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Molecular imaging and patho-functional analysis of cerebral ischemia : focused on prostaglandin synthases

脑缺血的分子影像和病理功能分析：聚焦前列腺素合酶

基本信息

批准号：
14370266
负责人：
KUGE Yuji
金额：
$ 8.77万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

In order to clarify 1)the roles of cyclooxygenase-2(COX-2) in the pathophysiology of cerebral ischemia and 2)the potentials of COX-2 molecular imaging in the patho-functional analysis of the disease, we planed the present project using molecular imaging technique. Our findings in this project were as follows :1.Temporal changes of cerebral blood flow, metabolism, and neuro-receptor in animal models of cerebral ischemiaIn ischemic regions where neuro-receptor function was preserved, neuronal DNA is still intact and cellular integrity is maintained. COX-2 expression was often observed in these regions.2.Cyclooxygenase-2 expression in animal models of stroke(1)The time course of COX-2 mRNA expression in the ischemic core was different from that of the peri-infarct area. The expression of COX-2 in focal ischemic tissues is determined by the depth and duration of CBF reduction.(2)Upregulation of bilateral S-100A9 and ipsi-lateral IL-1β and IL-6 genes, induced by the Spreading Depression(SD) elicitation were demonstrated to be downregulated by a selective COX-2 inhibitor JTE-522.3.Development of molecular probes for imaging COX-2 expressionWe intended to develop a radioiodinated coxib as a SPECT tracer for imaging COX-2 expression and designed 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (IMTP). ^<125>I-IMTP was successfully synthesized with a high specific activity. Our results showed a high inhibitory potency and selectivity of IMTP for COX-2, indicating its potential as a SPECT tracer for imaging COX-2 expression.

为了阐明环氧化酶-2（cyclooxygenase-2，考克斯-2）在脑缺血病理生理中的作用和考克斯-2分子成像技术在脑缺血病理功能分析中的应用价值，本课题拟利用分子成像技术对COX-2进行研究。本课题的研究结果如下：1.脑缺血动物模型脑血流、代谢和神经受体的时间变化在神经受体功能保留的缺血区，神经元DNA仍然完整，细胞完整性得以维持。考克斯-2在脑梗死动物模型中的表达（1）缺血中心区和梗死周边区考克斯-2 mRNA表达的时程不同。局部缺血组织中考克斯-2的表达取决于CBF减少的深度和持续时间。（2）双侧S-100 A9和同侧IL-1β和IL-6基因上调，3.考克斯-2表达显像的分子探针的研制我们打算研制一种放射性碘标记的coxib作为显像考克斯-2表达的SPECT示踪剂，并设计了一种5-（4-碘苯基）-1-[4-（甲磺酰基）苯基]-3-（三氟甲基）-1H-吡唑（IMTP）。成功<125>合成了具有高比活的α-I-IMTP。我们的研究结果显示IMTP对考克斯-2具有高的抑制效力和选择性，表明其作为显像考克斯-2表达的SPECT示踪剂的潜力。