臺灣博碩士論文加值系統

過去幾年來越來越多的證據顯示腦內的金屬離子不平衡會導致許多疾病。由於磁振造影(MRI)具有非侵入性及高解析度之優點，使磁振造影成為臨床醫療診斷上相當重要之影像工具。且磁振造影之對比劑也愈來愈被重視，各種不同功能之對比劑也漸漸被開發。在本研究中，設計並合成可偵測細胞中二價銅離子之磁振造影對比劑[Gd(HQ-DO3A)]。在銅離子存在的環境下，[Gd(HQ-DO3A)]的內層水分子數及弛緩率有顯著上升。除此之外，[Gd(HQ-DO3A)]與其他金屬離子比較對於銅離子也有良好的選擇性。另一方面，當Cu2+ 存在時，因為Cu2+會削弱quinolin之螢光，使得原先由quinolin轉移至銪金屬(Eu3+)之能量減少，進而使銪金屬(Eu3+)所發出之螢光也被削弱。由結果顯示[Gd(HQ-DO3A)]相當具有潛力可成為利用磁振造影來偵測二價銅離子之雙功能磁振造影對比劑。

Over the past few years, more and more evidence indicated that the metal ion imbalance in the brain will give rise to many diseases. Magnetic resonance imaging (MRI) is a non-invasive and high resolution technique that has become a powerful diagnostic tool in medicine. In this study, we have developed a new contrast agent [Gd(HQ-DO3A)] that can recognize Cu2+ ion in the cells. The significant increases in the relaxivity (r1) and hydration number (q) in the present of Cu2+ were observed. Moreover, the Gd3+ complex attributes excellent selectivity for Cu2+ over a choice of other metal ions. A gradual increase was shown in the signal enhancement of MR imaging upon copper ion detection. On the other hand, we observed fluorescence intensity decreased via transferring the inner system energy from qunoline ring to Eu3+ when copper was absent. These results implicate that a new MR based contrast agent can serve as a Cu2+ sensor using MR imaging.

摘要 I
Abstract II
誌謝 III
目錄 IV
圖目錄 VII
一、前言 1
1-1磁振造影成像原理 1
1-2磁振造影對比劑 2
1-3釓金屬錯合物之穩定度及弛緩率 3
1-4磁振造影對比劑之種類 5
1-4-1非專一型對比劑 5
1-4-2目標化對比劑 7
1-5各式偵測金屬離子之磁振造影對比劑 9
1-5-1鈣離子磁振造影對比劑 9
1-5-2鉀離子磁振造影對比劑 10
1-5-3鎂離子磁振造影對比劑 11
1-5-4鋅離子磁振造影對比劑 12
1-5-5鐵離子磁振造影對比劑 13
1-5-6銅離子磁振造影對比劑 14
1-6研究目的與動機 16
二、 儀器與試藥 18
2-1 儀器 (Instrumentation) 18
2-2 試藥 (reagents) 19
三、實驗方法 21
3-1製備 [Gd(HQ-DO3A)] 22
3-1-1 2-methylquinolin-8-yl benzoate (1)之合成 22
3-1-2 (bromo ethyl) quinolin-8-yl benzoate (2)之合成 22
3-1-3 1-(2-methylquinolin-8-yl benzoate)-4, 7, 10-tris(acetic acid)-1, 4, 7, 10-tetraazacyclododecane (3)之合成 23
3-1-4 釓金屬錯化合物與銪金屬錯化合物之配製 24
3-1-5高效能液相層析（HPLC）的使用方法 25
3-2 弛緩率（relaxivity）的測定 25
3-3內層水分子數之測定 26
3-4 細胞培養 26
3-5細胞毒性測試 26
3-6 細胞吞噬銅離子時間測試 27
3-7體外細胞(In vitro)之磁振造影影像之測定 27
四、結果與討論 28
4-1有機配位子合成之探討 28
4-2 弛緩率（relaxivity, r1）的研究 29
4-4內層水分子數之探討 30
4-3 選擇性探討 31
4-4 [Gd(HQ-DO3A)]與銅離子作用之螢光研究 32
4-4-1 quinolin 之螢光削弱之研究 32
4-4-2 銪金屬(Eu3+)之螢光削弱之研究 33
4-5 解離常數(Kd)之研究 34
4-5 細胞毒性之研究 35
4-6 細胞攝入[Gd(HQ-DO3A)]之時間研究 36
4-7體外細胞 (In vitro)之磁振造影影像之研究 37
五、結論 39
六、參考文獻 40
附錄 43

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