3B-O1-1050（3P-19） PDF
イメージング質量分析によるPET診断用低酸素イメージング剤“FMISO”の腫瘍内集積機序の解明
[18F]fluoromisonidazole (FMISO) is a positron emission tomography (PET) probe widely used for detecting hypoxia. FMISO has been supposed to undergo reductive metabolism on its 2-nitroimidazole-moiety and then to be trapped in hypoxic cells. However, its accumulation mechanism is still unclear in detail, due to the difficulty to estimate by conventional radioisotope analysis Mass spectrometry, especially imaging mass spectrometry can distinguish the distribution patterns of the administrated agent and its metabolites. Thus, to reveal the mechanism of FMISO accumulation in hypoxic cells, we performed in vitro and ex vivo studies in combination with mass spectrometry. We first revealed that the glutathione conjugate of the reduced FMISO (amino-FMISO-GS) distributed specifically in the hypoxic regions of tumors. The in vitro cellular uptake study showed that the FMISO accumulation in hypoxic cells depended on the cell type. In the cells showing higher FMISO uptake, the reactive glutathione level and enzyme (GST) activity catalyzing the glutathione conjugation reaction were significantly higher, while the expression level of efflux transporter (MRP1) was significantly lower. Our study suggests that FMISO is accumulated in hypoxic cells by the process of glutathione conjugation following reductive metabolism, which depends on glutathione levels in the cells as well as hypoxic condition.