Fenbufen boron-pinacol (FBpin)與celecoxib皆為非類固醇類消炎藥 (NSAIDs)之類似物，並可利用CH3COO[18F]F進行親電加成反應合成[18F]F-celecoxib產率為20% 與[18F]F-FBpin兩種結構異構物 ([18F]F-FBpin1、[18F]F-FBpin2)產率各為18%、5%；以正子電腦斷層掃描評估放射性氟標幟化合物在膽管癌動物模式中的表現。
富含環氧合酶的膽管癌腫瘤可累積[18F]F-celecoxib到 1.15±0.24 %ID/g (n = 5)、腫瘤對肝臟的比率高達1.38±0.23 (n = 5)且清除率低，因此PET影像上也能明顯看出腫瘤與其它正常組織的差別。[18F]F-FBpin1能在膽管癌腫瘤有1.08±0.13 %ID/g (n = 3)之累積、T/N ratio數值為1.38±0.12 (n = 3)而[18F]F-FBpin2卻有更高之T/N ratio (1.7)，不過兩張PET影像上的腎臟與腸道之劑量卻比肝臟還要高許多；動態造影上來看，膽管癌腫瘤的[18F]F-FBpin1放射活度曲線下降的十分快速，主要的原因可能是[18F]F-FBpin1的代謝物對腫瘤有較低親和力之關係。
利用硼中子捕獲治療 (BNCT)方法將FBpin做為含硼藥物以治療含膽管癌腫瘤之動物。將60 mg/kg劑量之FBpin從大鼠尾靜脈注入，40分鐘後以(2.3 ± 0.5)×〖10〗^9 n/s.cm^2之中子束照射治療大鼠。以[18F]FDG-PET觀察治療前後之差異，受FBpin投藥的BNCT組可減少28.49 ± 4.68% (n = 7)的腫瘤，此種結果明顯高於neutron only組的19.14 ± 9.57% (n = 5)。

In this research, [18F]F-celecoxib, [18F]F-FBpin1 and [18F]F-FBpin2 were prepared via the useful electrophilic radiofluorinating agent, 18F-lablled acetyl hypofluorite, from its precursors in 20%, 18% and 5% yield, respectively. Furthermore, we conducted Positron Emission Tomography (PET) on cholangiocarcinoma to clarify the relationship between those Fluoro-NSAIDs and the tumor.
[18F]F-celecoxib could be a promising targeting tracer due to high uptake of cyclooxygenase (COX)-expressed tumor 1.15±0.24 %ID/g (n = 5), low clearance rate and the moderate tumor to liver ratio 1.38±0.23 (n = 5). Thus, the PET image comparable to gross picture which indicates the non-invasive [18F]F-celecoxib PET imaging was able to detect COX-2 tumor in vivo study.
[18F]F-FBpin1 had a higher tumor uptake 1.08±0.13 %ID/g (n = 3) than [18F]F-FBpin2 0.59 (n = 1) %ID/g ,but lower T/N ratio 1.38±0.12 (n = 3). [18F]F-FBpin1 time activity curve in dynamic study showed a rapidly decrease in tumor could be due to the low binding affinity of its metabolite.
In addition, cholangiocarcinoma bearing rats were injected FBpin with 60 mg/kg body weight via tail veins before (2.3 ± 0.5)×〖10〗^9 n/s.cm^2 neutron irradiation at the Tsing Hua Open-pool Reactor, and the efficacy of Boron neutron capture therapy (BNCT) was evaluated from the tumor size with [18F]FDG-PET study. Finally, the larger reduction of [18F]FDG uptake in tumor was measured in BNCT group (28.49 ± 4.68 %, n = 7) than neutron only group (19.14 ± 9.57 %, n = 5). However, we can observe the trend of reduction in tumor uptake with BNCT.

