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研究生:林宏銘
研究生(外文):Hung Ming Lin
論文名稱:TBZ新衍生物結合第二型囊泡單胺類轉運體之研究
論文名稱(外文):Evaluation of New Derivatives of TBZ Targeting Vesicular Monoamine Transporter 2
指導教授:魏孝萍李仁盛李仁盛引用關係
指導教授(外文):S. P. WeyR. S. Lee
學位類別:碩士
校院名稱:長庚大學
系所名稱:醫學影像暨放射科學系
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
論文頁數:106
中文關鍵詞:第二型囊泡單胺類轉運結合實驗
外文關鍵詞:vesicular monoamine transporter 2binding assay
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大腦神經細胞藉由釋放神經傳導物質達成神經訊號的傳遞。第二型囊泡單胺類轉運體 (VMAT2) 負責調控單胺類神經傳導物質在神經細胞中的囊泡之貯存與釋放。由於VMAT2存在單胺類神經細胞中,一些神經退化性疾病 (例如帕金森氏病) 可以藉由量化VMAT2的分布加以檢測。此外,由於VMAT2也分布於胰臟胰島的  細胞,藉由量化胰臟VMAT2的分佈可以研究  細胞功能與糖尿病的診斷。近年來以放射性核種標幟TBZ衍生物,例如碳-11-TBZ、碳-11-DTBZ、氟-18-FE-DTBZ及氟-18-FP-DTBZ,被研發作為VMAT2造影劑。這些能與VMAT2特異性結合的TBZ衍生物第3號碳連接的官能基都是異丙基。為探討第3號碳鍵結直鏈烷基的TBZ衍生物是否具有特異性結合VMAT2的生物性質,本研究以TBZ結構骨幹合成一系列TBZ-直鏈烷基衍生物,包括鍵結甲基的TBZ-M、鍵結乙基的TBZ-E,以及鍵結正丁基 (n-butyl) 的TBZ-B,並且分別評估這些衍生物競爭氟-18-FP-(+)-DTBZ與大鼠紋狀體組織均質中的VMAT2的特異性結合的程度。研究結果顯示鍵結直鏈烷基的三種TBZ衍生物對紋狀體組織均質之結合能力不佳 (Ki值均大於10,000 nM),明顯不如鍵結異丙基的FP-TBZ (平均Ki值0.44 nM )。
The release of neurotransmitters by cerebral nerve cells plays a key mechanism in the transmission of nerve signals. The second type of vesicular monoamine transporter (VMAT2), a vesicle membrane protein, is responsible for the storage and the release of monoamine neurotransmitter through the vesicles in nerve cells. Since the presence of VMAT2 in monoamine nerve cells, some neurodegenerative diseases, such as Parkinease`s disease, may be diagnosed by quantitative detection of VMAT2 distribution in cerebral neurons. In addition, VMAT2 also distributes in the pancreatic islet  cells, quantifation of VMAT2 distribution in the pancrease may be helpful to study pancreatic  cell function and for diabetes diagnosis. For imaging VMAT2 with PET, several radiolabeled tetrabenazine (TBZ) derivatives, such as C-11-TBZ, C-11-dihydrotetrabenazine (DTBZ), F-18-FE-DTBZ and F-18-FP-DTBZ, were recently developed. Among these known TBZ analogs, an isopropyl group attached to the carbon No. 3 of TBZ/DTBZ backbone is common. The objective of this study was to evaluate if TBZ derivatives with straight-chain alkyl group on the carbon No. 3 possess specific binding affinity to VMAT2. A series of straight-chain alkyl derivatives, including TBZ-M, TBZ-E and TBZ-B were prepared and the competition of these derivatives against F-18-FP-(+)-DTBZ were evaluated in the rat striatum homogenates ( VMAT2-enriched region ). The results showed that the binding of three straight-chain alkyl derivatives of TBZ prepared bound poorly to VMAT2 sites in the striatum homogeneous (Ki values were greater than 10,000 nM ), far inferior to the isopropyl bond derivative, FP-TBZ ( Ki value of 0.44 nM ).
