Development of Anti-apoptoic Drugs for Neuronal Cells and Distribution Analysis in Brain

15R-TIC是一种新型前列环素受体（IP_2）在中枢神经系统中的特异性分子探针，可预防高氧气氛或血清剥夺诱导的海马神经元凋亡细胞死亡。通过侧脑室直接输注，该化合物对沙鼠短暂性缺血后海马CA1神经元的延迟性神经元死亡也有明显的神经保护作用。对这一效应进行精确的构效关系研究有助于开发15-脱氧- tic，这是一种结构简化的15R-TIC类似物，具有更高的活性和化学代谢稳定性。15-脱氧- tic甲酯（0.03 mg/kg）在大鼠模型缺血24小时后显著减少35%的脑损伤体积。为了将TIC及其类似物应用于正电子发射断层扫描（PET）研究，设计了快速stille型芳香甲基化反应，建立了高重复性合成…More ^<11> c标记的TIC衍生物，具有足够的放射性，适用于人体水平。用15R-[^< 11b> C]TIC甲酯进行PET实验，完成了活体大鼠和恒河猴脑内受体的成像。15-Deoxy-[^<11>C]TIC甲酯也按照上述方案合成，并应用于大鼠和恒河猴的PET实验。15R-TIC甲酯和15-脱氧- tic甲酯对血脑屏障（BBB）通透性的影响存在物种特异性，但在恒河猴中较弱。预计药物转运蛋白负责调节亲脂分子通过血脑屏障的通道。因此，转运蛋白功能的调节可能会改善亲脂性PET探针的血脑屏障通透性。在本研究中，我们将重点放在了药物转运蛋白之一的GS-X泵上，并成功合成了一些对GS-X泵功能具有有效调节活性的探针分子。此外，我们发现某些烯酮型前列腺素可以抑制氧化应激诱导的神经元细胞死亡。通过合理的分子设计，初步制备出活性增强、毒性较低的有效类似物NEPP11。少

15R-TIC, a specific molecular probe for a novel prostacyclin receptor (IP_2) in the central nervous system, prevents the apoptotic cell death of hippocampal neurons induced under high oxygen atmosphere or serum deprivation. The compound also exhibited potent neuroprotective effect on delayed neuronal death of hippocampal CA1 neurons following transient ischemia in gerbils via direct infusion to lateral ventricle. Precise structure-activity relation ship study on this effect could lead to the development of 15-deoxy-TIC, a structurally simplified analog of 15R-TIC with enhanced activity and chemical and metabolic stability. Intravenous (i.v.) administration of 15-deoxy-TIC methyl ester (0.03 mg/kg) to a rat model significantly reduced the volume of brain damage by 35% at 24-hours after ischemia. In order to apply TIC and analogs to positron emission tomography (PET) study, rapid Stille-type aromatic methylation reaction was devised, which established the highly reproducible syntheses of … More ^<11>C-labeled TIC derivatives with sufficient radioactivity applicable to the human level. The PET experiments using 15R-[^<11>C]TIC methyl ester accomplished the imaging of the receptor in the brain of living rats and rhesus monkeys. 15-Deoxy-[^<11>C]TIC methyl ester was also synthesized by the above protocol and applied to the PET experiments with rats and rhesus monkey. The similar accumulation of the tracer molecule to the rat brain was observed, but that of rhesus monkey was weaker, indicating the existence of species specificity in the blood-brain-barrier (BBB) permeability between 15R-TIC methyl ester and 15-deoxy-TIC methyl ester. Drug transporter proteins are anticipated to be responsible for the regulation of the passage of lipophilic molecules through the BBB. Thus the modulation of the transporter function can possibly improve the BBB permeability of lipophilic PET probes. In this research, we focused our attention on the GS-X pump, one of the drug transporter proteins, and succeeded in synthesizing some probe molecules with potent activity for the modulation of GS-X pump function. Additionally, we found that certain enone-type prostaglandins could suppress the neuronal cell death induced by oxidative stress. A potent analog, termed NEPP11, with enhanced activity and lower toxicity was preliminarily elaborated by rational molecular design. Less