本研究開發一芬布芬衍生物(簡稱[18F]FFOA)，結合放射性氟標誌及正子造影技術，研究於生物體內的累積及分佈。非放射性合成由市售化合物4-bromobiphenyl作為起始物進行Friedel-Crafts reation 合成溴化芬布芬(1)產率93 %，下一步進行醯胺耦合反應合成溴化辛基醯胺芬布芬(2)產率87 %，再經由鈀金屬催化進行錫化反應合成三甲基錫化辛基醯胺芬布芬(3)產率60 %，三步驟合成總產率50 %，放射性合成經由[18F]F2進行親電子性取代，合成最終產物[18F]FFOA，放射產率24 %，比活度23.9 MBq/μmole。
FFOA體外穩定性實驗，在胎牛血清蛋白(FBS)中維持37℃及120分鐘後，利用RP-HPLC分析此藥物結構約維持60 % 穩定存在。放射性競爭抑制試驗，利用與[18F]FFOA結構相似之氫化物fenbufen octyl amide (簡稱FOA)作為競爭物，[18F]FOA對於COX-1及COX-2的半結合抑制值(IC50)分別為5.13 μM及4.79 μM，對於COX-2選擇性指數(SI)為1.07，與其母體化合物芬布芬(COX-2 SI = 0.48)相比，[18F]FFOA成功提升對於COX-2的選擇性。
動物正子造影分析，[18F]FFOA在C6 Glioma腦瘤大鼠注射25分鐘後造影，肺部造影顯示肺部累積量為32 % ID/g，腦部造影腫瘤區域累積量為3.9 % ID/g，周圍腦部區域累積為2.9 % ID/g，於腦部周圍的骨頭區域也有累積現象。 [18F]FFOA在U87-MG腦瘤小鼠注射10分鐘後，各器官累積ID/g分別為肺(70 %)、肝臟(20 %)、腎臟(10 %)、脾臟(3 %)。
本研究成功開發一具備抗癌功效之非類固醇抗發炎藥物。結合放射性氟標幟賦予藥物，能夠在正子造影下追蹤藥物於生物體內的分佈，達到診斷的應用；期望能提升生物體應用及治療之效率。

In this study, we reported the synthesis, characterization and in vivo application of a radioactive fluorine labeled non-steroidal anti-inflammatory drugs [18F]FFOA, which can be combined with positron emission tomography (PET) imaging to research in vivo distribution.
In this synthesis, starting from commercial 4-bromobiphenyl via Friedel Crafts acylation to give bromo-fenbufen (1) in 93 % yield, amide coupling reaction to give bromo-fenbufen octyl amide (2) in 87 % yield, and Pd catalyzed stannylation to give trimethyltin-fenbufen octyl amide (3) in 60 % yield, The totoal yield was 50 %. [18F]FFOA was obtained by fluorodestannylation using [18F]F2. The radiochemical yield was 24 % and specific activity was 23.9 MBq/ μmole.
Stability test using RP-HPLC showed that FFOA 60% of intact form was maintained after 2 h. Radioactive competitive inhibition study showed that [18F]FFOA exhibited highly selective for COX-2 by using similarity compound fenbufen octyl amide (FOA) as a competitor. The selectivity index (SI) for COX-2 was two times greater than its parent compound fenbufen.
PET imaging of C6 Glioma brain tumor rat revealed that significant amount [18F]FFOA was accumulated in lung with 31.8 % ID/g, in tumor lesion with 3.9 % ID/g, and brain tissues with 2.9 % ID/g. A parallel study using U87-MG brain tumor mice studies revealed that [18F]FFOA accumulated in lung with 70 % ID/g、20 % ID/g for liver、10 % ID/g for kidney、3 % ID/g for spleen.

摘要 I
Abstract II
致謝 III
縮寫對照表 IV
目錄 VI
圖目錄 X
表目錄 XIV
第一章 緒論 1
1.1生物體之發炎反應 1
1.1.1誘導發炎反應之機制 2
1.1.1.1前列腺素 (Prostaglandins，PGs） 2
1.1.1.2環氧化合酶 (Cyclooxygenases，COX） 3
1.1.2癌症與發炎反應 4
1.1.2.1癌症 4
1.1.2.2癌症之發炎反應 6
1.2抗發炎藥物 7
1.2.1非類固醇抗發炎藥物 (Non-steroidal anti-inflammatory drugs, NSAIDs) 7
1.2.2非類固醇抗發炎藥物之發展 9
1.2.3非類固醇發炎藥物之應用 13
1.2.3.1芬布芬(Fenbufen) 13
1.2.3.2芬布芬衍生物之相關研究發展 14
1.3藥物發展之應用 15
1.3.1正電子發射斷層掃描(Positron Emission Tomography, PET) 15
1.3.2放射性標誌物 17
1.3.2.1放射性氟-18標誌 18
1.3.3 體內藥物代謝途徑及影像解析 19
1.4研究動機與目的 21
第二章 實驗結果與討論 25
2.1 實驗架構與路徑分析 25
2.1.1 錫化物合成反應 26
2.1.2非放射性氟化合物合成 27
2.2 N-octyl-4-oxo-4-(4'-(trimethylstannyl)-[1,1'-biphenyl]-4-yl)butan 28
amide (3)之放射性氟-18標幟 28
2.3 FFOA 體外穩定性測試 31
2.4 [18F]FFOA體外環氧合酶(COX)競爭抑制結合試驗 33
2.5 [18F]FFOA動物正子造影分析 38
2.5.1 大鼠正子造影 38
第三章 實驗材料與方法 50
3.1 實驗方法、材料與儀器 50
3.1.1 非放射性化合物合成方法、材料與儀器 50
3.1.2化合物鑑定 51
3.1.3 放射性化合物合成 52
3.1.4 FFOA 體外穩定性測試 52
3.1.5 [18F]FFOA體外環氧合酶(COX)酵素競爭抑制試驗 53
3.1.6 [18F]FFOA動物正子造影分析 53
3.2 前驅物之合成 55
3.2.1製備 4-(4’-bromo-[1,1’-biphenyl]-4-yl)-4-oxobutanoic acid (1) 55
3.2.2製備4-(4'-bromo-[1,1'-biphenyl]-4-yl)-N-octyl-4- oxobutanamide (2) 56
3.2.3製備N-octyl-4-oxo-4-(4'-(trimethylstannyl)-[1,1'-biphenyl]-4-yl)butanemide (3) 58
3.2.4製備 4-([1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide (FOA) 60
3.3 放射性氟-18標幟合成 61
3.3.1製備4-(4'-fluoro-[1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide [18F]FFOA 61
3.4 生物實驗 66
3.4.1 FFOA 體外穩定性測試 66
3.4.2[18F]FFOA體外環氧合酶(COX)酵素抑制試驗 67
3.4.2.1 [18F]FFOA儲備液配置 67
3.4.2.2 [18F]FFOA體外環氧合酶(COX)競爭抑制試驗方法 68
3.4.3 [18F]FFOA動物正子造影分析 70
3.4.3.1 [18F]FFOA儲備液配置 70
3.4.3.2大鼠靜態造影 70
3.4.3.3 小鼠靜態造影 71
3.4.3.4 小鼠動態造影 71
第四章 結論 72
圖表補充 73

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