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  • 學位論文

氟-18標誌血清素轉運器造影劑之發展

Development of 18F-labelled serotonin transporter imaging agents

指導教授 : 朱鐵吉 薛晴彥 傅應凱
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摘要


在中樞神經系統中,血清素器轉運體(SERT)濃度的變化與許多神經精神性異常疾病有關,例如憂鬱症、焦慮症、精神分裂、藥物濫用、酒癮、飲食失調、阿茲海默氏症(Alzheimer’s disease)及帕金森氏症(Parkinson’s disease)等。此外,它也是普遍使用的抗憂鬱處方藥物的主要作用標的。因此,以非侵入性的正子掃瞄 (Positron Emission Tomography, PET)或單光子射出電腦斷層攝影 (Single Photon Emission Computed Tomography, SPECT)活體造影技術探討血清素轉運器在腦部區域的分布將有助於探討血清素系統在神經精神性異常疾病的病理生理學及治療上所扮演的角色。本論文的總目標即為氟-18標誌血清素轉運器造影劑的發展與評估。近來,2-(2-amino-4-[18F] -fluorophenylthio)benzylamine ( 4-[18F] -ADAM )已被證實為具潛力的氟-18標誌血清素轉運器造影劑,並適用於動物及臨床前研究。然而,其低放化產率卻會妨礙其廣泛的應用性。因此,我們已發展一方法以改善其放化產率。此方法是基於分子軌域計算而推導出會發生親核性芳香環氟化反應之碳原子的電子電荷。基於計算所得結論,我們亦發展了一改良合成方法以製備4-[18F] –ADAM,並得到比之前所發表的合成方法更好的放化產率。而此計算方法也因此可作為一個預測親核性芳香環氟化反應發生位置的工具,並由結果證明此計算方法亦可以應用在其他系列的化合物上。 4-[18F]–ADAM更在大鼠及台灣彌猴體內以定量自動放射顯影術與microPET進一步地評估其是否為一具潛力的血清素轉運器造影劑。結果顯示4-[18F]–ADAM確實為一具潛力的氟-18標誌血清素轉運器造影劑。而由大鼠與台灣彌猴體內進行4-[18F]-ADAM的毒性與輻射劑量評估結果也發現4-[18F]–ADAM適合用於人體PET研究(在大鼠,單一劑量與五天連續劑量皆不會造成臨床上顯著的副作用。在猴子,大部分器官接受的輻射劑量介於7.1與35.7μGy/MBq之間,並且膀胱被視為是危急器官。)。在人體實驗中,研究結果顯示4-[18F]-ADAM PET在人腦中評估血清素轉運器狀態上為一個有用的工具。除了4-[18F]-ADAM之外,其一系列的同系物如[18F]-AFM, 2-[18F]-ADAM與4-[18F]-NMADAM也皆被合成,並在大鼠內評估其是否亦為具潛力的血清素轉運器造影劑。結果顯示[18F]-AFM為一有潛力的血清素轉運器造影劑,儘管其低放化產率(~1%)也許會妨礙其應用性。相反地,2-[18F]-ADAM與4-[18F]-NMADAM則不是一個有潛力的血清素轉運器造影劑。

並列摘要


Alterations of serotonin transporters (SERT) densities have been implicated in a number of neuropsychiatric disorders, including major depression, anxiety disorders, schizophrenia, drug abuse, alcoholism, eating disorders, Alzheimer’s disease and Parkinson’s disease. In addition, it is also the primary target for widely prescribed antidepressant agents. Thus, in vivo imaging the regional brain distribution of SERT with Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) will provide an important tool to study the role of the serotonergic system in the pathophysiology and treatment of neuropsychiatric disorders. The overall objective of this dissertation is to develop and evaluate the F-18 labelled SERT imaging agents. Recently, N,N-dimethyl -2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) has been proved to be a potent 18F-labelled SERT imaging agent and is suitable for animal and preclinical studies. However, its low radiochemical yield (RCY) has hampered its widespread use. Hence, we have developed a method to improve its RCY. The method is based on molecular orbital calculation to derive the electron charges on carbon atom at which the nucleophilic aromatic fluorination will occur. Based on this method, we have developed an improved method to prepare 4-[18F]-ADAM in a better yield than the one previously reported (15% v.s. 6%). The calculation method thus has been used as a tool to predict the position of nucleophilic aromatic fluorination and the results show it is applicable to other class of compounds. 4-[18F]-ADAM was further characterized in rats and Formosa Rock monkeys as a potential SERT imaging agent with autoradiography and microPET. The results show 4-[18F]-ADAM is indeed a potent F-18 labelled SERT imaging agent. Toxicity and radiation dosimetry studies in rats and monkeys show that 4-[18F]-ADAM is suitable for use in human PET imaging studies (In the rats, neither the single dose nor the five daily doses of 4-[18F]-ADAM produced overt adverse effects clinically. In the monkeys, the radiation doses received by most organs ranged between 7.1 and 35.7 μGy/MBq, and the urinary bladder was considered to be the critical organ). Human studies show that 4-[18F]-ADAM PET may be a useful tool in assessing the status of SERT in human brain. In addition to 4-[18F]-ADAM, a series of its analogs, [18F]-AFM, 2-[18F]-ADAM and 4-[18F]-NMADAM were synthesized and evaluated in rats as potential SERT imaging agents. The results show that [18F]-AFM is also a potent SERT imaging agent although the low RCY (~1%) may hamper its usage as a SERT imaging agent. In contrast, both 2-[18F]-ADAM and 4-[18F]-NMADAM are not potent SERT imaging agents.

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