Wei Ling, Tominaga Hideyuki, Ohgaki Ryuichi, Wiriyasermkul Pattama, Hagiwara Kohei, Okuda Suguru, Kaira Kyoichi, Kato Yukio, Oriuchi Noboru, Nagamori Shushi, Kanai Yoshikatsu
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan.
J Pharmacol Sci. 2016 Feb;130(2):101-9. doi: 10.1016/j.jphs.2016.01.001. Epub 2016 Jan 21.
A PET tracer for tumor imaging, 3-(18)F-l-α-methyl-tyrosine ([(18)F]FAMT), has advantages of high cancer-specificity and low physiological background. In clinical studies, FAMT-PET has been proved useful for the detection of malignant tumors and their differentiation from inflammation and benign lesions. The tumor specific uptake of FAMT is due to its high-selectivity to cancer-type amino acid transporter LAT1 among amino acid transporters. In [(18)F]FAMT PET, kidney is the only organ that shows high physiological background. To reveal transporters involved in renal accumulation of FAMT, we have examined [(14)C]FAMT uptake on the organic ion transporters responsible for the uptake into tubular epithelial cells. We have found that OAT1, OAT10 and OCTN2 transport [(14)C]FAMT. The [(14)C]FAMT uptake was inhibited by probenecid, furosemide and ethacrynic acid, consistent with the properties of the transporters. The amino acid uptake inhibitor, 2-amino-2-norbornanecarboxylic acid (BCH), also inhibited the [(14)C]FAMT uptake, whereas OCTN2-mediated [(14)C]FAMT uptake was Na(+)-dependent. We propose that FAMT uptake by OAT1, OAT10 and OCTN2 into tubular epithelial cells could contribute to the renal accumulation of FAMT. The results from this study would provide clues to the treatments to reduce renal background and enhance tumor uptake as well as to designing PET tracers with less renal accumulation.
一种用于肿瘤成像的正电子发射断层显像（PET）示踪剂，3-(18)F-l-α-甲基酪氨酸（[(18)F]FAMT），具有癌症特异性高和生理本底低的优点。在临床研究中，FAMT-PET已被证明可用于检测恶性肿瘤以及将其与炎症和良性病变区分开来。FAMT对肿瘤的特异性摄取归因于其在氨基酸转运体中对癌型氨基酸转运体LAT1的高选择性。在[(18)F]FAMT PET中，肾脏是唯一显示出高生理本底的器官。为了揭示参与FAMT肾脏蓄积的转运体，我们研究了[(14)C]FAMT在负责摄取进入肾小管上皮细胞的有机离子转运体上的摄取情况。我们发现有机阴离子转运体1（OAT1）、有机阴离子转运体10（OAT10）和有机阳离子转运体2（OCTN2）可转运[(14)C]FAMT。[(14)C]FAMT的摄取受到丙磺舒、呋塞米和依他尼酸的抑制，这与这些转运体的特性一致。氨基酸摄取抑制剂2-氨基-2-降冰片烷羧酸（BCH）也抑制[(14)C]FAMT的摄取，而OCTN2介导的[(14)C]FAMT摄取是钠依赖性的。我们提出，OAT1、OAT10和OCTN2将FAMT摄取到肾小管上皮细胞中可能导致FAMT在肾脏的蓄积。本研究结果将为减少肾脏本底和增强肿瘤摄取的治疗方法以及设计肾脏蓄积较少的PET示踪剂提供线索。
