Qu Wenchao, Kung Mei-Ping, Hou Catherine, Oya Shunichi, Kung Hank F
Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Med Chem. 2007 Jul 12;50(14):3380-7. doi: 10.1021/jm070467l. Epub 2007 Jun 15.
Accumulation of beta-amyloid aggregates (Abeta) in the brain is linked to the pathogenesis of Alzheimer's disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Abeta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showing excellent binding affinities to Abeta aggregates (Ki = 4-30 nM), were conveniently assembled by "click chemistry." Two radioiodinated probes, [125I]10a and [125I]10b, and two radiofluorinated probes, [18F]17a and [18F]17b, exhibited moderate lipophilicities and showed excellent initial brain penetrations and fast washouts from the normal mouse brain. In vitro autoradiography of postmortem AD brain sections and homogenates showed that these triazoles were binding to Abeta plaques. Preliminary results strongly suggest that use of click chemistry, which led to a 1,4-diphenyltriazole-based core, is a highly convenient and flexible approach for assembling novel imaging agents for targeting Abeta aggregates in senile plaques in the living human brain.
大脑中β-淀粉样蛋白聚集体（Aβ）的积累与阿尔茨海默病（AD）的发病机制相关。我们报道了一种制备1,4-二苯基三唑的新方法，该化合物可作为靶向大脑中Aβ聚集体的探针。通过“点击化学”方便地组装了一系列成像探针，即一系列对Aβ聚集体具有优异结合亲和力（Ki = 4 - 30 nM）的取代三环1,4-二苯基三唑。两种放射性碘化探针[125I]10a和[125I]10b以及两种放射性氟化探针[18F]17a和[18F]17b具有适度的亲脂性，在正常小鼠脑中表现出优异的初始脑渗透和快速清除。对死后AD脑切片和匀浆的体外放射自显影显示，这些三唑与Aβ斑块结合。初步结果有力地表明，使用点击化学生成基于1,4-二苯基三唑的核心，是一种高度方便且灵活的方法，可用于组装新型成像剂，以靶向活人脑中老年斑中的Aβ聚集体。
