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

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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