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Novel PET Tracers for Prostaglandin Receptors

前列腺素受体的新型 PET 示踪剂

基本信息

批准号：
11694143
负责人：
SUZUKI Masaaki
金额：
$ 7.87万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694143/
关键词：
PET Prostacyclin IP_2 15R-TIC 15-deoxy-TIC apoptosis brain アポトーシス IP_2 ^<11>C[CH_3]光親和性標識神経突起伸展促進 PET法 in vivo 制癌性PG

项目摘要

An artificial prostaglandin, 15R-MTC, selectively binds to a novel prostacyclin receptor, IP_2, expressed in the central nervous system. In order to analyze function of IP_2 receptor by positron emission tomography ( PET ), design and synthesis of PET tracers and specific molecular probes based on 15R-T1C were conducted. First, rapid methylation reaction using a coordinatively unsaturated palladium ( O ) complex was elaborated for the synthesis of PET tracers with ^<11>C-CH3. This reaction was successfully applied to the synthesis of ^<11>C-labeled 15fl-TIC methyl ester with a synthetic apparatus at Uppsala University PET Centre. Specific location of the IP_2 in the brain of a living rhesus monkey was then clearly visualized by PET using the tracer. Furthermore, stepwise operation for the rapid methylation was developed, which allowed for the highly reproducible synthesis of ^<11>C-15R-TIC methyl ester with total radioactivity of ca. 2.5 GBq. This protocol enables to supply efficient radioactive PET tracers applicable to the study of human brains with volumes ten-times those of monkeys. Biological function of 15R-TIC was also investigated. Thus the compound was found to prevent the apoptotic cell death of hippocampal neurons induced under high oxygen atmosphere or serum deprivation in vitro, and in vivo, reduce the volume of brain damage in a rat model of focal cerebral ischemia. Additionally, 15-deoxy-TIC, a structurally simplified analog of 15R-TIC, was designed and synthesized. The binding affinity of 15-deoxy-TIC to IP_2 receptor was more than ten-times that of 15R-TIC, and the apoptotic death of hippocampal neurons was completely prevented by the low dose of the compound. The methyl ester of 15-deoxy-TIC could pass through the BBB to reach the brain efficiently, and revealed strong activity for brain protection in the rat model of ischemia. The synthesis of ^<11>C-labeled 15-deoxy-TIC methyl ester was also accomplished by the stepwise methylation protocol.

人工合成的前列腺素15 R-MTC可与中枢神经系统表达的新型前列环素受体IP_2选择性结合。为了利用正电子发射断层扫描（PET）技术分析IP_2受体的功能，设计并合成了基于15 R-T1 C的PET示踪剂和特异性分子探针。首先，阐述了使用配位不饱和钯（O）络合物的快速甲基化反应用于合成具有^C-CH 3的PET示踪剂<11>。该反应成功地应用于<11>Uppsala大学PET中心的合成装置合成15 C-标记的15 fl-TIC甲酯。然后用PET显像技术观察到IP_2在活体恒河猴脑内的具体位置。此外，开发了用于快速甲基化的分步操作，其允许高度可重复地合成<11>总放射性为约1000的^ C-15 R-TIC甲酯。2.5 GBq。该协议能够提供有效的放射性PET示踪剂，适用于研究人类大脑的体积是猴子的十倍。并对15 R-TIC的生物学功能进行了初步研究。因此，发现该化合物在体外可防止在高氧气氛或血清剥夺下诱导的海马神经元的凋亡性细胞死亡，并且在体内可减少局灶性脑缺血大鼠模型中的脑损伤体积。此外，15-脱氧-TIC，一种结构简化的类似物的15-R-TIC，被设计和合成。15-deoxy-TIC与IP_2受体的结合亲和力是15 R-TIC的10倍以上，低剂量的15-deoxy-TIC可完全阻止海马神经元的凋亡。15-deoxy-TIC甲酯能有效地通过血脑屏障到达脑组织，对缺血性脑损伤大鼠具有较强的脑保护作用。15 <11>C标记的15-脱氧-TIC甲酯的合成也通过逐步甲基化方案完成。