IMPY:: an improved thioflavin-T derivative for in vivo labeling of β-amyloid plaques
IMPY:: an improved thioflavin-T derivative for in vivo labeling of β-amyloid plaques
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DOI：
10.1016/s0006-8993(02)03436-4
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发表时间：
2002-11-29
期刊：
影响因子：
2.9
通讯作者：
Kung, HF
中科院分区：
文献类型：
--
作者：
Kung, MP;Hou, C;Kung, HF
开发小分子探针用于体内标记和检测阿尔茨海默病(AD)患者的β-淀粉样蛋白(Abeta)斑块具有重要的科学意义，也可能有助于开发针对Abeta斑块的治疗AD的药物。以过氧化氢为催化剂，通过碘去单宁化反应，成功地合成了一种新型的探针[I-123/I-125]impy，6-碘-2-(4‘-二甲氨基)苯基-咪唑并[1，2-a]吡啶。修饰的硫代黄素-T衍生物与溶液中预先形成的人工合成Abeta40聚集体(K-I=15+/-5 nm)具有良好的结合亲和力，并在死后AD脑切片上显示选择性斑块标记。正常小鼠静脉注射[I-125]ImPy后的生物分布研究表明，[I-125]ImPy具有良好的脑摄取(2min时2.9%初始剂量/脑)和快速洗脱(60min时0.2%初始剂量/脑)。这些特性是淀粉样斑块显像剂非常需要的。在体内，斑块标记在转基因小鼠模型(Tg2576)中进行了评估，该模型被设计为在大脑中产生多余的淀粉样斑块。TG2576小鼠静脉注射后4h的体外脑切片放射自显影。注射[I-125]ImPy后，明显显示出背景活度较低的斑块标记。用硫代黄素-S荧光染料对同一脑切片进行染色时，相同的Aβ斑块显示出与放射自显影结果一致的显著荧光标记。综上所述，这些发现清楚地表明，放射性碘标记的Impy在体内标记Abeta斑块具有理想的特性，它可能作为一种分子显像剂用于研究活体AD患者脑内淀粉样蛋白的发生。(C)2002 Elsevier Science B.V.保留所有权利。
Development of small molecular probes for in vivo labeling and detection of beta-amyloid (Abeta) plaques in patients of Alzheimer's disease (AD) is of significant scientific interest, and it may also assist the development of drugs targeting Abeta plaques for treatment of AD. A novel probe, [I-123/I-125]IMPY, 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo [1,2-a]pyridine, was successfully prepared with an iododestannylation reaction catalyzed by hydrogen peroxide. The modified thioflavin-T derivative displayed a good binding affinity for preformed synthetic Abeta40 aggregates in solution (K-i = 15+/-5 nM) and showed selective plaque labeling on postmortem AD brain sections. Biodistribution study in normal mice after an iv injection of [I-125]IMPY exhibited excellent brain uptake (2.9% initial dose/brain at 2 min) and fast washout (0.2% initial dose/brain at 60 min). These properties are highly desirable for amyloid plaque imaging agents. In vivo plaque labeling was evaluated in a transgenic mouse model (Tg2576) engineered to produce excess amyloid plaques in the brain. Ex vivo autoradiograms of brain sections of the Tg 2576 mouse obtained at 4 h after an i.v. injection of [I-125]IMPY clearly displayed a distinct plaque labeling with a low background activity. When the same brain section was stained with a fluorescent dye, thioflavin-S, the same Abeta plaques showed prominent fluorescent labeling consistent with the results of the autoradiogram. In conclusion, these findings clearly suggest that radioiodinated IMPY demonstrates desirable characteristics for in vivo labeling of Abeta plaques and it may be useful as a molecular imaging agent to study amyloidogenesis in the brain of living AD patients. (C) 2002 Elsevier Science B.V. All rights reserved.