合成有潛力做為正子斷層掃描腫瘤造影劑的氟取代蒽醌類化合物

Abstract

根據本實驗室先前對一系列氟化胺基蒽醌類化合物的藥理活性篩選結果，選定研究合成氟-十八標記之化合物48以應用於正子斷層掃描；合成原則是將導入氟-十八的反應盡量安排至整個合成路徑的末端，並且最佳化整體反應所需要的時間，使氟-十八之放射損失減至最小，理論上可將氟-十八經由直接親核取代導入前驅物2，或間接的利用氟-十八取代之輔基的方式分別導入前驅物1來得到氟-十八標記之目標化合物48；本論文成功合成可應用之前驅物1 (49)及2 (39)，氟化標準品38及48；首先，將買來之N-(3-羥丙基)乙二胺側鏈末端之羥基利用TBDMS保護基保護，進行氧化縮合反應接至Leucoquinizarin上，接著胺基(R1和R3)用三苯基甲基保護基保護，再利用氟化鉀和Kryptofix 222將羥基上之TBDMS保護基移去，進行甲磺醯化反應(Mesylation)可得前驅物39；此外，將買來之乙二胺用Teoc保護基保護後，一樣進行氧化縮合反應接至Leucoquinizarin上，接著胺基(R1)用三苯基甲基保護基保護，再利用氟化鉀和Kryptofix 222將羥基上之Teoc保護基移去，得到前驅物49，接著前驅物49和和輔基，3-氟丙基對甲苯磺酸，做親核取代反應，可得氟化標準品48，產率為26%；最後將三苯基甲基保護基保護標準品48的胺基，可得氟化標準品38。

Based on the results of a series of studies on the pharmacological activity of fluoroaminoqnthraquinones in our laboratory, fluorine-18 labeled compound 48 was selected to be synthesized for the application of positron emission tomography in this study. The synthetic principle is to introduce fluorine-18 at the terminal step of the whole synthetic route and to optimize the total reaction time, as to minimize the decay of radioactive fluorin-18. Theoretically, this can be achieved by two synthetic methods: direct nucleophilic substitution through introducing fluorine-18 into precursor 2 and indirect substitution through introducing fluoring-18 labeled prosthetic group into precursor 1 to get the fluorine-18 labeled target compound 48. Precursor 1 (49), precursor 2 (39) and fluorination standard compound 38 and 48 were successfully synthesized in this study. First, the terminal hydroxyl group of commercial available starting material, N-(3-hydroxylpropyl)ethylenediamine, was protected with TBDMS protecting group and then bound to the Leucoquinizarin by condensation and oxidation reactions. The amino groups (R1 and R3) were protected by triphenylmethyl protecting group and then the TBDMS protecting group was removed by potassium fluoride and Kryptofix 222. Eventually, precursor 39 was obtain by Mesylation. Whereas for precursor 49, standard compound 48 and standard compound 38, the amino group (R2) in ethylenediamine was protected by Teoc protecting group and bound to Leucoquinizarin by condensation and oxidation reactions. Then, then the amino group (R1) was protected by triphenylmethyl protecting group and the Teoc protecting group was removed by potassium fluoride and Kryptofix 222 to get precursor 49. The standard compound 48, yield: 26%, was obtained from precursor 49 by nucleophilic substitution with the prosthetic group, 3-fluoropropyl-p-toluene sulfonate. Finally, the amino group in standard compound 48 was protected by triphenylmethyl protecting group to gain fluorination standard compound 38.