指導教授推薦書…………………………………………………………ii
口試委員審定書………………………………………………………...iii
國家圖書館授權書………………………………………………….......iv
長庚大學博碩士紙本論文著作授權書…………………………………v
誌謝……………………………………………………………………...vi
中文摘要……………………………………………………………….viii
英文摘要………………………………………………………………...ix
目錄……………………………………………………………………....x
第一章 前言及文獻探討………………………………………………..1
1.1囊泡單胺類轉運體 (Vesicular monoamine transporter; VMAT)……1
1.1.1第一型囊泡單胺類轉運體 (VMAT1)……….…………………….1
1.1.2第二型囊泡單胺類轉運體 (VMAT2)……………………………..2
1.2 第二型單胺類囊泡轉運體的相關抑制劑………………………….4
1.2.1 Reserpine (蛇木鹼)………………………………………………...4
1.2.2 Tetrabenazine (TBZ)………………………………………………..4
1.3 第二型單胺類囊泡轉運體造影藥物的發展……………………….5
1.3.1 腦神經診斷的應用………………………………………………..5
1.3.2 胰臟胰島  細胞偵測的應用……………………………………6
1.4 氟-18-FP-(+)-DTBZ…………………………………………………7
1.5 論文主旨……………………………………………...……………..9
第二章 實驗材料與方法………………………………………………10
2.1 藥品與材料………………………………………………………...10
2.2 儀器與設備………………………………………………………...12
2.3 實驗動物…………………………………………………………...14
2.4 實驗方法…………………………………………………………...15
2.4.1化學合成…………………………………………………………..15
2.4.1.1 4-(Dimethylamino)-3-methylbutan-one (TBZ-M衍生物前驅物) 之合成…………………………………………………………15
2.4.1.2 9,10-Dimethoxy-3-methyl-3,4,6,7-tetrahydro-1H-pyrido
[2,1-]isoquinolin-2(11bH)-one (TBZ-M衍生物) 之合成…..16
2.4.1.3 3-(Dimethylamino-methyl)-pentan-2-one (TBZ-E衍生物前驅物) 之合成…………………………………………………………19
2.4.1.4 3-Ethyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-]
isoquinolin-2(11bH)-one (TBZ-E衍生物) 之合成…………...21
2.4.1.5 3-Dimethylaminomethyl-heptan-2-one (TBZ-B衍生物前驅物)之合成…………………………………………………………22
2.4.1.6 2-Butyl-6,7-dimethoxy-1,2,4,4a,10,10a-hexahydro
-phenanthren-3(9H)-one (TBZ-B衍生物) 之合成…………..……23
2.5 競爭結合試驗 (Competition binding assay)………………………25
2.5.1 大鼠腦紋狀體取樣及均質化組織樣品製備……………………25
2.5.2 FP-(+)-DTBZ與氟-18-FP-(+)-DTBZ在大鼠腦紋狀體組織均質之競爭結合試驗…………………………………………………26
2.5.3 氟-18-FP-(+)-DTBZ與TBZ衍生物在大鼠腦紋狀體組織均質之競爭結合試驗……………………………………………………29
2.5.4 大鼠腦紋狀體均質蛋白質定量…………………………………31
第三章 結果與討論……………………………………………………33
3.1化學合成…………………………………………………………….33
3.1.1 4-(Dimethylamino)-3-methylbutan-one (TBZ-M衍生物前驅物) 之合成……………………………………………………………33
3.1.2 9,10-Dimethoxy-3-methyl-3,4,6,7-tetrahydro-1H-pyrido[2,1-]
isoquinolin-2(11bH)-one (TBZ-M衍生物) 之合成…………….34
3.1.3 3-(Dimethylamino-methyl)-pentan-2-one (TBZ-E衍生物前驅物) 之合成……………………………………………………………35
