Quick assembly of 1,4-diphenyltriazoles as probes targeting β-amyloid aggregates in Alzheimer's disease
Quick assembly of 1,4-diphenyltriazoles as probes targeting β-amyloid aggregates in Alzheimer's disease
复制标题
DOI：
10.1021/jm070467l
复制
发表时间：
2007-07-12
影响因子：
7.3
通讯作者：
Kung, Hank F.
中科院分区：
文献类型：
--
作者：
Qu, Wenchao;Kung, Mei-Ping;Kung, Hank F.
大脑中β-淀粉样蛋白聚集体(A-β)的积累与阿尔茨海默病(AD)的发病机制有关。我们报道了一种新的方法来生产1，4-二苯基三氮唑作为靶向大脑中Aβ聚集体的探针。成像探针是一系列取代的三环1，4-二苯基三氮唑，它们与Aβ聚集体(K-I=4-30 nm)具有良好的结合亲和力，通过“点击化学”可以方便地组装。两个放射性碘化探针[I-125]10a和[I-125]10b以及两个放射性氟化探针[F-18]17a和[F-18]17b表现出中等的脂亲性，并显示出良好的初始脑渗透和正常小鼠脑内的快速洗脱。死后AD脑切片和匀浆的体外放射自显影显示，这些三氮唑与Aβ斑块结合。初步结果强烈表明，使用点击化学，导致了1，4-二苯基三氮唑为基础的核心，是一种高度方便和灵活的方法来组装新的显像剂，以靶向活体人脑衰老斑块中的Aβ聚集体。
Accumulation of beta-amyloid aggregates (A beta) 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 A beta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showing excellent binding affinities to A beta aggregates (K-i = 4-30 nM), were conveniently assembled by "click chemistry." Two radioiodinated probes, [I-125]10a and [I-125]10b, and two radiofluorinated probes, [F-18]17a and [F-18]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 A beta 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 A beta aggregates in senile plaques in the living human brain.