生物正交點擊反應具有高選擇性、良好的反應速率和生物相容性且不會去干擾生物體內的反應，在生物化學和藥物開發領域中有著相當廣泛的應用。生物正交點擊反應，例如: 疊氮-炔烴環加成反應 (Strain-Promoted Azide-Alkyne Cycloaddition, SPAAC)、逆電子需求的狄爾斯-阿爾德反應 (Inverse-Electron Demand Diels-Alder Reaction, IEDDA)，其反應速率快的特性適用於短半衰期放射性核種的標記，在發展新藥及醫學成像探針的開發上扮演著重要的角色。
近年來，來自螢光素生合成的2-氰基苯並噻唑 (Cyanobenzothiazole, CBT)/1,2-胺基硫醇 (1,2-aminothiol)點擊反應受到了關注，其被認為是一種新的生物正交反應。該反應利用氰基和1,2-胺基硫醇基團之間的快速縮合反應形成穩定的噻唑環。CBT/1,2-胺基硫醇點擊反應已被直接應用於標記蛋白質、碳水化合物、脂質和其他生物分子，用於分子成像研究。然而，儘管有許多基於CBT的研究，但其他CBT衍生物尚未研究，CBT基團結構修改的影響仍然有限。這裡我們報告了一系列CBT衍生物的合成與動力學研究，將這些類似物的結構作為CBT替代物進行點擊反應。
由於我們對新成像探針標記技術的開發感興趣，衍生物合成後，需要展示其與胺基硫醇反應的放射標記能力，合成了類似物與金屬螯合劑 (DOTA)鍵結的產物，並與各種肽耦合後再將鎵標記於產物。我們預計從我們所合的產物中，找到一個反應速率最優良的，進而使其點擊化學反應為成像探針的開發提供一個新方向。

Bioorthogonal click reactions have been widely studied in the field of biochemistry and drug development due to their high selectivity, good reaction rate, and biocompatibility without interfering with biological metabolism. These bio-orthogonal click reactions, such as strain-promoted azide-alkyne cycloaddition (SPAAC) and inverse-electron demand Diels-Alder reaction (IEDDA), are particularly suitable for labeling short-lived radioactive isotopes. Therefore, they play an important role in many aspects of drug discovery and nuclear medicine imaging probe development.
In recent years, the click reaction between Cyanobenzothiazole (CBT) derived from luciferin biosynthesis and 1,2-aminothiol has attracted attention as a new bioorthogonal reaction. This reaction utilizes the fast condensation reaction between the cyano and 1,2-aminothiol groups to form a stable thiazole ring. The CBT/1,2-aminothiol click reaction has been directly applied to label proteins, carbohydrates, lipids, and other biomolecules for molecular imaging studies. However, despite numerous studies based on CBT, other CBT derivatives have not been studied, and the effects of structural modifications on the CBT group are still limited. Here, we report the synthesis and kinetic studies of a series of CBT analogs, which were used as CBT substitutes for click reactions.
Since we are interested in the development of new imaging probe labeling techniques, after synthesizing a series of analogs, we needed to demonstrate their radiolabeling ability with amino thiols. We synthesized products that were linked to a metal chelator (DOTA) and coupled with various peptides before gallium labeling. We expect to find the analog with the best reaction rate among the products we synthesized, which will provide a new direction for the development of click chemistry reactions as imaging probes.

謝誌 i
中文摘要 ii
Abstract iv
目錄 vi
Scheme 目錄 viii
Figure 目錄 ix
Table 目錄 x
壹、 前言 1
一、 文獻討論 1
1.1 點擊化學 1
1.2 生物正交點擊反應 1
1.3 氰基苯並噻唑/1,2-胺基硫醇點擊反應 5
1.4 氰基苯並噻唑 6
1.5 放射性核種 13
1.6 直接標記法 15
1.7 兩步標記法 15
二、 研究動機 17
貳、 結果與討論 19
第一部分、 開發氰基吡啶咪唑/1,2-胺基硫醇點擊反應 19
1.1 氰基苯並噻唑的合成 19
1.2 氰基苯並咪唑的合成 21
1.3 氰基吡啶咪唑的合成 24
1.4 氰基吡啶咪唑/1,2-胺基硫醇點擊反應的選擇性 27
1.5 氰基吡啶咪唑的穩定性 29
1.6 標記測試 31
1.7 氰基吡啶咪唑與胜肽結合 34
第二部分、 開發氰基吡啶噻唑/1,2-胺基硫醇點擊反應 37
2.1 氰基吡啶噻唑的合成 37
2.2 CPT與DOTA偶合 40
第三部分、 動力學測試 42
參、 結論 45
肆、 實驗步驟 47
一、 實驗儀器 47
二、 實驗方法 48
伍、 參考文獻 77
陸、 化合物之1H、13C光譜 83
柒、 化合物之質譜 121

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