Novel PET Tracers for Prostaglandin Receptors

人工前列腺素15R-MTC选择性结合在中枢神经系统中表达的新型前列腺素受体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，设计和合成了基于15R-T1C的PET示踪剂和特异性分子探针。首先，利用配位不饱和钯(O)配合物进行快速甲基化反应，合成了^<11>C-CH3的PET示踪剂。该反应在乌普萨拉大学PET中心的合成装置上成功地应用于^< 11b> c标记的15fl-TIC甲酯的合成。利用示踪剂，利用PET清晰地观察了IP_2在活体恒河猴大脑中的具体位置。此外，开发了快速甲基化的分步操作，该操作允许高重复性合成^<11>C-15R-TIC甲酯，总放射性约为2.5 GBq。该方案能够提供有效的放射性PET示踪剂，适用于人类大脑的研究，其体积是猴子的十倍。研究了15R-TIC的生物学功能。由此可见，该化合物在体外可防止高氧或血清剥夺诱导的海马神经元凋亡细胞死亡，在体内可减轻局灶性脑缺血大鼠模型的脑损伤体积。设计并合成了15R-TIC的结构简化类似物15-deoxy-TIC。15-脱氧- tic对IP_2受体的结合亲和力是15R-TIC的10倍以上，低剂量可完全阻止海马神经元的凋亡死亡。15-脱氧tic的甲酯能通过血脑屏障有效到达脑，在缺血大鼠模型中显示出较强的脑保护活性。^<11> c标记的15-脱氧- tic甲酯也通过逐步甲基化方案完成了合成。

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.