Metabolic stability of 6,7-dialkoxy-4-(2-, 3-and 4-[18F]fluoroanilino)quinazolines, potential EGFR imaging probes
Metabolic stability of 6,7-dialkoxy-4-(2-, 3-and 4-[18F]fluoroanilino)quinazolines, potential EGFR imaging probes
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DOI：
10.1016/j.bmc.2011.03.032
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发表时间：
2011-05-01
影响因子：
3.5
通讯作者：
VanBrocklin, Henry F.
中科院分区：
文献类型：
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作者：
Vasdev, Neil;Dorff, Peter N.;VanBrocklin, Henry F.
表皮生长因子受体（EGFR）在许多肿瘤类型中上调，已成为治疗开发和分子成像的靶标。本研究的目的是评估氟-18标记的苯胺喹唑啉的分布和代谢特征，作为EGFR酪氨酸激酶表达的潜在显像剂。以隐氟化钾[F-18]与1,2-二硝基苯和1,4-二硝基苯以及3-硝基N，N，N-三甲基三氟酸铵在5 min内反应制备了氟-18标记的氟硝基苯。对于2-、3-和4-氟异构体，[F-18]氟掺入硝基芳香族化合物的衰变校正放射化学产率分别为81 +/- 2%、44 +/- 4%和77 +/- 5% （n = 3-5）。硼氢化钠在5 min内还原为相应的[F-18]氟苯胺，转化率大于80%。耦合(f - 18) fluoroaniline-hydrochlorides 6日7-dimethoxy-4 chloro-quinazoline给相应的6,7-dimethoxy-4 -(2 -, 3 -和4 - [f - 18] fluoroanilino)喹唑啉在31 + / - 5%,17 + / - 2%,55 + / - 2%放射化学的产量,分别耦合到6,7-diethoxy-4-chloro-quinazoline产生6 7-diethoxy-4 -(2 -, 3 -和4 - [f - 18] fluoroanilino)喹唑啉在19 + / - 6%,9 + / - 3%,36 + / - 6%放射化学的产量,分别在90分钟结束氟(f - 18)的合成。2-和4-[F-18]氟苯胺喹啉在荷瘤小鼠（MDA-MB-435和MDA-MB-468异种移植物）中的生物分布进行了研究。观察到低肿瘤摄取（注射放射性示踪剂后3小时内每克（ID/g）组织注射剂量< 1%）。4-[F-18]氟苯胺喹唑啉具有较高的骨吸收率（5-15% ID/g）。放射性标记喹唑啉类药物的代谢稳定性通过低温保存的人女性分离肝细胞进一步评估。通过放射性薄层色谱观察到4-氟取代的化合物迅速退化为基线极性代谢物，而2-和3-[F-18]氟苯胺衍生物在长达2小时内明显更稳定，证实了体内生物分布研究。对取代[F-18]氟苯胺是放射性药物中常见的结构基序，极易被代谢降解。(C) 2011 Elsevier Ltd.版权所有。
Epidermal growth factor receptors (EGFR), upregulated in many tumor types, have been a target for therapeutic development and molecular imaging. The objective of this study was to evaluate the distribution and metabolic characteristics of fluorine-18 labeled anilinoquinazolines as potential imaging agents for EGFR tyrosine kinase expression. Fluorine-18 labeled fluoronitrobenzenes were prepared by reaction of potassium cryptand [F-18] fluoride with 1,2- and 1,4-dinitrobenzenes, and 3-nitro-N,N,N-trimethylanilinium triflate in 5 min. Decay-corrected radiochemical yields of [F-18] fluoride incorporation into the nitro-aromatic compounds were 81 +/- 2%, 44 +/- 4% and 77 +/- 5% (n = 3-5) for the 2-, 3- and 4-fluoro isomers, respectively. Sodium borohydride reduction to the corresponding [F-18]fluoroanilines was achieved with greater than 80% conversion in 5 min. Coupling of [F-18]fluoroaniline-hydrochlorides to 6,7-dimethoxy-4- chloro-quinazoline gave the corresponding 6,7-dimethoxy-4-(2-, 3- and 4-[F-18]fluoroanilino) quinazolines in 31 +/- 5%, 17 +/- 2% and 55 +/- 2% radiochemical yield, respectively, while coupling to the 6,7-diethoxy-4-chloro-quinazoline produced 6,7-diethoxy-4-(2-, 3- and 4-[F-18] fluoroanilino) quinazolines in 19 +/- 6%, 9 +/- 3% and 36 +/- 6% radiochemical yield, respectively, in 90 min to end of synthesis from [F-18] fluoride. Biodistribution of 2- and 4-[F-18]fluoroanilinoquinazolines was conducted in tumor-bearing mice (MDA-MB-435 and MDA-MB-468 xenografts). Low tumor uptake (< 1% injected dose per gram (ID/g) of tissue up to 3 h postinjection of the radiotracers) was observed. High bone uptake (5-15% ID/g) was noted with the 4-[F-18] fluoroanilinoquinazolines. The metabolic stabilities of radiolabeled quinazolines were further evaluated by incubation with human female cryopreserved isolated hepatocytes. Rapid degeneration of the 4-fluoro-substituted compounds to baseline polar metabolites was observed by radio-TLC, whereas, the 2- and 3-[F-18] fluoroaniline derivatives were significantly more stable, up to 2 h, corroborating the in vivo biodistribution studies. para-Substituted [F-18] fluoroanilines, a common structural motif in radiopharmaceuticals, are highly susceptible to metabolic degradation. (C) 2011 Elsevier Ltd. All rights reserved.