Synthesis and evaluation of 1-(4-[¹⁸F]fluoroethyl)-7-(4'-methyl)curcumin with improved brain permeability for β-amyloid plaque imaging.
Synthesis and evaluation of 1-(4-[¹⁸F]fluoroethyl)-7-(4'-methyl)curcumin with improved brain permeability for β-amyloid plaque imaging.
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DOI：
10.1016/j.bmcl.2011.08.003
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发表时间：
2011-10
影响因子：
2.7
通讯作者：
Iljung Lee;Jehoon Yang;J. H. Lee;Y. Choe
中科院分区：
文献类型：
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作者：
Iljung Lee;Jehoon Yang;J. H. Lee;Y. Choe
阿尔茨海默病的特征在于β-淀粉样蛋白（Aβ）斑块和神经纤维缠结（NFT）在脑中的积累。我们先前开发了[18 F]氟丙基姜黄素（[18 F] FP-姜黄素），其对Aβ（1-40）聚集体表现出优异的结合亲和力（Ki= 0.07 nM），并在正常小鼠脑中表现出良好的药代动力学。然而，其初始脑摄取较差（注射后2分钟为0.52%ID/g）。因此，本研究合成了氟取代的4，4 ′-双取代或聚乙二醇化姜黄素衍生物并对其进行了评价。结果表明，1-（4-氟乙基）-7-（4′-甲基）姜黄素（1）与Aβ（1-42）聚集体的结合亲和力最高（Ki=2.12nM）。Tg APP/PS-1小鼠脑切片的荧光染色显示，皮质区域中的1对Aβ斑块进行了高度特异性标记，这一点通过相邻脑切片中相同斑点的硫磺素-S染色得到证实。发现放射性配体[18 F]1具有适当的分配系数（logPo/w=2.40），并且其在正常小鼠中的组织分布证明与[18 F] FP-姜黄素相比，脑渗透性提高（注射后2分钟为1.44%ID/g），提高了2.8倍，并且从小鼠脑中快速洗脱（注射后30分钟为0.45%ID/g）。这些结果表明，[18 F]1可能有望作为PET放射性配体用于Aβ斑块成像。
Alzheimer’s disease is characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. We previously developed [18F]fluoropropylcurcumin ([18F]FP-curcumin), which demonstrated excellent binding affinity (Ki=0.07nM) for Aβ(1–40) aggregates and good pharmacokinetics in normal mouse brains. However, its initial brain uptake was poor (0.52% ID/g at 2min post-injection). Therefore, in the present study, fluorine-substituted 4,4′-bissubstituted or pegylated curcumin derivatives were synthesized and evaluated. Their binding affinities for Aβ(1–42) aggregates were measured and 1-(4-fluoroethyl)-7-(4′-methyl)curcumin (1) had the highest binding affinity (Ki=2.12nM). Fluorescence staining of Tg APP/PS-1 mouse brain sections demonstrated high and specific labeling of Aβ plaques by 1 in the cortex region, which was confirmed with thioflavin-S staining of the same spots in the adjacent brain sections. Radioligand [18F]1 was found to have an appropriate partition coefficient (logPo/w=2.40), and its tissue distribution in normal mice demonstrated improved brain permeability (1.44% ID/g at 2min post-injection) compared to that of [18F]FP-curcumin by a factor of 2.8 and fast wash-out from mouse brains (0.45% ID/g at 30min post-injection). These results suggest that [18F]1 may hold promise as a PET radioligand for Aβ plaque imaging.