製備與評估氟-18芬布芬衍生物4-硼頻那醇甲基[18F]氟芬布芬於正子照影和硼中子捕獲治療之應用

Preparation and biological assessment of 4-boron pinacol methyl [18F] fluorofenbufen for potential application in positron emission tomography and boron neutron capture therapy

田世維(Shih-Wei Tien)

指導教授 ： 俞鐘山

國立清華大學/原子科學院/生醫工程與環境科學系/碩士(2015年)

摘要

4-bromobiphenyl經三步合成methyl 4-oxo-4-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)butanoate (6)，總產率81.6%，經由通入[18F] F2 30分鐘進行放射化學標幟，得到4-硼頻那醇甲基[18F]氟芬布芬 ([18F] FFBpin)，放射化學產率為3.3%，比放射活度為12.3 MBq/ μmole，非放射性產率為：16.2%。
　　利用核磁共振儀及質譜分析FFBpin的結構與前驅物methyl 4-oxo-4-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)butanoate (6)比較，前驅物1H-NMR於δ 7.80和δ 7.85訊號在FFBpin的1H-NMR中消失，而生成了δ 7.51, 7.56和7.65三個新的訊號，且19F-NMR於δ -119.07和δ -119.6各出現了一個訊號，以Hesse Meier Zeeh公式計算推測，氟連接於硼原子鄰位與間位的兩種分子均有生成。FFBpin質譜預測值為m/z : 412.1857，低解析質譜的實驗值為：[M+H]+ 413.21，高解析質譜的實驗值為：412.1858。
　　 [18F]FFBpin對COX-1的半結合抑制值為：3.16 μM，對COX-2的半結合抑制值為：11.22 μM；而[18F] fluorocelecoxib對COX-1的半結合抑制值為：12.59 nM，對COX-2的半結合抑制值為：0.13 nM。 [18F] FFBpin對膽管癌細胞的累積情形隨時間遞增，至120分鐘時，累積量從1 %提升至1.5 %。而對纖維母細胞隨時間沒有明顯的變化。

關鍵字

氟十八 ； 硼中子捕獲治療 ； 非類固醇抗發炎藥物

並列摘要

By using 4-bromobiphenyl as starting material, via three steps synthesis, we obtain methyl 4-oxo-4-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)butanoate (6) with chemical yield 81.6%. After radio-labeling by [18F] F2, 4-boron pinacol methyl [18F] fluorofenbufen (FFBpin) was prepared with a radiochemical yield 3.3% and the specific activity was 12.3 MBq/ μmole.
To figure out the structure of FFBpin, we compared FFBpin’s NMR and mass spectrometry with precursor’s. The 1H-NMR signal of precursor at δ 7.80 and δ 7.85 disappeared, and three new signals raised at δ 7.51, 7.56 and 7.65. The 19F-NMR showed that there were two signals at δ -119.07 and δ -119.6. Calculated by the Hesse Meier Zeeh equation, we deduced the fluorine atom locating on the ortho and meta site of boron atom.
The result showed that [18F] FFBpin preferentially interacts with COX-1 and the IC50 is 3.16 μM comparing with that of COX-2 in 11.22 μM. [18F] fluorocelecoxib binds COX-2 with IC50 0.13 nM and that of COX-1 with IC50 12.59 nM. Besides, increasing accumulation of [18F] FFBpin from 1% to 1.5% in HuCCT1 was observed during 2 hrs-study, in contradictory to a plain accumulation by fibroblast cell.

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