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.

人工前列腺素 15R-MTC 选择性结合中枢神经系统中表达的新型前列环素受体 IP_2。为了利用正电子发射断层扫描(PET)分析IP_2受体的功能，设计合成了基于15R-T1C的PET示踪剂和特异性分子探针。首先，详细阐述了使用配位不饱和钯(O)络合物的快速甲基化反应，用于用11 C-CH 3 合成PET示踪剂。该反应已成功应用于利用乌普萨拉大学PET中心的合成装置合成11C标记的15fl-TIC甲酯。然后使用示踪剂通过 PET 清晰地观察到 IP_2 在活恒河猴大脑中的具体位置。此外，开发了用于快速甲基化的逐步操作，其允许高度可重复地合成总放射性约为1的11C-15R-TIC甲酯。 2.5 GBq。该协议能够提供有效的放射性 PET 示踪剂，适用于研究人脑，其体积是猴子的十倍。还研究了15R-TIC 的生物学功能。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凋亡细胞死亡，并在体内减少局灶性脑缺血大鼠模型中的脑损伤体积。此外，还设计并合成了 15R-TIC 的结构简化类似物 15-deoxy-TIC。 15-deoxy-TIC与IP_2受体的结合亲和力是15R-TIC的10倍以上，低剂量的化合物可以完全阻止海马神经元的凋亡。 15-脱氧-TIC甲酯可通过血脑屏障有效到达大脑，在大鼠缺血模型中显示出较强的脑保护活性。 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。