Biological evaluation of the radioiodinated imidazo[1,2-a]pyridine derivative DRK092 for amyloid-β imaging in mouse model of Alzheimer's disease
Biological evaluation of the radioiodinated imidazo[1,2-a]pyridine derivative DRK092 for amyloid-β imaging in mouse model of Alzheimer's disease
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DOI：
10.1016/j.neulet.2014.08.036
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发表时间：
2014-10-03
影响因子：
2.5
通讯作者：
Ji, Bin
中科院分区：
文献类型：
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作者：
Chen, Chun-Jen;Bando, Kazunori;Ji, Bin
无创测定β淀粉样肽（Aβ）沉积对于阿尔茨海默病（AD）的早期诊断和医疗干预具有重要意义。在这项研究中，我们研究了放射性碘标记的咪唑并[1,2-a]吡啶衍生物（称为 I-125-DRK092）作为单光子发射计算机断层扫描 (SPECT) 配体用于体内 Aβ 沉积检测的可用性。 DRK092 对合成人 Aβ 原纤维或来自淀粉样前体蛋白转基因 (Tg) 小鼠 (PS1-ki/JU-Tg2576) 和 AD 患者的脑匀浆表现出高结合亲和力，解离常数 (K-d) 为一位数 nM，并且具有出色的脑通透性（摄取峰值：约注射剂量/g 大鼠脑的 0.9%）。离体放射自显影分析表明，在 Tg 小鼠中，使用 I-125-DRK092 进行的测量比使用 I-125-IMPY（一种众所周知的淀粉样蛋白 SPECT 配体）进行的 Aβ 积累检测具有更高的灵敏度。使用 I-125-DRK092 进行的体外放射自显影也证实，与非 Tg 小鼠和健康对照大脑的相应区域相比，Tg 小鼠和 AD 患者大脑的富含 A β 斑块的皮质区域的放射性积累更高。上述所有数据使我们得出这样的结论：放射性碘标记的 DRK092 是 AD 淀粉样蛋白成像的潜在 SPECT 配体。 (C) 2014 Elsevier Ireland Ltd. 保留所有权利。
Non-invasive determination of amyloid-beta peptide (A beta) deposition has important significance for early diagnosis and medical intervention in Alzheimer's disease (AD). In this study, we investigated the availability of a radioiodinated imidazo[1,2-a]pyridine derivative, termed I-125-DRK092, as single photon emission computed tomography (SPECT) ligand for in vivo detection of A beta deposition. DRK092 showed high binding affinity for either synthetic human A beta fibrils or brain homogenates from amyloid precursor protein transgenic (Tg) mouse (PS1-ki/JU-Tg2576) and AD patient with a dissociation constant (K-d) of one-digit nM, and excellent brain permeability (peak value of uptake: approximately 0.9% of injection dose/g rat brain). Ex vivo autoradiographic analysis showed that measurement with I-125-DRK092 has higher sensibility for detecting A beta accumulation than with I-125-IMPY, a well-known amyloid SPECT ligand, in Tg mice. In vitro autoradiography with I-125-DRK092 also confirmed higher accumulation of radioactivity in the cortical area, enriched with A beta plaques, of Tg mouse and AD patient brains, as compared with the corresponding areas in non-Tg mouse and healthy control brains. All the data presented above lead us to draw the conclusion that radioiodinated DRK092 is a potential SPECT ligand for amyloid imaging in AD. (C) 2014 Elsevier Ireland Ltd. All rights reserved.