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By Organic Ion Transporters Explains Renal Background in [18F]FAMT Positron Emission Tomography

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By Organic Ion Transporters Explains Renal Background in [18F]FAMT Positron Emission Tomography Journal of Pharmacological Sciences 130 (2016) 101e109 HOSTED BY Contents lists available at ScienceDirect Journal of Pharmacological Sciences journal homepage: www.elsevier.com/locate/jphs Full paper Transport of 3-fluoro-L-a-methyl-tyrosine (FAMT) by organic ion transporters explains renal background in [18F]FAMT positron emission tomography Ling Wei a, Hideyuki Tominaga b, Ryuichi Ohgaki a, Pattama Wiriyasermkul a, Kohei Hagiwara a, Suguru Okuda a, Kyoichi Kaira c, Yukio Kato d, Noboru Oriuchi b, * Shushi Nagamori a, Yoshikatsu Kanai a, a Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan b Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan c Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan d Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan article info abstract 18 18 Article history: A PET tracer for tumor imaging, 3- F-L-a-methyl-tyrosine ([ F]FAMT), has advantages of high cancer- Received 23 November 2015 specificity and low physiological background. In clinical studies, FAMT-PET has been proved useful for Received in revised form the detection of malignant tumors and their differentiation from inflammation and benign lesions. The 17 December 2015 tumor specific uptake of FAMT is due to its high-selectivity to cancer-type amino acid transporter LAT1 Accepted 6 January 2016 among amino acid transporters. In [18F]FAMT PET, kidney is the only organ that shows high physiological Available online 21 January 2016 background. To reveal transporters involved in renal accumulation of FAMT, we have examined [14C] FAMT uptake on the organic ion transporters responsible for the uptake into tubular epithelial cells. We Keywords: 14 14 PET tracer have found that OAT1, OAT10 and OCTN2 transport [ C]FAMT. The [ C]FAMT uptake was inhibited by Organic anion probenecid, furosemide and ethacrynic acid, consistent with the properties of the transporters. The 14 Transporter amino acid uptake inhibitor, 2-amino-2-norbornanecarboxylic acid (BCH), also inhibited the [ C]FAMT 14 þ Epithelial transport uptake, whereas OCTN2-mediated [ C]FAMT uptake was Na -dependent. We propose that FAMT uptake Kidney 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. © 2016 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction expression of glucose transporters responsible for cellular uptake of FDG in non-tumor tissues (2e4). Amino acid PET tracers have, thus, In positron emission tomography (PET) for tumor imaging, a been developed to overcome such disadvantages of [18F]FDG PET, 18 18 glucose analog, 2- F-fluoro-2-deoxy-D-glucose ([ F]FDG), has most because they generally exhibit more tumor-selective properties (5). 18 11 11 18 commonly been used as a PET tracer (1). Although [ F]FDG PET has For example, L-[ C-methyl]methionine ([ C]MET) and O-(2-[ F] 18 been used successfully for the clinical diagnosis of malignant tumors, fluoroethyl)-L-tyrosine ([ F]FET) (Supplemental Fig. 1) have been it sometimes suffers from false-positive findings in inflammatory shown to be less accumulated in brain and inflammatory lesions tissues and benign lesions and high physiological backgrounds compared with [18F]FDG (5), although they still exhibit some extent particularly in brain (2). It is due to the upregulation or high level of of false-positives and physiological backgrounds in PET (6, 7). In single photon emission computed tomography (SPECT), an 123 123 amino acid tracer 3- I-L-a-methyl-tyrosine ([ I]IMT) (Supplemental Fig. 1) has been used for tumor imaging (5).[123I]IMT * Corresponding author. Department of Bio-system Pharmacology, Graduate accumulates in malignant tumors with less false positives and with School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. low background in brain (5). Based on such high tumor specificity of Tel.: þ81 6 6879 3521; fax: þ81 6 6879 3529. 123 18 a 18 E-mail address: [email protected] (Y. Kanai). [ I]IMT, 3- F-L- -methyl-tyrosine ([ F]FAMT) (Supplemental Fig. 1) Peer review under responsibility of Japanese Pharmacological Society. hasbeendevelopedasaPETtracerfortumorimagingbysubstituting http://dx.doi.org/10.1016/j.jphs.2016.01.001 1347-8613/© 2016 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 102 L. Wei et al. / Journal of Pharmacological Sciences 130 (2016) 101e109 123Iof[123I]IMT with 18F (8). We have demonstrated in clinical studies 19). It is predominantly expressed in primary tumors of various tis- that [18F]FAMT accumulates specifically in malignant tumors (9e16). sue origins and their metastatic lesions except some non-tumor cells [18F]FAMT-PET has been