第一章、前言與研究目的 1
1. 膽管癌(bile duct carcinoma)的臨床意義與診斷 1
2. 環氧合酶 (Cyclooxygenase，COX)的生化機制 3
3. 氟乙酸之氟-18分子影像藥物合成 5
4.硼中子捕獲治療 (boron neutron capture therapy，BNCT)與含硼藥物的發展 6
5. 研究目的 9
第二章、材料與方法 12
1. 實驗用之材料 12
1.1. 清華大學實驗室使用之材料與儀器 12
1.2. 台北榮總正子中心所使用之材料與設備 12
1.3. 貴重儀器 13
2. 放射性氟化物的合成與儲備液的製成步驟 15
2.1. 氟化物的合成 15
2.1.1. 製備4-(5-(3-fluoro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-l)benzenesulfonamide (F-celecoxib) 15
2.1.2. 製備methyl 4-(2'-fluoro-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoate (F-FBpin1)、F-FBpin2、F-FBpin3、F-FBpin4與methyl 4-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-oxobutanoate (m-FFbf) 20
2.1.3. 以CH3COOF/CF3COOH方法氟化trans-resveratrol的過程 31
2.2. 製備動物造影用之放射性儲備液 36
2.2.1. 製備[18F]F-CLX的儲備液 37
2.2.2. 製備[18F]F-FBpin的儲備液 40
3. 動物造影實驗 43
3.1. [18F]F-CLX與[18F]F-FBpin於罹患膽管癌大鼠之正子放射斷層造影 45
3.1.1. 動態 (dynamic)造影 45
3.1.2. 靜態 (static)造影 45
3.1.3. 藥物競爭 (competition blocking)實驗 45
4. 硼中子捕獲治療實驗 47
4.1. FBpin在血清之穩定性 47
4.2. 測量FBpin對細胞之毒性 49
4.3. 細胞的硼含量累積實驗 50
4.4. 動物對FBpin的最高劑量測試 51
4.5. 硼中子捕獲治療實驗 52
第三章、結果與討論 55
1. F-CLX混合物的純化與結構鑑定 55
1.1. F-CLX混合物的1H-NMR結構鑑定 55
1.2. F-CLX混合物的13C-NMR結構鑑定 57
1.3. 混合物的19F-NMR光譜與質譜分析 60
2. F-FBpin的純化與結構鑑定 62
2.1. F-FBpin的1H-NMR結構鑑定 62
2.2. F-FBpin的13C-NMR結構鑑定 63
2.2.1. F-FBpin1的13C-NMR結構鑑定 63
2.2.2. F-FBpin2的13C-NMR結構鑑定 65
2.2.3. tR = 12沖提液的成分分析 67
2.2.4. 預測F-FBpin的分子模型 71
2.3. CH3COOF/CF3COOH反應之副產物分析 73
2.3.1. m-FFbf之化合物結構分析 73
3. 以CH3COOF/CF3COOH方法對NSAIDs標幟氟原子之效能探討 76
3.2. CH3COOF/CF3COOH反應之氟化物生成比例 76
3.2.1. CLX氟標幟反應的氟化產物比例 76
3.2.2. FBpin氟標幟反應的氟化產物比例 77
3.3. CH3COOF在不同溶劑中對boronic ester的取代能力差異 77
3.4. CH3COOF/CF3COOH反應之限制 79
4. 利用micro-PET觀察[18F]F-CLX在老鼠肝臟之分布 80
4.1. 動態造影的結果 80
4.2. 靜態造影的結果 83
4.3. 藥物競爭實驗的結果 85
4.4. 正常動物的靜態造影與藥物競爭實驗之結果 88
4.5. [18F]F-CLX應用於膽管癌治療之發展性 89
5. 利用micro-PET觀察[18F]F-FBpin在大鼠肝臟之分布 91
5.1. 動態造影的結果 91
5.2. 靜態造影的結果 92
5.3. 藥物競爭實驗的結果 95
5.4. [18F]F-FBpin應用於膽管癌治療之發展性 96
6. FBpin應用在硼中子捕獲治療的效果 99
6.1. FBpin在血清之測試 99
6.1.1. FBpin在血清之穩定性 99
6.1.2. FBpin在血清之代謝物分析 101
6.2. 測量FBpin對細胞之毒性結果 103
6.2.1. FBpin對CGCCA細胞珠的毒性測試 103
6.2.2. FBpin對HuCCT1細胞珠的毒性測試 103
6.3. 細胞的硼含量累積實驗 105
6.4. 動物對FBpin的最高劑量測試 107
6.5. 膽管癌腫瘤之硼中子捕獲治療效果 108
6.5.1. BNCT組之膽管癌腫瘤變化 109
6.5.2. Neutron only組之膽管癌腫瘤變化 110
6.5.3. BNCT組與neutron only組的大鼠膽管癌腫瘤結果比較 111
第四章、結論 117
第五章、參考文獻 118
第六章、附錄 124
1. RP-HPLC圖譜 124
1.1. 製備非放射性之F-CLX 124
1.2. 製備動物造影用之[18F]F-CLX 125
1.3. 製備動物造影用之[18F]F-FBpin 127
1.4. FBpin與FBS反應之圖譜 129
1.5. FBpin與FBS的代謝物與標準品之圖譜 131
2. ICP-MS 133
3. 光譜與質譜 135
3.1. Celecoxib 135
3.2. F-celecoxib mixture (F-CLX/CLX = 3/2) 138
3.3. FBpin 144
3.4. F-FBpin1 147
3.5. F-FBpin2 153
3.6. m-FFbf 159
3.7. F-FBpin3&4 mixture 165
3.8. Trans-resveratrol 170
3.9. 待測物(1) 173

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