Synthesis and evaluation of ¹⁸F labeled FET prodrugs for tumor imaging.
Synthesis and evaluation of ¹⁸F labeled FET prodrugs for tumor imaging.
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DOI：
10.1016/j.nucmedbio.2013.09.011
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发表时间：
2014-01
影响因子：
3.1
通讯作者：
Kung HF
中科院分区：
文献类型：
--
作者：
Wang L;Lieberman BP;Ploessl K;Kung HF
O-（2-[18 F]氟乙基）-L-酪氨酸（FET，[18 F]1）是一种基于氨基酸的脑肿瘤显像剂。本文报道了三种FET前药：O-（2-[18 F]氟乙基）-L-酪氨酰-L-甘氨酸（FET-Gly，[18 F]2）、O-（2-[18 F]氟乙基）-L-酪氨酰-L-丙氨酸（FET-Ala，[18 F]3）和N-乙酰基O-（2-[18 F]氟乙基）-L-酪氨酸（AcFET，[18 F]4）的合成和评价。我们研究了它们在血液中的代谢和与FET（[18F]1）相比的成像特性。三个新的[18F]FET衍生物，2 - 4，从它们相应的甲苯磺酸盐前体通过亲核取代和随后的脱保护反应制备。在9 L胶质瘤癌细胞系中进行体外摄取研究。进行体外和体内水解研究以评价FET前药在血液和Fisher 344大鼠中的水解。然后在携带9 L肿瘤的大鼠中进行生物分布和PET成像研究。制备了具有3 - 28%衰变校正放射化学产率、良好对映体纯度（> 95%）和高放射化学纯度（> 95%）的新FET前药。在9 L细胞中，与FET（[18 F]1）的高摄取相比，FET-Gly（[18 F]2）、FET-Ala（[18 F]3）和AcFET（[18 F]4）的摄取可忽略不计。大鼠和人血液中FET-Gly（[18 F]2）、FET-Ala（[18 F]3）和AcFET（[18 F]4）的代谢研究表明，FET-Ala（[18 F]3）水解为FET（[18 F]1）的速度快于FET-Gly（[18 F]2）或AcFET（[18 F]4）。在体内血液中，大多数FET-Ala（79%）在5 min内转化为FET（[18 F]1）。生物分布研究表明，FET-Ala（[18 F]3）显示出最高的肿瘤摄取。FET-Ala（[18 F]3）和FET（[18 F]1）的肿瘤与背景比相当，并且似乎优于FET-Gly（[18 F]2）和AcFET（[18 F]4）。PET成像研究表明，FET（[18 F]1）和FET-Ala（[18 F]3）都可以有效地显示肿瘤，并且它们具有相似的成像特征。FET-Ala（[18 F]3）作为FET（[18 F]1）的前体药物，有望用于肿瘤氨基酸代谢的PET显像。
O-(2-[18F]fluoroethyl)-L-tyrosine (FET, [18F]1) is a useful amino-acid-based imaging agent for brain tumors. This paper reports the synthesis and evaluation of three FET prodrugs, O-(2-[18F]fluoroethyl)-L-tyrosyl-L-glycine (FET-Gly, [18F]2), O-(2-[18F]fluoroethyl)-L-tyrosyl-L-alanine (FET-Ala, [18F]3) and N-acetyl O-(2-[18F]fluoroethyl)-L-tyrosine (AcFET, [18F]4), which could be readily hydrolyzed to FET in vivo for tumor imaging. We investigated their metabolism in the blood and imaging properties in comparison to FET ([18F]1). Three new [18F]FET derivatives, 2 – 4, were prepared from their corresponding tosylate-precursors through nucleophilic fluorination and subsequent deprotection reactions. In vitro uptake studies were carried out in 9L glioma cancer cell lines. In vitro and in vivo hydrolysis studies were conducted to evaluate the hydrolysis of FET prodrugs in blood and in Fisher 344 rats. Biodistribution and PET imaging studies were then performed in rats bearing 9L tumors. New FET prodrugs were prepared with 3 – 28 % decay corrected radiochemical yields, good enantiomeric purity (> 95 %) and high radiochemical purity (> 95 %). FET-Gly ([18F]2), FET-Ala ([18F]3), and AcFET ([18F]4) exhibited negligible uptake in comparison to the high uptake of FET ([18F]1) in 9L cells. Metabolism studies of FET-Gly ([18F]2), FET-Ala ([18F]3), and AcFET ([18F]4) in rat and human blood showed that FET-Ala ([18F]3) was hydrolyzed to FET ([18F]1) faster than FET-Gly ([18F]2) or AcFET ([18F]4). Most of the FET-Ala (79 %) was converted to FET ([18F]1) within 5 min in blood in vivo. Biodistribution studies demonstrated that FET-Ala ([18F]3) displayed the highest tumor uptake. The tumor-to-background ratios of FET-Ala ([18F]3) and FET ([18F]1) were comparable and appeared to be better than those of FET-Gly ([18F]2) and AcFET ([18F]4). PET imaging studies showed that both FET ([18F]1) and FET-Ala ([18F]3) could visualize tumors effectively, and that they share similar imaging characteristics. FET-Ala ([18F]3) demonstrated promising properties as a prodrug of FET ([18F]1), which could be used in PET imaging of tumor amino acid metabolism.
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影响因子：
2.1
作者：
del Amo, Vicente;McGlone, Adam P.;Davis, Anthony P.
通讯作者：
Davis, Anthony P.
影响因子：
3.1
作者：
Ishiwata, K;Shinoda, M;Senda, M
通讯作者：
Senda, M
影响因子：
9.3
作者：
Heiss, Wolf-Dieter;Raab, Peter;Lanfermann, Heinrich
通讯作者：
Lanfermann, Heinrich
影响因子：
9.8
作者：
ADIBI, SA;PALEOS, GA;MORSE, EL
通讯作者：
MORSE, EL
影响因子：
3.1
作者：
Inoue, Osamu;Hosoi, Rie;Gee, Antony
通讯作者：
Gee, Antony