proved useful for the prediction of prognosis (20, 21).Weshowedthata-methyl moiety of FAMT is responsible for and for the differentiation of malignant tumors from inflammation its preference for LAT1 (17,22e24). In fact, the accumulation of [18F] and benign lesions (9e16). In the previous study, we showed that FAMT in PET is well correlated with the level of LAT1 expression in FAMT is specifically transported by cancer-type amino acid transporter various tumors (11, 12, 14, 16). L-type amino acid transporter 1 (LAT1, SLC7A5), which explains tumor- In [18F]FAMT PET, kidney is the only organ that shows high þ specificaccumulationof[18F]FAMT in PET (17).LAT1isaNa -inde- physiological uptake of [18F]FAMT, limiting its use for the diagnosis pendent amino acid transporter mediating the uptake of large neutral of renal carcinoma (9, 10, 13, 16, 25). Renal accumulation of SPECT amino acids including aromatic and branched-chain amino acids (18, tracer [123I]IMT with the FAMT-related structure (Supplemental Fig. 1. [14C]FAMT transport by organic anion transporters. The uptake of 50 mM[14C]FAMT (FAMT) and a typical substrate [14C]p-aminohippurate (PAH) was measured for OAT1 (A),OAT3(B) and OAT10 (D). The uptake of 50 mM[14C]FAMT (FAMT) and a typical substrate [14C]urate was measured for URAT1 (E). The uptake of 5 mM[14C]FAMT (FAMT) and a typical substrate [3H]estrone-3-sulfate (ES) was measured for OAT4 (C). The uptake was measured for 30 min on the control oocytes (“À”) and the oocytes expressing transporter (“þ”) in ND96 buffer. The uptake rate was expressed as mean ± SEM (n ¼ 6e10). *, p < 0.05; n.s., not significant. L. Wei et al. / Journal of Pharmacological Sciences 130 (2016) 101e109 103 Fig. 1) was reported to be highly suppressed by probenecid and p- Functional expression of each transporter in Xenopus oocytes aminohippurate (26, 27), suggesting it to be a transporter-mediated was confirmed by measurement of the uptake of its typical sub- process (28). Furthermore, probenecid, furosemide and ethacrynic strate as described in the legends to figures. To examine the acid, which interact with organic anion transporters (29e31), dependence of the transport on substrate concentrations, the up- reduced tubular secretion of [125I]IMT in mice (28). Therefore, in take of [14C]FAMT was measured in the oocytes expressing OAT10 the present study, in order to reveal transporters involved in renal at varied concentration of FAMT. Transport rate at each concen- accumulation of FAMT in PET, we have examined the transport of tration was obtained by subtracting the uptake rate of control oo- 14C-labeled FAMT on the organic ion transporters responsible for cytes without cRNA injection from that of the oocytes expressing the uptake of organic solutes into tubular epithelial cells in kidney. OAT10. The transport rate was plotted against FAMT concentration and fitted to a MichaeliseMenten curve to obtain Michaelis con- 2. Materials and methods stant (Km) and maximal transport rate (Vmax) using enzyme kinetics module of SigmaPlot 12.5 (Systat Software, San Jose, CA). 2.1. Radiolabeled chemicals EadieeHofstee plot was also obtained using enzyme kinetics module of SigmaPlot 12.5 (Systat Software, San Jose, CA). In the [14C]FAMT was synthesized by Sekisui Medical (Tokyo, Japan) to inhibition experiments, the uptake of 5 mM[14C]FAMT were obtain high specific radioactivity by BücherereStrecker reaction measured in the presence of inhibitors (500 mM for probenecid, using 3-fluoro-4-methoxyphenylacetone (NARD Institute, Ltd., furosemide and ethacrynic acid; 0.1, 0.5 and 5 mM for BCH). Amagasaki, Japan) as a starting material (32).[14C]FAMT was For transport measurements, 5 to 13 oocytes were used for each identified by 1H nuclear magnetic resonance analysis (AV400M, measurement. Each data in the figures represents the mean ± SEM Bruker Biospin), high-performance liquid chromatography (Agilent To confirm the reproducibility of the results, three separate ex- 1200) and mass spectrometry (LTQ XL, Thermo Fisher Scientific) periments using different batches of oocytes were performed. (17). The purity of the [14C]FAMT was determined to be 99% by Statistical differences were determined using the Student's un- high-performance liquid chromatography. Its specific activity was paired t-test. Differences were considered significant at p < 0.05. 1.77 GBq/mmol. [14C]p-aminohippurate (2.04 GBq/mmol), [14C]urate (2.04 GBq/ mmol) and [14C]tetraethylammonium (2.04 GBq/mmol) were pur- chased from American Radiolabeled Chemicals (St. Louis, MO). [3H] estrone-3-sulfate (1.665 TBq/mmol) was obtained from Perki- nElmer (Boston, MA). 2.2. Chemicals p-Aminohippurate, estrone-3-sulfate, tetraethylammonium and 2-amino-2-norbornanecarboxylic acid (BCH) were purchased from Sigma-Aldrich (St.
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