的 APP/PS1 小鼠模型中，我们通过小动物 PET 证明了 [(11)C]5 在含有 Aβ 的大脑区域中的特异性摄取，这通过区域脑分布、离体放射自显影和免疫组织化学得到了证实。分析接受 [(11)C]5 和 [(3)H]1a 单次静脉注射的 Tg 小鼠的脑切片显示，示踪剂以类似的模式与 Tg 小鼠脑内的 Aβ 斑块结合。总之，这些数据表明 IBTs 是用于高灵敏度检测 Aβ 斑块的有用的 PET 成像剂。