3.1.4 3-Ethyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-]
isoquinolin-2(11bH)-one (TBZ-E衍生物) 之合成………...……36
3.1.5 3-Dimethylaminomethyl-heptan-2-one (TBZ-B衍生物前驅物)之合成………………………………………………………………38
3.1.6 2-Butyl-6,7-dimethoxy-1,2,4,4a,10,10a-hexahydrophenanthren
-3(9H)-one (TBZ-B衍生物) 之合成……………………………39
3.2 競爭結合試驗 (Competition binding assay)…………………..…41
3.2.1 FP-(+)-DTBZ與氟-18-FP-(+)-DTBZ在大鼠腦紋狀體組織均質之競爭結合試驗………………………………………………...41
3.2.2 TBZ-M衍生物與氟-18-FP-(+)-DTBZ在大鼠腦紋狀體組織均質之競爭試驗………………………………………………………41
3.2.3 TBZ-E衍生物與氟-18-FP-(+)-DTBZ在大鼠腦紋狀體組織均質之競爭試驗……………………………………………………..42
3.2.4 氟-18-FP-(+)-DTBZ與TBZ-B衍生物在大鼠腦紋狀體組織均質之競爭試驗………………………………………………………43
3.3 討論………………………………………………...………………44
第四章 結論與未來展望………………………………………………47
4.1結論………………………………………………………………….47
4.2 未來展望…………………………………………...………………48
參考文獻………………………………………………………………..49
附圖……………………………………………………………………..58
圖1-1. VMAT結構圖。….……………………………………………….58
圖1-2. 人類VMAT1的胺基酸序列和二維結構的推測圖。…………58
圖1-3. 多巴胺在神經元間的傳遞。…………………………………...59
圖1-4. Reserpine結構式。………………………………………………59
圖1-5. Tetrabenazine (TBZ)結構式。…………………………………...60
圖1-6. 11C- (+)-DTBZ結構式。…………………………………………60
圖1-7. 18F-FP-(+)-DTBZ結構式。……………………………………...60
圖1-8. TBZ-M、TBZ-E、TBZ-B衍生物結構圖。TBZ-M的R為-CH3,TBZ-E的R為-CH2CH3,TBZ-B的R為-(CH2)3CH3。………………….61
圖2-1. TBZ衍生物合成總流程圖。……………………………………62
圖2-2. TBZ-M衍生物前驅物4-(dimethylamino)-3-methylbutan-one合成流程圖。………………………………………………………………63
圖2-3. TBZ-M衍生物9,10-dimethoxy-3-methyl-3,4,6,7-tetrahydro-1H-
pyrido[2,1-] isoquinolin-2(11bH)-one合成流程圖。………………….63
圖2-4. TBZ-E衍生物前驅物3-(dimethylamino-methyl)-pentan-2-one合成流程圖。………………………………………………………………63
圖2-5. TBZ-E衍生物3-ethyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-
pyrido[2,1-]isoquinolin-2(11bH)-one的合成流程圖。………………..64
圖2-6. TBZ-B衍生物前驅物3-dimethylaminomethyl-heptan-2-one的合成流程圖。………………………………………………………………64
圖2-7. TBZ-B衍生物2-butyl-6,7-dimethoxy-1,2,4,4a,10,10a-hexahydro-
phenanthren-3(9H)-one的合成流程圖。………………………………..64
圖2-8. 腦組織均質結合試驗實驗流程圖。………………………….65
圖2-9. Brandel 24孔harvester。…………………………………………………………..66
圖2-10. 加馬計數器。………………………………………………….66
圖3-1. TBZ-M衍生物前驅物之400 MHz氫-1核磁共振圖譜。……...67
圖3-2. TBZ-M衍生物紫外光吸收光譜圖。…………………………...67
圖3-3. 逆相HPLC分析TBZ-M衍生物之紫外光吸收圖譜。………….68
