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

为了阐明环氧合酶-2(COX-2)在脑缺血病理生理机制中的作用和COX-2分子成像在脑缺血病理功能分析中的作用，我们利用分子成像技术对本课题进行了研究。本课题的研究结果如下：1.脑缺血动物模型脑血流、代谢和神经受体的一过性变化在保留神经受体功能的缺血区，神经元DNA仍然完整，细胞完整性保持不变。环氧合酶-2在卒中动物模型中的表达(1)缺血中心区和梗死区COX-2mRNA表达的时程不同。(2)选择性COX-2抑制剂JTE-5223可下调脑缺血大鼠双侧S-100A9和同侧IL-1β和IL-6基因的表达。成功地合成了比活性较高的I-IMTP。我们的结果显示，IMTP对COX-2具有很高的抑制效力和选择性，这表明它有可能作为SPECT示踪剂来成像COX-2的表达。

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.