Novel PET Tracers for Prostaglandin Receptors

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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.