Synthesis and Biological Evaluation of 18F-Labeled Fluoroethoxy Tryptophan Analogues as Potential PET Tumor Imaging Agents
Synthesis and Biological Evaluation of 18F-Labeled Fluoroethoxy Tryptophan Analogues as Potential PET Tumor Imaging Agents
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DOI：
10.1021/mp500312t
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发表时间：
2014-11-01
影响因子：
4.9
通讯作者：
Ametamey, Simon M.
中科院分区：
文献类型：
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作者：
Chiotellis, Aristeidis;Muller, Adrienne;Ametamey, Simon M.
作为我们的研究工作的继续，以正电子发射断层扫描（PET）的肿瘤成像的基于色氨酸的放射性示踪剂的发展，三个新的氟乙氧基色氨酸类似物的合成和体内评价。这些新的示踪剂（即4-（2-[F-18]氟乙氧基）-dl-色氨酸（[F-18]4-FEHTP）、6-（2-[F-18]氟乙氧基）-dl-色氨酸（[F-18]6-FEHTP）和7-（2-[F-18]氟乙氧基）-dl-色氨酸（[F-18]7-FEHTP）在吲哚核心的4-、6-或7-位携带氟乙氧基侧链。通过多步法合成参考化合物和前体。放射合成通过无载体添加的亲核（18）F-benzo完成，遵循间接方法（用[F-18]氟乙基甲苯磺酸酯对相应的羟基色氨酸进行O-烷基化）或直接方法（使用受保护的甲磺酰基前体的亲核[F-18] benzo）。两种方法的放射化学产率（衰变校正）均在10- 18%范围内。对携带异种移植物的小鼠进行的小动物PET成像显示，[F-18]6-FEHTP的肿瘤/背景比最高，在直接比较中，其优于其他两种色氨酸示踪剂以及公认的酪氨酸类似物O-（2-[F-18]氟乙基）-l-酪氨酸（[F-18]l-FET）。对[F-18]6-FEHTP在小细胞肺癌细胞（NCI-H69）中转运机制的研究表明，它最有可能仅通过大型中性氨基酸转运蛋白（LAT）摄取。
As a continuation of our research efforts toward the development of tryptophan-based radiotracers for tumor imaging with positron emission tomography (PET), three new fluoroethoxy tryptophan analogues were synthesized and evaluated in vivo. These new tracers (namely, 4-(2-[F-18]fluoroethoxy)-dl-tryptophan ([F-18]4-FEHTP), 6-(2-[F-18]fluoroethoxy)-dl-tryptophan ([F-18]6-FEHTP), and 7-(2-[F-18]fluoroethoxy)-dl-tryptophan ([F-18]7-FEHTP) carry the fluoroethoxy side chain either at positions 4-, 6-, or 7- of the indole core. Reference compounds and precursors were synthesized by multistep approaches. Radiosynthesis was accomplished by no-carrier-added nucleophilic (18)F-fluorination following either an indirect approach (O-alkylation of the corresponding hydroxytryptophan with [F-18]fluoroethyltosylate) or a direct approach (nucleophilic [F-18] fluorination using a protected mesyl precursor). Radiochemical yields (decay corrected) for both methods were in the range of 10-18%. Small animal PET imaging with xenograft-bearing mice revealed the highest tumor/background ratio for [F-18]6-FEHTP which, in a direct comparison, outperformed the other two tryptophan tracers and also the well-established tyrosine analogue O-(2-[F-18]fluoroethyl)-l-tyrosine ([F-18]l-FET). Investigation of the transport mechanism of [F-18]6-FEHTP in small cell lung cancer cells (NCI-H69) revealed that it is most probably taken up exclusively via the large neutral amino acid transporter(s) (LAT).