圖3-4. Chiral HPLC分析TBZ-M衍生物之光學異構物紫外光吸收圖譜。………………………………………………………………………68
圖3-5. TBZ-M衍生物之400 MHz氫-1核磁共振圖譜。……………...69
圖3-6. TBZ-M衍生物之100 MHz碳-13核磁共振圖譜。…………….69
圖3-7. TBZ-M衍生物質譜圖。………………………………………...70
圖3-8. TBZ-M衍生物紅外線光譜圖。………………………………...70
圖3-9. TBZ-E衍生物前驅物之400 MHz氫-1核磁共振圖譜。……….71
圖3-10. TBZ-E衍生物前驅物之400 MHz氫-1核磁共振圖譜 (0.5-3.0 ppm 範圍)。……………………………………………………………..71
圖3-11. TBZ-E衍生物紫外線吸收光譜圖。…………………………...72
圖3-12. 逆相HPLC分析TBZ-E衍生物之紫外光吸收圖譜。…………72
圖3-13. Chiral HPLC分析TBZ-E衍生物之光學異構物紫外光吸收圖譜。………………………………………………………………………73
圖3-14. TBZ-E衍生物之400 MHz氫-1核磁共振圖譜。……………...73
圖3-15. TBZ-E衍生物之400 MHz氫-1核磁共振圖譜 (0.70~1.10 ppm範圍)。……………………………………………………...……………74
圖3-16. TBZ-E衍生物之400 MHz氫-1核磁共振圖譜 (1.00~2.00 ppm範圍)。…………………………………………………………………...74
圖3-17. TBZ-E衍生物之400 MHz氫-1核磁共振圖譜 (2.25~3.00 ppm範圍)。…………………………………………...………………………75
圖3-18. TBZ-E衍生物之400 MHz氫-1核磁共振圖譜 (3.75~4.00 ppm範圍)。…………………………………………………………………...75
圖3-19. TBZ-E衍生物之100 MHz碳-13核磁共振圖譜。…………….76
圖3-20. TBZ-E衍生物質譜圖。………………………………………...76
圖3-21. TBZ-E衍生物紅外線光譜圖。……………………………...…77
圖3-22. TBZ-B衍生物前驅物3-dimethylaminomethyl-heptan-2-one之400 MHz氫-1核磁共振圖譜。………………………………………….77
圖3-23. TBZ-B衍生物紫外線吸收光譜圖。…………………………..78
圖3-24. 逆相HPLC分析TBZ-B衍生物之紫外光吸收圖譜。………..78
圖3-25. Chiral HPLC分析TBZ-B衍生物之光學異構物紫外光吸收圖譜。………………………………………………………………………79
圖3-26. TBZ-B衍生物之400 MHz氫-1核磁共振圖譜。……………..79
圖3-27. TBZ-B衍生物之400 MHz氫-1核磁共振圖譜 (0.50-4.00 ppm範圍)。…………………………………………………………………...80
圖3-28. TBZ-B衍生物之400 MHz氫-1核磁共振圖譜 (1.15-2.90 ppm範圍)。…………………………………………………………………...80
圖3-29. TBZ-B衍生物之400 MHz氫-1核磁共振圖譜 (2.40~3.50 ppm範圍)。…………………………………………………………………...81
圖3-30. TBZ-B衍生物之100 MHz碳-13核磁共振圖譜。……………81
圖3-31. TBZ-B衍生物之100 MHz碳-13核磁共振圖譜 (10-70 ppm範圍)。……………………………………………………………………...82
圖3-32. TBZ-B衍生物之質譜圖。……………………………………..82
圖3-33. TBZ-B衍生物紅外線光譜圖。………………………………..83
圖3-34. TBZ-B衍生物紫外線吸收光譜圖。…………………………..83
圖3-35. Ro 4-1632結構式。…………………………………………….83
圖3-36. FP-(+)-DTBZ與氟-18-FP-(+)-DTBZ在大白鼠腦紋狀體組織均質之競爭結合試驗曲線圖。……………………………………………84
圖3-37. TBZ-M衍生物與氟-18-FP-(+)-DTBZ在大白鼠腦紋狀體組織均質之競爭試驗曲線圖。………………………………………………85
圖3-38. TBZ-E衍生物與氟-18-FP-(+)-DTBZ在大白鼠腦紋狀體組織均質之競爭試驗曲線圖。………………………………………………86圖3-39. TBZ-B衍生物與氟-18-FP-(+)-DTBZ在大白鼠腦紋狀體組織均質之競爭試驗曲線圖。………………………………………………87

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