Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Life Sciences Division, TRIUMF, Vancouver, British Columbia, Canada.
J Nucl Med. 2019 Jul;60(7):1003-1009. doi: 10.2967/jnumed.118.220483. Epub 2019 Jan 25.
The large, neutral L-type amino acid transporters (LAT1-LAT4) are sodium-independent transporters that are widely distributed throughout the body. LAT expression levels are increased in many types of cancer, and their expression increases as cancers progress, leading to high expression levels in high-grade tumors and metastases. Because of the key role and overexpression of LAT in many types of cancer, radiolabeled LAT substrates are promising candidates for nuclear imaging of malignancies that are not well revealed by conventional radiotracers. The goal of this study was to examine the structure-activity relationships of a series of F-labeled amino acids that were predicted to be substrates of the LAT transport system. Using a photocatalytic radical fluorination, we prepared a series of 11 fluorinated branched-chain amino acids and evaluated them and their nonfluorinated parents in a cell-based LAT affinity assay. We radiofluorinated selected branched-chain amino acids via the same radical fluorination reaction and evaluated tumor uptake in U-87 glioma xenograft-bearing mice. Structure-activity relationship trends observed in a LAT affinity assay were maintained in further studies, as well as using a U-87 xenograft model. LAT1 uptake was tolerant of fluorinated amino acid stereochemistry and chain length. PET imaging and biodistribution studies showed that the tracer ()-5-F-fluorohomoleucine had rapid tumor uptake, favorable kinetics, and good stability. By using an affinity assay, we could predict LAT-mediated cancer cell uptake in a panel of fluorinated amino acids. These predictions were consistent when applied to different cell lines and murine tumor models, and several new tracers may be suitable for further development as oncologic PET imaging agents.
大型中性 L 型氨基酸转运体（LAT1-LAT4）是不依赖钠离子的转运体，广泛分布于全身。许多类型的癌症中 LAT 的表达水平升高，并且随着癌症的进展其表达增加，导致高级别肿瘤和转移瘤中表达水平升高。由于 LAT 在许多类型的癌症中起着关键作用并且过表达，放射性标记的 LAT 底物是用于核成像恶性肿瘤的有前途的候选物，而常规放射性示踪剂不能很好地揭示这些恶性肿瘤。本研究的目的是研究一系列预测为 LAT 转运系统底物的 F 标记氨基酸的构效关系。使用光催化自由基氟化，我们制备了一系列 11 个氟化支链氨基酸，并在基于细胞的 LAT 亲和力测定中评估了它们及其非氟化亲本。我们通过相同的自由基氟化反应对选定的支链氨基酸进行放射性氟化，并在 U-87 神经胶质瘤异种移植瘤荷瘤小鼠中评估肿瘤摄取。在 LAT 亲和力测定中观察到的构效关系趋势在进一步研究中得到了维持，并且在 U-87 异种移植模型中也得到了维持。LAT1 摄取可以耐受氟化氨基酸的立体化学和链长。PET 成像和生物分布研究表明，示踪剂 ()-5-F-氟同型亮氨酸具有快速的肿瘤摄取、良好的动力学和良好的稳定性。通过使用亲和力测定，我们可以预测一系列氟化氨基酸中 LAT 介导的癌细胞摄取。这些预测在应用于不同的细胞系和小鼠肿瘤模型时是一致的，并且几种新的示踪剂可能适合进一步开发作为肿瘤 PET 成像剂。
