Development of Radioiodinated Glucose Derivative to Evaluate Energy Metabolism in vivo with SPECT

为了维持生物器官内的动态平衡，葡萄糖代谢是产生能量的必要生化反应，即三磷酸腺苷。核医学诊断以糖代谢的某些反应速率参数为指标，可用于确定病变器官的生理生化变化。评价糖代谢参数是核医学诊断的重要内容。在此基础上，设计、合成了一种新型的放射性碘化葡萄糖衍生物，并对其进行了体内外评价。合成了N-(对碘苯乙基)氨基葡萄糖(IBGA)，并观察到该化合物在体外对己糖激酶的竞争性抑制作用。然后通过碘-碘交换反应将其标记为I-125，以评价其体内特性。在小鼠体内的生物分布研究表明，尽管大脑对放射性的摄取较低，但心脏对放射性的摄取较高。虽然这种心脏高摄取的机制尚不清楚，但已经表明，可以有趣地获得与葡萄糖代谢有关的心脏图像。另一方面，研究表明葡萄糖的第二位是引入某些基团以抑制己糖激酶反应的合适位置。为了评价引入基团大小对缓蚀活性的影响，合成了2-硫代葡萄糖(2-TG)作为模型化合物。硫醇在碱性条件下易发生烷基化反应。作为初步评价，合成了C-11-甲基化2-甘油三酯，并研究了其在体内的生物分布。心脏摄取量虽低于葡萄糖摄取量，但仍呈累积型时间活动曲线。这一结果表明，本研究设计的人工葡萄糖类似物具有临床应用的可能性。

In order to maintain homeostasis in the living organ, glucose metabolism is an essential biochemical reaction to produce energy, ATP. Nuclear medicine diagnosis is useful to determine the physiological and biochemical changes in diseased organs using some reaction rate parameters of glucose metabolism as indices. Evaluation of glucose metabolism parameters is an important point for nuclear medicine diagnosis. On these basis, a new radioiodinated glucose derivative was designed, synthesized and evaluated in vitro and in vivo.N-(p-iodophenethyl)-glucosamine (IBGA) was synthesized and it was observed this compound inhibits competitively hexokinase reaction in vitro. Then it was radiolabeled with I-125 by iodine-iodine exchange reaction to evaluate in vivo characteristics. In vivo biodistribution study in mice showed a high uptake of the radioactivity in the heart in spite of low uptake in the brain. Although this mechanism of high uptake in the heart is still unclear, it was indicated that heart images related to glucose metabolism can be obtained interestingly. On the other hand ,it was shown that the second position of the glucose is proper position for introduction of some groups to inhibit hexokinase reaction. To evaluate the effect of the introduced group size on the inhibition reactivity, 2-thioglucose (2-TG) was synthesized as a model compound. Thiol group is easily alkylated in alkaline condition. As a preliminary evaluation, C-11-methylated 2-TG was synthesize and studied in vivo biodistribution. Although the heart uptake was lower than of glucose, an accumulating type time activity curve was obtained. This result indicates probability of clinical usefulness of the artificial glucose analogues designed by this research.