Synthesis and evaluation of benzothiophene derivatives as ligands for imaging β-amyloid plaques in Alzheimer's disease
Synthesis and evaluation of benzothiophene derivatives as ligands for imaging β-amyloid plaques in Alzheimer's disease
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DOI：
10.1016/j.nucmedbio.2006.06.006
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发表时间：
2006-08-01
影响因子：
3.1
通讯作者：
Lee, Myung Chul
中科院分区：
文献类型：
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作者：
Chang, Young Soo;Jeong, Jae Min;Lee, Myung Chul
β-淀粉样蛋白（A β）斑块在脑中分布的成像正在成为阿尔茨海默病（AD）的重要诊断方式。在这里，我们合成了新的苯并噻吩衍生物，并用F-18标记它们，用于使用正电子发射断层扫描对AD患者进行潜在的诊断成像。采用2-（3 '-[I-125]碘-4'-N-甲基氨基苯基）苯并噻唑作为放射性配体，A β（1-40）或A β（1-42）聚集体作为受体，通过竞争性结合试验评价苯并噻吩衍生物的Ki值。所有合成的苯并噻吩衍生物对A β（1-40）和A β（1-42）聚集体均显示出高结合亲和力（Ki =0.28-6.50 nM）。通过2-（4 '-羟基苯基）苯并噻吩或2-（4'-氨基苯基）苯并噻吩的O-烷基化或N-烷基化增加结合亲和力。2-（4 '-O-（2-[F-18]氟乙基）羟基苯基）苯并噻吩（[F-18]2d）和2-（4'-O-（3 '-[F-18]氟丙基）羟基苯基）苯并噻吩（[F-18]2d）经尾静脉注射后在正常小鼠中进行生物分布研究。在生物分布数据中，[F-18]2c和[F-18]2d在2 min时显示出较高的初始脑摄取（分别为5.2 +/- 0.4%和3.3 +/- 0.2% ID/g），4 h时脑活性分别洗脱至2.0 +/- 0.2%和0.5 +/- 0.1% ID/g。总之，苯并噻吩衍生物显示出良好的A β聚集体的结合亲和力和正常小鼠的高初始脑摄取。(c)2006年爱思唯尔公司All rights reserved.
The imaging of the distribution of beta-amyloid (A beta), plaques in the brain is becoming an important diagnostic modality in Alzheimer's disease (AD). Here, we synthesized novel benzothiophene derivatives and labeled them with F-18 for the potential diagnostic imaging of AD patients using positron emission tomography. The K-i values of benzothiophene derivatives were evaluated by competitive binding assay using 2-(3'-[I-125]iodo-4'-N-methylaminophenyl)benzothiazole as a radioligand and A beta(1-40) or A beta(1-42) aggregates as receptors. All synthesized benzothiophene derivatives showed high binding affinities (K-i=0.28-6.50 nM) to both A beta(1-40) and A beta(1-42) aggregates. Binding affinities were increased by 0-alkylation or N-alkylation of 2-(4'-hydroxyphenyl)benzothiophene or 2-(4'-aminophenyl)benzothiophene. Biodistribution studies of 2-(4'-O-(2-[F-18]fluoroethyl)hydroxyphenyl)benzothiophene ([F-18]2d) and 2-(4'-O-(3'-[F-18]fluoropropyl)hydroxyphenyl)benzothiophene ([F-18]2d) in normal mice were performed after intravenous injection through the tail vein. In biodistribution data, [F-18]2c and [F-18]2d showed high initial brain uptakes at 2 min (5.2 +/- 0.4% and 3.3 +/- 0.2% ID/g, respectively), and brain activities washed out to 2.0 +/- 0.2% and 0.5 +/- 0.1% ID/g at 4 h, respectively. In conclusion, benzothiophene derivatives showed excellent binding affinities for A beta aggregates and high initial brain uptakes in normal mice. (c) 2006 Elsevier Inc. All rights reserved.