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研究生:郭諭燁
研究生(外文):kuoyuyeh
論文名稱:利用4-[18F]-ADAM微正子電腦斷層造影活體研究大鼠腦血清素轉運體
論文名稱(外文):In Vivo study of Serotonin Transporters with 4-[18F]-ADAM Micro-PET in Rat Brain
指導教授:馬國興馬國興引用關係
指導教授(外文):Makuohsing
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生物及解剖學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:79
中文關鍵詞:微正子電腦斷層造影血清素轉運體4-[18F]-ADAM
外文關鍵詞:Micro-PETserotonin transporter4-[18F]-ADAM
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血清素轉運體位於突觸前神經元,可作為選擇性血清素再吸收抑制劑的主要作用標的。 4-[18F]-ADAM 是一種新研發的正子造影藥物,具專一性的結合於血清素轉運體,因此對於大鼠不同的腦區如 ( 中腦、下視丘、尾殼核、海馬迴、額葉皮質區等等 ) 可表現高度的親合性及選擇性。本研究運用 4-[18F]-ADAM ,分別使用不同劑量的 paroxetine 、神經毒劑 PCA 以及使用自動放射造影等技術以探討大鼠腦中血清素轉運體的相關性。在實驗設計方面,利用15隻正常的SD 大鼠,使用 4-[18F]-ADAM 微正子電腦斷層造影,計算注射不同劑量 paroxetine 後,血清素轉運體被阻斷之比率,相同條件之下,同時利用自動放射造影術定量大鼠腦中 4-[18F]-ADAM 的生物分佈情形。此外,注射PCA造成血清素系統缺損也進一步探討 4-[18F]-ADAM 對血清素轉運體之專一性。實驗數據顯示, 4-[18F]-ADAM 於正常大鼠活體內或體外腦區生物分佈實驗,與已知的血清素轉運體分佈的區域相符合。我們發現在中腦、下視丘有較高的 4-[18F]-ADAM 結合情形,尾殼核及海馬迴次之,額葉皮質區及小腦較少。在預先給予 paroxetine 及神經毒劑 PCA 的實驗同時顯現出 4-[18F]-ADAM 結合率,有良好的線性關係;當給予注射 PCA 及給予 paroxetine 量增加時, 4-[18F]-ADAM 結合率確時有明顯減少。本實驗結果顯示, 4-[18F]-ADAM 適合用於正子電腦斷層造影,尤其使用於體內及體外藥物標幟血清素轉運體之相關研究,而進一步應用於臨床上人類腦部血清素轉運體的定量。
The serotonin transporter (SERT), located in the presynaptic serotonergic neurons, is the primary target for selective serotonin reuptake inhibitors (SSRIs). A novel 18F-labeled SERT PET radioligand N, N-dimethyl-2-
(2-amino-4-18F-fluoropheylthio) benzylamine (4-[18F]-ADAM) specific for SERT has been reported and showed a high affinity and selectivity to SERT in various rat brain regions including midbrain, hypothalamus, caudate putamen, and hippocampus. The aims of this study are to 1) validate its biological activities (pharmacology, autoradiography, PET imaging) in rodents; and 2) develop PCA-lesioned animal models, and evaluate the usefulness of 4-[18F]-ADAM in studying this rat model. The radioligand was evaluated with pre-treating different paroxetine dosages in rat brains using micro-PET, respectively. The ex vivo quantitative autoradiography studies in rat brains were also conducted. Fifteen healthy SD rats were measured with 4-[18F]-ADAM and micro-PET for the blocked proportion of SERT by pre-treating different dosages of paroxetine, respectively. Emission data were collected continuously for 30 min after one hour injection of 0.3mCi 4-[18F]-ADAM. In addition, same amount of rats were intravenously injected with 4mCi 4-[18F]-ADAM to access its biodistribution in the brain via quantitative autoradiography. Further, rats model of