合成並評估新穎血清素轉運體配體做為正子斷層掃描示蹤劑

Abstract

N,N-Dimethyl-2-(arylthio)benzylamines被報導對血清素轉運體具有高度的結合力與選擇性，其中較具潛力的有[11C]MADAM和[18F]5-FADAM，並利用它們作為先導化合物，以氟18聚乙二醇側鏈在B環4’位置做修飾，合成MADAM衍生物7、14與18與其氟-18標定前驅物26-28，5-FADAM衍生物45與46。另外也合成已知化合物43與44當作比較。 使用2-amino-5-methoxybenzoic acid為起始物，經過diazotization轉換成thiol group並個別與1-bromo-4-methyl-2-nitrobenzene、1-bromo-2-nitrobenzene與1-bromo-4-fluoro-2-nitrobenzene進行SNAr反應，並經過二甲胺置換羧酸與去甲基得到關鍵中間體3、33與34。關鍵中間體經過氧-烷化、醇-氟基置換及還原反應得到標準品7、14、18與43-46。氟-18標定前驅物26-28由關鍵中間體3經氧-烷化、還原反應與甲磺醯化反應而得。另外利用SnCl2還原硝基而意外得到的化合物8與18，藥理實驗還在進行中。 化合物7、14和18在分布係數評估中，隨著聚乙二醇長度增加，其Log D減少，水溶性增加。藥理實驗中，7、14和18隨著聚乙二醇長度增加，其結合力並無顯著下降，Ki分別為0.25、0.5和1.32 nM。而氟18標定化合物18F-7、18F-14和18F-18中，只有18F-7和18F-14在大鼠腦內有高度吸收，但此兩個化合物清除率慢，且SERT特異性結合尚需進一步確認。 已知化合物43與44與[18F]5-FADAM衍生物45與46，其Log D值為3.37、3.30、3.70、3.63。綜合比較Log D值，A環五位置取代其脂溶性由大到小分別是氟取代、甲基取代和無取代，而當聚乙二醇越長時其Log D越小，極性越大。已知化合物43和44與具潛力化合物45與46之藥理評估還在進行中。

N, N-Dimethyl-2-(arylthio)benzylamines were reported to have high affinity and selectivity toward SERT. Choosing the promising [11C]MADAM and [18F]5-FADAM as lead compound, we designed and synthesis of the B ring on 4’ position by adding several PEG unit to afford [11C]MADAM derivatives 7, 14, 18 and their F-18 labeled precursor 26-28, and [18F]5-FADAM derivatives 45, 46. In addition, we also prepared known compound 43 and 44 for comparison. Using 2-amino-5-methoxybenzoic acid as the starting material and then go through diazotization into thiol group. The thiol group individually reacts with 1-bromo-4-methyl-2-nitrobenzene, 1-bromo-2-nitrobenzene and 1-bromo-4-fluoro -2-nitrobenzene for SNAr reaction and then through displacement of carboxylic acid and demethylation to afford key intermediate 3, 33 and 34. The key intermediate undergo SN2, conversion from alcohols to the alkyl fluorides, and reduction to afford 7、14、18 and 43-46 and also using key intermediate to prepare F-18 labeled precursor 26-28 by SN2 reaction, reduction and mesylation. The in vitro binding assay are in progress. As 7, 14, 18 PEG substitution chain length increase, Log D value were reduced and accompanied by increased water solubility. In vitro binding assay of compound 7, 14, 18, the longer the PEG, the decreasing affinity toward SERT will happen. The Ki value are 0.25、0.5 and 1.32 nM, respectively. From the the rat biodistribution evaluation of 18F-7, 18F-14 and 18F-18, only 18F-7 and 18F-14 showed high brain uptake but showed slow washed out rate. Furthermore, it is necessary to confirm that 18F-7, 18F-14 and 18F-18 are specific binding toward SERT in vivo. The Log D of known compound 43, 44 and the [18F]5-FADAM derivatives 45, 46 are 3.37、3.30、3.70、3.63 respectively. Comprehensive comparison of the Log D value can conclude: (1) the increasing hydrophilicity on 5 position substitution is fluorine-substituted, methyl substituted, unsubstituted and (2) the longer the PEG side chain substitution on 4’ position, the more the hydrophilicity will be. The known compound 43, 44 and our potential SERT ligand 45, 46 in vitro assay are in progress.