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

15R-TIC是中枢神经系统中一种新的前列环素受体(IP_2)的特异性分子探针，可防止高氧或血清剥夺诱导的海马神经元细胞凋亡。该化合物对沙土鼠短暂性脑缺血后迟发性神经元死亡有明显的神经保护作用。对这一效应的精确构效关系研究可能导致15-脱氧-TIC的发展，15-脱氧-TIC是15R-TIC的结构简化类似物，具有更高的活性以及化学和代谢稳定性。静脉注射(静脉注射)大鼠脑缺血后24小时给予15-脱氧-TIC甲酯(0.03 mg/kg)可显著减少脑损伤体积的35%。为了将TIC及其类似物应用于正电子发射断层扫描研究，设计了快速Stille型芳香族甲基化反应，建立了…的高重复性合成更多适用于人体水平的具有足够放射性的标记TIC衍生物。使用15R-[11&gt；C]TIC甲酯的PET实验完成了活体大鼠和恒河猴大脑中受体的成像。用上述方法合成了15-脱氧-[11&gt；C]TIC甲酯，并将其应用于大鼠和恒河猴的PET实验。示踪分子在大鼠脑中的蓄积与大鼠相似，但恒河猴的蓄积较弱，表明15R-TIC甲酯和15-脱氧TIC甲酯之间的血脑屏障(BBB)通透性存在种属特异性。药物转运蛋白预计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，我们以药物转运蛋白之一的GS-X泵为研究对象，成功地合成了一些具有调节GS-X泵功能的探针分子。此外，我们还发现某些烯酮类前列腺素可以抑制氧化应激诱导的神经细胞死亡。通过合理的分子设计，初步筛选出一种活性强、毒性低的类似物，命名为NEPP11。较少

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