serotonergic dysfunction by intraperitoneal injection of p- chloroamphetamine (PCA) were used to evaluate the specificity of 4-[18F]-ADAM to SERT. The data showed that ex vivo and in vivo biodistribution of 4-[18F]-ADAM in normal rat brains were parallel to known SERT-rich brain distributions. We found high 4-[18F]-ADAM uptake in midbrain and hypothalamus, moderate uptake in caudate putamen、Hippocampus, and low uptake in frontal cortex and cerebellum. The SSRI pretreatment / p- chloroamphetamine (PCA) studies showed good linear correlation between 4-[18F]-ADAM uptake and different paroxetine dosages. The results revealed that 4-[18F]-ADAM binding in SERT-rich brain regions were markedly reduced, the decrement in 4-[18F]-ADAM uptake was more prominent at higher dosages of paroxetine and p- chloroamphetamine (PCA). This appears that 4-[18F]-ADAM is suitable PET radioligand for measuring drug occupancy of the SERT in vivo and ex vivo. The novel radiotracer could be a potential tool to quantify SERT in living human brain.
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目錄 ……………………………………………………………………Ⅰ
圖目錄 .…………………………………………………………………Ⅳ
表目錄 …………………………………………………………………Ⅵ
中文摘要 ………………………………………………………………VIII
英文摘要 ………………………………………………………………X
第一章 緒言 …………………………………………………………1
第一節 血清素神經系統
壹、 血清素神經系統投射路徑 …………………………………2
貳、 血清素的神經傳導 …………………………………………3
參、 血清素之生合成作用機轉 …………………………………4
肆、 血清素轉運體 ………………………………………………6
伍、 血清素的功用 ………………………………………………6
陸、 血清素相關的神經用藥 ……………………………………7
第二節 血清素轉運體之醫學影像
壹、 核子醫學造影 ………………………………………………8
貳、 血清素轉運體之放射造影劑 ………………………………9
參、 正子電腦斷層造影之核醫新藥 4-[18F]-ADAM ……………10
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肆、 實驗目的 ……………………………………………………11
第二章 材料與方法
第一節 材料
壹、 實驗動物 ……………………………………………………12
貳、 放射藥物製 …………………………………………………13
參、 4-[18F]-ADAM 大鼠生物分佈實驗所需材料 ……………14
肆、 4-[18F]-ADAM 大鼠腦部微正子電腦斷層造影實驗所需材料 15
伍、 4-[18F]-ADAM大鼠腦部自動放射顯影術實驗所需材料 …16
第二節 實驗設計與方法
壹、 微正子電腦斷層造影4-[18F]-ADAM 在大鼠腦部
生物分佈實驗 (藥物處理組) …………………………………18
貳、 微正子電腦斷層造影4-[18F]-ADAM 在大鼠腦部
生物分佈實驗 (神經毒劑處理組) ……………………………20
叁、 4-[18F]-ADAM 大鼠腦部自動放射顯影術 ……………………21
肆、 資料分析與統計方法 ……………………………………………22
第三章 結果
壹、 微正子電腦斷層造影4-[18F]-ADAM 在大鼠腦部
生物分佈實驗(藥物處理組) …………………………………………23
頁次
貳、 4-[18F]-ADAM 大鼠腦部自動放射顯影術在大鼠腦部
生物分佈實驗 (藥物處理組) ………………………………………25
參、 微正子電腦斷層造影4-[18F]-ADAM 在大鼠腦部
生物分佈實驗 (神經毒劑處理組) ……………………………26
肆、 4-[18F]-ADAM 大鼠腦部自動放射顯影術在大鼠腦部
生物分佈實驗 (神經毒劑處理組) ……………………………………27
第四章 討論
壹、微正子電腦斷層造影及自動放射造影術
4-[18F]-ADAM 在大鼠腦部生物分佈 …………………………48
貳、微正子電腦斷層造影及自動放射造影術
4-[18F]-ADAM 在大鼠腦部生物分佈實驗(藥物處理組) ……50
叁、微正子電腦斷層造影及自動放射造影術
4-[18F]-ADAM 在大鼠腦部生物分佈實驗(神經毒劑處理組) …52
第五章 結論 …………………………………………………………… 54
第六章 參考資料 ……………………………………………………… 55

