Ji Bin, Chen Chun-Jen, Bando Kazunori, Ashino Hiroki, Shiraishi Hideaki, Sano Hiroaki, Kasahara Hiroyuki, Minamizawa Takao, Yamada Kazutaka, Ono Maiko, Zhang Ming-Rong, Seki Chie, Farde Lars, Suhara Tetsuya, Higuchi Makoto
Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan.
Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
J Neurochem. 2015 Dec;135(5):859-66. doi: 10.1111/jnc.13293. Epub 2015 Sep 17.
Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB. (11)C-PiB, (3)H-AZD2184, and (125)I-DRK092 showed overt binding to presubicular Aβ deposits, while (125)I-DRM106 barely bound to these aggregates despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as (125)I-DRM106, may selectively capture Aβ deposits tightly associated with TSPO neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aβ pathologies. Non-invasive determination of amyloid-β peptide (Aβ) serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). We found that there are at least two different amyloid components in hippocampal CA1 and presubiculum providing distinct binding sites for the current amyloid radioligands. Comparative analysis for radioligand binding in these two regions could serve for developing novel imaging agents selectively visualizing neurotoxicity-related Aβ pathologies.
用放射性配体对淀粉样β肽（Aβ）沉积进行无创测定有助于阿尔茨海默病（AD）的早期诊断和发病机制的阐明。然而，目前放射性配体在多聚体Aβ上的多态性结合位点尚不清楚。在本研究中，我们研究了几种放射性配体的结合情况，包括（11）C-匹兹堡化合物B（（11）C-PiB）、（3）H-AZD2184以及最近开发的两种化合物（125）I-DRM106和（125）I-DRK092，它们与独特的海马下脚Aβ沉积物结合，且这些沉积物与常用的淀粉样染料FSB无相互作用。（11）C-PiB、（3）H-AZD2184和（125）I-DRK092显示出与海马下脚Aβ沉积物有明显结合，而（125）I-DRM106尽管在海马CA1区有强烈结合，但几乎不与这些聚集体结合。与CA1区的神经炎性斑块不同，海马下脚的Aβ病变不伴有富含18 kDa转位蛋白（TSPO）的炎性胶质细胞增生。因此，Aβ聚集体中至少有两种不同成分，为目前的淀粉样放射性配体提供了不同的结合位点，其中一种结合成分明显存在于海马下脚Aβ沉积物中。缺乏对该成分亲和力的淀粉样放射性配体，如（125）I-DRM106，可能会选择性地捕获与TSPO神经炎症和神经退行性变紧密相关的Aβ沉积物，如CA1区神经炎性斑块所示。因此，对CA1区和海马下脚放射性配体结合的比较放射自显影评估可用于开发一种能可视化与神经毒性相关的Aβ病变的淀粉样PET成像剂。用淀粉样β肽（Aβ）进行无创测定有助于阿尔茨海默病（AD）的早期诊断和发病机制的阐明。我们发现海马CA1区和海马下脚中至少有两种不同的淀粉样成分，为目前的淀粉样放射性配体提供了不同的结合位点。对这两个区域放射性配体结合的比较分析可用于开发能选择性可视化与神经毒性相关的Aβ病变的新型成像剂。
