利用正子斷層掃描進行新穎具古柯鹼濫用治療潛力藥物的活體動態分佈研究

In Vivo Dynamic Distribution Study of Novel Potential Cocaine-abuse Therapeutic Agents Using Positron Emission Tomography

郭品辰(Pin-Chen Kuo)

指導教授 ： 忻凌偉

國立臺灣大學/醫學院/藥學研究所/碩士(2021年)

https://doi.org/10.6342/NTU202103213

摘要

古柯鹼是一種中樞神經興奮劑，會與多巴胺競爭多巴胺轉運體的結合位置，間接導致突觸間隙的多巴胺濃度提升，進而使人體產生過度興奮與成癮之效果，也引發許多社會問題，因此有必要開發具有古柯鹼戒斷治療潛力的藥物。先前本實驗室已經合成出一系列新穎GBR12935衍生物作為古柯鹼濫用治療藥物，並從中篩選出針對多巴胺轉運體具有高度親和力、選擇性，以及適當脂溶性的候選藥物：化合物4與化合物5，而目前需要更進一步地探討此二候選藥物在活體內的動態分佈。
傳統藥物動力學進行藥物在體內的分佈研究，必須犧牲大量的實驗動物，而利用正子斷層掃描技術，僅需給予少量的放射性藥物，就能夠以非侵入性的方式獲得實時監測的影像，再透過生物體學影像定量分析軟體將正子斷層掃描影像數據化，計算出標準攝取值 (standardized uptake value, SUV) 與標準攝取值比 (standardized uptake value ratio, SUVR)，即能夠得到客觀且準確的藥物在活體內動態分佈資訊，不僅可以縮減實驗動物的消耗，還能夠使用同一隻實驗動物完成數個時間點的藥物分佈分析。
故本研究中，利用正子斷層掃描技術監測18F-4和18F-5在小鼠全身的動態分佈情形；而紋狀體已被報導具有最高密度的多巴胺轉運體，因此紋狀體將會是本研究中重要的觀察目標之一，藉此判斷放射性追蹤劑是否能夠累積於紋狀體並與多巴胺轉運體選擇性結合。
由PET影像發現，靜脈注射給予18F-4和18F-5的初期，心臟與肺臟的攝取量較高，然後隨著血液循環分佈至肝臟、腸道、腎臟、膀胱等器官；而18F-4在腦部的累積量比18F-5多，代表18F-4的血腦障壁穿透性較好，因此比較容易進入到腦部。在腦部可觀察到18F-4和18F-5選擇性累積於紋狀體，該結果表示此二候選藥物是具有潛力的，有機會發展為後續臨床使用古柯鹼濫用治療的藥物。

關鍵字

古柯鹼 ； 正子斷層掃描 ； 動態分佈

並列摘要

Cocaine is a kind of central nervous stimulants, which competes with dopamine for the binding site of dopamine transporter (DAT), indirectly increasing dopamine extracellular concentration to make people over-excited and addicted. Therefore, it is necessary to develop drugs with cocaine therapeutic potential. Previously, there were a series of novel GBR12935 derivatives had been synthesized as cocaine-abuse therapeutic agents. Compound 4 and compound 5 which had high DAT binding affinity, selectivity and appropriate lipophilicity were selected as the candidates for further studies of in vivo dynamic distribution.
In traditional pharmacokinetics, a large number of experimental animals must be sacrificed to study the distribution of drugs, but using positron emission tomography (PET) only needs to administer a trace amount of radiopharmaceuticals to animals ,which can obtain the real-time PET images in non-invasive way. With biological imaging quantitative analysis software to calculate standardized uptake value (SUV) and standardized uptake value ratio (SUVR), the PET images can be converted to objective and accuracy information of in vivo dynamic distribution of drugs. It not only reduces the consumption of experimental animals but also completes different time points analysis of drug distribution by using the same animal.
In this study, we used PET to monitor the whole body distribution of 18F-4 and 18F-5 in mice. Striatum was reported to have the highest density of DAT in brain. Thus, we observed this vital target whether the radiotracers can accumulate in to selectively binding with DAT.
The results shown that the initial uptake of 18F-4 and 18F-5 was higher in the heart and lungs, and then as the blood circulation distributed to other organs such as the liver, intestine, kidneys, bladder. The brain uptake of 18F-4 is higher than 18F-5, which meant 18F-4 has better permeability of blood-brain barrier. Additionally, it can be observed that 18F-4 and 18F-5 selectively accumulated in the striatum. The result suggested these two candidates are promising to become further clinical use in the treatment of cocaine abuse.

並列關鍵字

cocaine ； positron emission tomography ； dynamic distribution

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