Novel PET Tracers for Prostaglandin Receptors

人工前列腺素15R-MTC选择性地与中枢神经系统表达的新型前列环素受体IP_2结合。为了用正电子发射断层扫描(PET)技术分析IP2受体的功能，设计并合成了基于15R-T1C的正电子发射断层扫描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，以合成与^&lt；11&gt；C-CH3的PET示踪剂。该反应已在乌普萨拉大学PET中心的合成装置上成功地应用于~&lt；11&gt；C标记的15fl-TIC甲酯的合成。然后，使用示踪剂的正电子发射计算机断层扫描(PET)清楚地显示了IP_2在活恒河猴脑中的具体位置。此外，还开发了快速甲基化的分步操作，使得^&lt；11&gt；C-15R-TIC甲酯的合成具有很高的重复性，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，适用于对人脑的研究，体积是猴子的十倍。并对15R-TIC的生物学功能进行了研究。因此，该化合物在体外可防止高氧气氛或血清剥夺诱导的海马神经元凋亡，并在体内缩小大鼠局灶性脑缺血模型的脑损伤体积。此外，还设计合成了结构简化的15R-TIC类似物--15-脱氧TIC。15-脱氧-TIC与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。15-脱氧-TIC的甲酯能有效地通过血脑屏障到达脑内，对大鼠脑缺血模型具有较强的脑保护作用。用分步甲基化的方法合成了~&lt；11&gt；C标记的15-脱氧-TIC甲酯。

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.