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研究生:林 明 賢
研究生(外文):Ming-Hsien Lin
論文名稱:以正子影像與全身性放射顯影術評估神經性成癮藥物對多巴胺神經系統之抑制性
論文名稱(外文):Evaluation of Inhibitory Effect of Recreational Drugs on Dopaminergic Terminal Neuron by PET and Whole-Body Autoradiography
指導教授:劉 仁 賢陳 志 成
指導教授(外文):Ren-Shyan LiuJyh-Cheng Chen
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生物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:2014
畢業學年度:103
語文別:中文
論文頁數:86
中文關鍵詞:[18F]FDOPA甲基安非他命K他命古柯鹼微正子造影全身性放射顯影
外文關鍵詞:[18F]FDOPAmethamphetamineketaminecocainemicroPETwhole body autoradiography
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關於多巴胺在週邊神經系統的研究並不多見,正子造影劑-[18F]FDOPA已被用於腫瘤影像(如神經內分泌瘤與胰臟腫瘤)與腦神經影像(如巴金森氏症與亨氏舞蹈症等)。本研究利用[18F]FDOPA小鼠微正子造影與全身性放射顯影技術探討常見青少年毒品(K他命、古柯鹼和甲基安非他命等神經成癮性藥物)對腦中樞與週邊神經系統的傷害。[18F]FDOPA在紋狀體的特異性結合率(specific binding ratios)以多巴胺神經元分佈量少的小腦為參考區。影像結果指出,正常小鼠[18F]FDOPA在紋狀體呈現高度特異性結合,中度結合區為胃黏膜與小腸;腎髓質的[18F]FDOPA吸收率則高於腎皮質。經K他命、古柯鹼合甲基安非他命急性中毒處理後的小鼠,[18F]FDOPA吸收率大量降低, 不僅見於紋狀體,也相同發生於腸胃道。三種神經成癮性藥物相較,K他命對多巴胺的抑制效果最高,次為古柯鹼, 後為甲基安非他命。本研究建立了[18F]FDOPA多影像模組技術,此技術將可應用於腦部疾病的多巴胺神經元變化或週邊組織癌化對多巴胺神經元的影響。
There is little investigation for the functional roles of peripheral dopamine. [18F]FDOPA has been used in cancer imaging (i.e. neuroendocrine tumors and pancreatic tumors) and neuroimaging (i.e. Parkinson’s disease and Huntington’s disease). Here, we accessed side effects of recreational drugs such as ketamine, cocaine and methamphetamine on dopamine neurons in peripheral organs by using positron emission tomography (PET) imaging and quantitative whole-body autoradiography (QWBAR) with [18F]FDOPA. The images were applied for the measurement of specific binding ratios (SBR) of striatum with the cerebellum as the reference region. Clear striatal [18F]FDOPA-derived radioactivity was observed. Moderate level of radiotracer accumulation was presented in the mucosal layers of the stomach and small intestine. The medulla layers of kidney had higher radioactivity than that of the cortex. Blocking images markedly eliminated the specific binding of [18F]FDOPA in the striatum and in peripheral organs such as stomachs, intestines and kidney. Ketamine showed the highest inhibitory effect on striatal [18F]FDOPA-derived radioactivity followed by cocaine and methamphetamine. The current results demonstrated a useful crossing-validating tool enhances the capability of [18F]FDOPA for further investigations of the alteration of dopaminergic neurons in the brain disorder or cancer diseases in peripheral tissues.
目錄
學位論文電子檔授權書 i
論文審定同意書 ii
誌 謝 iii
圖目錄 vi
表目錄 vii
第一部分 ix
中文摘要 x
英文摘要 xi
1. 緒論 1
1.1前言 1
1.2研究緣起 2
1.3關於多巴胺 2
1.4神經成癮性藥物: K他命(Ketamine)、古柯鹼(cocaine)與甲基安非他命( methamphetamine) 4
1.5 [18F]FDOPA正子醫學影像的應用 6
1.6研究目的 7
2.1 核醫藥物18F-FDOPA製備註 8
2.1.1藥品準備 9
2.1.2 ROBOTIC SYSTEM準備 9
2.1.3 Preparative LC之準備 10
2.1.4 ROBOTIC PROGRAM之執行 10
2.1.5 Q.C. of [18F]FDOPA 11
2.2 實驗動物 11
2.3 [18F]FDOPA全身性生物分佈的測定-傳統採檢法 11
2.4自動放射性影像(autoradiography) 12
2.4.1全身性自動放射影像術(Whole-body macroautoradiography) 12
2.4.2神經成癮藥物處理組(全身性自動放射影像術) 13
2.5 微正子造影註 (MicroPET) 14
2.5.1 造影參數 15
2.5.2 正子影像分析 15
2.5.3 正子影像量化 15
2.5.4神經成癮藥物處理組 (微正子造影) 16
3.研究結果 17
3.1 [18F]FDOPA小鼠生物分布-傳統式器官摘取法 17
3.2定量全身性自動放射顯影(quantitative whole-body autoradiography, QWBAR) 18
3.3微正子電腦斷層影像 22
4.討論 25
參考文獻 30
第二部分 32
1.緒論 37
2.材料與方法 40
2.1 111In-DOTA-Annexin V 及111In-DOTA-BSA 之製備 40
2.2 細胞培養 41
2.3 不同濃度GCV對於NG4TL4-STK腫瘤細胞及NG4TL4-WT腫瘤細胞細胞毒性評估 42
2.4 GCV對NG4TL4-STK腫瘤細胞引發之細胞凋亡評估 43
2.5 111In-DOTA-Annexin V及111In-DOTA-BSA與GCV-treated NG4TL4-STK腫瘤細胞結合率評估 44
2.6 動物腫瘤模式之建立 45
2.7 111In-DOTA-Annexin V 及111In-DOTA-BSA於經GCV治療,荷有NG4TL4-STK腫瘤及NG4TL4-WT腫瘤之FVB/N mice之生物分佈 45
3.研究結果 46
3.1 不同濃度GCV對於NG4TL4-STK腫瘤細胞及NG4TL4-WT腫瘤細胞毒性評估 46
3.2 GCV對NG4TL4-STK腫瘤細胞誘發細胞凋亡程度評估 47
3.3 111In-DOTA-Annexin V及111In-DOTA-BSA分別對GCV-treated NG4TL4-STK腫瘤細胞及non-treated NG4TL4-STK腫瘤細胞結合率評估 49
3.4 GCV對荷有NG4TL4-STK腫瘤及NG4TL4-WT腫瘤FVB/N mice之療效評估 49
3.5 111In-DOTA-Annexin V 及111In-DOTA-BSA於經GCV治療,荷有NG4TL4-STK腫瘤及NG4TL4-WT腫瘤之FVB/N mice之生物分佈 50
3.6 111In-DOTA-Annexin V 及 111In-DOTA-BSA於經GCV治療,荷有NG4TL4-STK及NG4TL4-WT腫瘤FVB/N mice之gamma camera造影 52
4.討論 52
5.結論 56
參考文獻 56
著作目錄 58
附 錄 60


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