Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093, Zurich, Switzerland.
Mol Imaging Biol. 2014 Jun;16(3):412-20. doi: 10.1007/s11307-013-0711-2. Epub 2013 Dec 5.
The concentrative amino acid transporter ATB(0,+) (SLC6A14) is under evaluation as a target for anticancer therapy. An ATB(0,+)-selective positron emission tomography (PET) probe could advance preclinical drug development. We characterised the cationic tyrosine analogue O-2((2-[(18)F]fluoroethyl)methyl-amino)ethyltyrosine ([(18)F]FEMAET) as a PET probe for ATB(0,+) activity.
Cell uptake was studied in vitro. ATB(0,+) expression was quantified by real-time PCR. [(18)F]FEMAET accumulation in xenografts was investigated by small animal PET with mice.
[(18)F]FEMAET accumulated in PC-3 and NCI-H69 cancer cells in vitro. As expected for ATB(0,+) transport, uptake was inhibited by LAT/ATB(0,+) inhibitors and dibasic amino acids, and [(18)F]FEMAET efflux was only moderately stimulated by extracellular amino acids. ATB(0,+) was expressed in PC-3 and NCI-H69 but not MDA-MB-231 xenografts. PET revealed accumulation in PC-3 and NCI-H69 xenografts and significant reduction by ATB(0,+) inhibition. Uptake was negligible in MDA-MB-231 xenografts.
ATB(0,+) activity can be imaged in vivo by PET with [(18)F]FEMAET.
集中氨基酸转运蛋白 ATB(0,+)（SLC6A14）正在被评估为癌症治疗的靶点。ATB(0,+) 选择性正电子发射断层扫描（PET）探针可以促进临床前药物开发。我们将阳离子酪氨酸类似物 O-2((2-[(18)F]氟乙基)甲基-氨基)乙基酪氨酸([(18)F]FEMAET) 鉴定为 ATB(0,+) 活性的 PET 探针。
在体外研究细胞摄取。通过实时 PCR 定量 ATB(0,+) 表达。用小鼠进行小动物 PET 研究 [(18)F]FEMAET 在异种移植中的积累。
[(18)F]FEMAET 在 PC-3 和 NCI-H69 癌细胞中体外积累。正如预期的 ATB(0,+) 转运，摄取被 LAT/ATB(0,+) 抑制剂和二碱基氨基酸抑制，并且仅适度地被细胞外氨基酸刺激 [(18)F]FEMAET 外排。ATB(0,+) 在 PC-3 和 NCI-H69 中表达，但在 MDA-MB-231 异种移植中不表达。PET 显示在 PC-3 和 NCI-H69 异种移植中积累，并通过 ATB(0,+) 抑制显著减少。在 MDA-MB-231 异种移植中摄取可忽略不计。
可以通过 [(18)F]FEMAET 进行体内 PET 成像来检测 ATB(0,+) 活性。
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