圖目錄
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圖一、4-[18F]-ADAM 注射後,動態造影兩小時大鼠腦部放射性活性分佈影像和核磁共振影像 ------------------------------------------------ 29
圖二、 4-[18F]-ADAM 在大鼠腦部“時間-放射活度”曲線圖( Time-activity curve ) -------------------------------------------- 30
圖三、 4-[18F]-ADAM 放射活度在大鼠腦部不同部位的專一性結合比率與時間關係圖 --------------------------------------------------- 31
圖四、預先注射不同劑量的paroxetine 後,注射4-[18F]-ADAM 0.3mCi ,一小時後,以微正子電腦斷層造影30分鐘之大鼠腦部冠狀切、水平切及矢狀切影像 -- 32

圖五、預先注射不同劑量 ( 0.01mg/kg、0.05mg/kg、0.1mg/kg、0.25mg/kg ) paroxetine,進行大鼠腦部 4-[18F]-ADAM 微正子電腦斷層造影,其 4-[18F]-ADAM 於所圈選之感興趣區域 (A) Midbrain (B) Hypothalamus (C) Caudate putmen (D) Hippocampus (E) Frontal cortex 的專一性攝取率變化圖 ---- 33
圖六、正常大鼠以及預先注射不同劑量 ( 0.01mg/kg、0.05mg/kg、0.1mg/kg、0.25mg/kg ) 的 paroxetine 後,大鼠腦部 4-[18F]-ADAM 自動放射造影影像-- 35


圖七、預先注射不同劑量 ( 0.01mg/kg、0.05mg/kg、0.1mg/kg、0.25mg/kg ) 的 paroxetine 後再進行大鼠腦部 4-[18F]-ADAM 自動放射造影,其 4-[18F]-ADAM 於所圈選之感興趣區域 (A) Midbrain (B) Hypothalamus (C)Caudate putmen (D) Hippocampus (E) Frontal cortex的專一性攝取率變化圖 ------------ 36
圖八、預先注射PCA ( 10mg/kg ),經一、二、三、四週,注射4-[18F]-ADAM 0.3mCi ,一小時後,以微正子電腦斷層造影30分鐘之大鼠腦部冠狀切、水平切及矢狀切影像 ------------------------------------------------------- 38
圖九、預先注射PCA ( 10mg/kg ) 後,經過一週、二週、三週、四週,分別進行大鼠腦部 4-[18F]-ADAM 微正子電腦斷層造影,其 4-[18F]-ADAM 於所圈選之感興趣區域 (A) Midbrain (B) Hypothalamus (C) Caudate putmen (D) Hippocampus (E) Frontal cortex 的專一性攝取率變化圖 ------------------------- 39
圖十、正常大鼠以及預先注射 PCA ( 10mg/kg ),經過四週造影完後,大鼠腦部 4-[18F]-ADAM 自動放射造影影像 ----------------------------------- 41
圖十一、預先注射 PCA ( 10mg/kg ),經過四週造影完後,進行大鼠腦部 4-[18F]-ADAM 自動放射造影術,其4-[18F]-ADAM 於所圈選之感興趣區域(A) Midbrain (B) Hypothalamus (C) Caudate putmen (D) Hippocampus (E) Frontal cortex 的專一性攝取率變化圖 -------------------------------------------- 42

表目錄
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表一、預先注射不同劑量 ( 0.01mg/kg、0.05mg/kg、0.1mg/kg、0.25mg/kg ) paroxetine,進行大鼠腦部4-[18F]-ADAM微正子電腦斷層造影,其 4-[18F]-ADAM 於所圈選之感興趣區域 (A) Midbrain (B) Hypothalamus (C) Caudate putmen (D) Hippocampus (E) Frontal cortex 的專一性攝取率變化數據 ------------- 44
表二、預先注射不同劑量 ( 0.01mg/kg、0.05mg/kg、0.1mg/kg、0.25mg/kg ) 的 paroxetine 後再進行大鼠腦部 4-[18F]-ADAM 自動放射造影,其 4-[18F]-ADAM 於所圈選之感興趣區域 (A) Midbrain (B) Hypothalamus (C) Caudate putmen (D) Hippocampus (E) Frontal cortex 的專一性攝取率變化數據 ------------ 45
表三、預先注射PCA ( 10mg/kg ) 後,經過一週、二週、三週、四週,分別進行大鼠腦部 4-[18F]-ADAM微正子電腦斷層造影,其 4-[18F]-ADAM 於所圈選之感興趣區域(A) Midbrain (B) Hypothalamus (C) Caudate putmen (D) Hippocampus (E) Frontal cortex 的專一性攝取率變化數據 -------------------------- 46


表四、預先注射 PCA ( 10mg/kg ),經過四週造影完後,進行大鼠腦部 4-[18F]-ADAM 自動放射造影術,其 4-[18F]-ADAM 於所圈選之感興趣區域(A) Midbrain (B) Hypothalamus (C)Caudate putmen (D) Hippocampus (E) Frontal cortex 的專一性攝取率變化數據 ----------------------------------------------- 47
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