Development of positron labeled polyunsaturated long chain fatty acid to image the brain phospholipid metabolism with positron emission tomography.

在两年的发展科学研究资助期内，我们完成了以下工作：1、以市售二十二碳六烯酸乙酯为原料，成功合成了放射性合成^<11>C标记二十二碳六烯酸（^<11>C- dha）的前体-全-1-溴- 3,6,9,12,15,18 -庚二碳六烯。2、通过溴物质与金属锂的反应，在反应容器中捕获^<11>CO_2，采用两步法合成^<11>C-DHA。3、观察了C-DHA给药20 min后的器官放射性分布。虽然对脑组织的摄取小于1%剂量/g组织，但利用放射自显像成功获得了脑组织图像。采用脑脂提取法和放射自显影薄层色谱法分析脑脂组分中放射性的分布。结果表明，放射性主要存在于脑磷脂部分，尤其是脑磷脂酰乙醇胺部分。研究了在接受和不接受胆碱能激动剂槟油碱系统治疗时^< 11bb0 C-DHA的摄取情况。富含毒蕈碱类胆碱能受体的大脑皮层对^<11>C-DHA的摄取率在胆碱能处理后增加。然而，进入缺乏毒蕈碱胆碱能受体的小脑则没有。6、大鼠单侧MCA闭塞模型梗死周围区^<11 b> C-DHA摄取在闭塞1小时后增加，这可能表明sn-2位脂肪酸释放增加，并伴随磷脂酶A2.7的激活，开始了大鼠颅脑损伤模型中sn-2位脂肪酸转换改变的实验。尚待完成的事情如下。1、为了获得商业销售的溴前体物质，用于连续临床使用^< 11bb0 C-DHA，我们询问了几家制药公司。然而，到目前为止，还无法从任何公司获得该协议。2、由于实验设施的一些限制，在这两年的时间里，不能使用猴子等大型动物进行脑成像实验，将这种成像方法应用于人类研究。这两家公司将在明年继续尝试。少

We have completed the following matters in these two year term under the Grant-in-Aid for Developmental Scientific Research.1, Precursor in the course of the radio synthesis of ^<11>C labeled docosahexaenoate (^<11>C-DHA), all-z-1-bromo-3, 6, 9, 12, 15, 18-heneicosahexaene, were successfully synthesized from commercially available ethyl docosahexaenoate. 2, The ^<11>C-DHA was synthesized with two step procedure through the reaction of bromo substances with metal lithium and the trapping of ^<11>CO_2 in the reaction vessel. 3, The organ distribution of radioactivity after 20 min. bolus injection of ^<11>C-DHA were examined. Although the uptake of brain was less than 1% dose/g tissue, brain images using autoradiography were successfully obtained. 4, The distribution of radioactivity in the brain lipid fraction were examined by extracting brain lipid and with autoradiographic TLC analysis. It revealed that the radioactivity mainly exist in the brain phospholipid fraction, especially in th … More e phosphatidylethanolamine fraction. 5, The uptake of ^<11>C-DHA with and without systemic treatment with cholinergic agonist arecoline were examined. The uptake ratio of ^<11>C-DHA into cerebral cortex, which is rich in the muscarinic cholinergic receptor, showed increase by cholinergic treatment. However, that into cerebellum, which lacks muscarinic cholinergic receptor did not. 6, The uptake of ^<11>C-DHA into periinfarct area of rat's unilateral MCA occlusion model showed increase 1 hour after occlusion, which may indicate the increased release of sn-2 position fatty acids coupled with the activation of phospholipase A2.7, The experiment to examine the alteration of the turnover of sn-2 position fatty acids using brain trauma model of rats were started.The things which are remained to be completed are as follows. 1, In order to obtain the commercially distributed bromoprecursor substances for the continuous clinical usage of ^<11>C-DHA, we asked several pharmaceutical companies. However, the agreement could not be obtained from any companies by now. 2, Brain imaging experiment using larger animal such as monkey to proceed this imaging method into human study could not be performed in these two year period because of several limitation in experimental facilities. These two will continuously tried in next year. Less