臺灣博碩士論文加值系統

雙官能基螯合劑乃放射性金屬核種標誌月生 月太 之樞紐，其扮演偶合月生 月太 及螯合放射性金屬離子的關鍵角色，月生 月太 偶合效率及放射性金屬的標誌效率皆決定於所選擇使用之雙官能基螯合劑，亦關係最後製成之放射性金屬標誌月生 月太 之穩定度、活性及生物體內分佈。本論文主要目的在於合成一屬二胺二硫之雙官能基螯合劑(Diaminodithiol, DADT)─硫丙酯(Thiolactone) ，並嘗試以苯胺(Benzylamine) 模擬月生月太鏈，試驗此雙官能基螯合劑偶合月生月太之可能性，再以鎝99m標誌製備成鎝99m─硫丙酯─苯胺藕合物，並測試其放化及生物特性。雙官能基螯合劑，硫丙酯之合成共需八個步驟，實驗條件均逐一確立完成，硫丙酯─苯胺藕合物以NMR光譜予以鑑定確認，鎝99m之標誌主要利用不同pH 值的緩衝溶液，以酒石酸亞錫(Stannous tartrate)還原過鎝酸根離子(99mTcO4-)，形成鎝氧核離子99mTcO3+再與硫丙酯之二胺二硫配位結合而得。放射化學特性的鑑定係利用電泳動分析法、溶劑萃取法及薄層分析法，以探討鎝99m─硫丙酯之標誌效率、親脂性大小、電性及穩定性。最後利用小鼠(C3H/HeN)行活動物器官分佈試驗，觀察鎝99m─硫丙酯─苯胺之藕合物於不同時間點在小鼠體內的生物分佈。
研究結果顯示鎝99m─硫丙酯─苯胺之標誌效率高(~90%)，呈親脂性、帶一正電荷且穩定性佳。經動物試驗證實具有快速的血液清除效率，主要經由肝膽道代謝而終由腸道排泄。

Bifunction chelating agents play an important role in conjugation of radionuclides with peptides and radionuclides. The coupling efficiency with peptides and labeling yield with radionuclides are determined by the choice of bifunctional chelating agents, and further related to the in vivo stability and biodistribution of the eventual radiolebeled conjugates. The main work of this study included synthesis of diaminothiol bifunctional chealting agent─thiolactone, and simulation of binding peptide with thiolactone by using benylamine as a model to assess the feasibility of coupling the bifunctional chelating agent with peptide. Thereafter, the coupling product was labeled by 99mTc to produce 99mTc—thiolactone-benzylamine conjugate. The radiochemical and biological characteristics of the resultant radiolabeled conjugate were examined.
The synthesis of the bifunctional chelating agent─thiolactone proceeded with 9 steps and all the conditions for the first step to the last step were confirmed. The structure of thiolactone and the couple with benzylamine were identified by NMR. Labeling the thioactone─benzylamine couple with 99mTc was carried out by adding 99mTcO4- in the presence of saturated stannous tartrate solution under different pH buffers, where 99mTcO4- was reduced to 99mTcO3+ and simultaneously bound to thiolactone. The labeling efficiency, lipophilicity and stability of 99mTc-thiolactone─benzylamine conjugate were determined by electrophoresis, solvent extraction and thin layer chromatography. Finally, the pharmacological kinetics and biological distribution of the 99mTc labeled conjugate was studied using the mice, C3H/HeN as an animal model.
According to the results, the 99mTc-thioactone─benzylamine conjugate was characterized to be of high labeling yield (~90%), neutrality, high lipophilicity, and good stability. The animal trial revealed that this 99mTc labeled conjugate had a rapid blood clearance rate, and excreted mainly via hepatobiliary metabolism.

中文摘要………………………………………………..I
英文摘要………………………………………………..III
謝誌………………………………………………..III
目錄………………………………………………..VI
表目錄………………………………………………..VIII
圖目錄………………………………………………..XI
第一章、前言……………………………………………1
1. 核醫藥物…………………………………………1
2. 鎝99m之化學…………………………………………1
3. 鎝99m標誌之腦造影藥物 …………………………….2
4. 鎝99m-雙官能基-月生 月太 藕合錯合物………………….4
第二章、特性分析原理……………………………………….7
1. 溶劑萃取法……………………………………….7
2. 電泳動分析法……………………………………….8
3. 薄層分析法……………………………………….9
4. X光繞射與晶體解析結構原理……………………...10
第三章、實驗部分…………………………………………….12
1. 實驗藥品…………………………………………12
2. 實驗儀器…………………………………………13
3. 配位子的合成…………………………………………15
4. 鎝99m標誌二胺二硫錯合物及硫丙酯-苯胺偶合物22
5. 鎝99m標誌化合物之放化特性分析………………….22
6. 鎝99m標誌化合物之動物實驗……………………..23
第四章、結果與討論…………………………………25
1. 雙官能基螯合劑-硫丙酯及其苯胺藕合物之合成與探討 ……………………………………………………….25
2. 二亞胺二硫化合物(DIDS)之晶體結構解析…………25
3. 99mTc-二胺二硫錯合物及99mTc-硫丙酯-苯胺藕合物的化學特性探討………………………………………………..26
4. 99mTc-二胺二硫錯合物及99mTc-硫丙酯-苯胺藕合物的生物特性探討………………………………………………..30
第五章、未來展望………………………………….33
第六章、參考文獻…………………………………71

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