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Research ArticleMetabolism, Transport, and Pharmacogenetics

Interaction of Halogenated Tyrosine/Phenylalanine Derivatives with Organic Anion Transporter 1 in the Renal Handling of Tumor Imaging Probes

Chunhuan Jin, Ling Wei, Ryuichi Ohgaki, Hideyuki Tominaga, Minhui Xu, Suguru Okuda, Hiroki Okanishi, Yasuharu Kawamoto, Xin He, Shushi Nagamori and Yoshikatsu Kanai
Journal of Pharmacology and Experimental Therapeutics December 2020, 375 (3) 451-462; DOI: https://doi.org/10.1124/jpet.120.000235
Chunhuan Jin
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Ling Wei
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Ryuichi Ohgaki
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Hideyuki Tominaga
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Minhui Xu
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Suguru Okuda
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Hiroki Okanishi
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Yasuharu Kawamoto
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Xin He
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Shushi Nagamori
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Yoshikatsu Kanai
Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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Abstract

Halogenated tyrosine/phenylalanine derivatives have been developed for use in tumor imaging and targeted alpha therapy. 3-Fluoro-α-methyl-l-tyrosine (FAMT), targeting amino acid transporter LAT1 (SLC7A5), is a cancer-specific positron emission tomography probe that exhibits high renal accumulation, which is supposed to be mediated by organic anion transporter OAT1 (SLC22A6). In the present study, we investigated the structural requirements of FAMT essential for interaction with OAT1. OAT1 transported FAMT with a Km of 171.9 μM. In structure-activity relationship analyses, removal of either the 3-halogen or 4-hydroxyl group from FAMT or its structural analog 3-iodo-α-methyl-l-tyrosine greatly decreased the interaction with OAT1, reducing the [14C]p-aminohippurate uptake inhibition and the efflux induction. By contrast, the α-methyl group, which is essential for LAT1 specificity, contributed to a lesser degree. In fluorinated tyrosine derivatives, fluorine at any position was accepted by OAT1 when there was a hydroxyl group at the ortho-position, whereas ortho-fluorine was less interactive when a hydroxyl group was at meta- or para-positions. The replacement of the ortho-fluorine with a bulky iodine atom greatly increased the interaction. In in vivo studies, probenecid decreased the renal accumulation (P < 0.001) and urinary excretion (P = 0.0012) of FAMT, whereas the plasma concentration was increased, suggesting the involvement of OAT1-mediated transepithelial organic anion excretion. LAT1-specific 2-fluoro-α-methyltyrosine, which had lower affinity for OAT1, exhibited lower renal accumulation (P = 0.0142) and higher tumor uptake (P = 0.0192) compared with FAMT. These results would provide a basis to design tumor-specific compounds that can avoid renal accumulation for tumor imaging and targeted alpha therapy.

SIGNIFICANCE STATEMENT We revealed the structural characteristics of halogenated tyrosine derivatives essential for interaction with the organic anion transporter responsible for their renal accumulation. We have confirmed that such interactions are important for renal handling and tumor uptake. The critical contribution of hydroxyl and halogen groups and their positions as well as the role of α-methyl group found in the present study may facilitate the development of tumor-specific compounds while avoiding renal accumulation for use in tumor imaging and targeted alpha therapy.

Footnotes

    • Received July 21, 2020.
    • Accepted September 16, 2020.
  • ↵1 Current affiliation: Osaka Police Hospital, Osaka, Japan.

  • This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science [19H03407] (to Y.K.) and the Project for Development of Innovative Research on Cancer Therapeutics from Japan Agency for Medical Research and Development [17cm0106118], [JP18cm0106131], [JP19cm0106151], and [JP20cm0106151] (to Y.K.).

  • This work was previously presented in part as follows: C.J. et al, L-type amino acid transporter 1 (LAT1) in endothelial cells of tumor vessels contributes to tumor angiogenesis, The 18th World Congress of Basic and Clinical Pharmacology, July 2, 2018, Kyoto, Japan. C.J. et al, Critical moieties of aromatic amino acid probes causing renal accumulation in tumor imaging, The 92nd Annual Meeting for the Japanese Pharmacological Society, March 14, 2019, Osaka, Japan.

  • https://doi.org/10.1124/jpet.120.000235.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 3
1 Dec 2020
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Research ArticleMetabolism, Transport, and Pharmacogenetics

Halogenated Tyrosine Probes Interact with Renal Transporter

Chunhuan Jin, Ling Wei, Ryuichi Ohgaki, Hideyuki Tominaga, Minhui Xu, Suguru Okuda, Hiroki Okanishi, Yasuharu Kawamoto, Xin He, Shushi Nagamori and Yoshikatsu Kanai
Journal of Pharmacology and Experimental Therapeutics December 1, 2020, 375 (3) 451-462; DOI: https://doi.org/10.1124/jpet.120.000235

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Research ArticleMetabolism, Transport, and Pharmacogenetics

Halogenated Tyrosine Probes Interact with Renal Transporter

Chunhuan Jin, Ling Wei, Ryuichi Ohgaki, Hideyuki Tominaga, Minhui Xu, Suguru Okuda, Hiroki Okanishi, Yasuharu Kawamoto, Xin He, Shushi Nagamori and Yoshikatsu Kanai
Journal of Pharmacology and Experimental Therapeutics December 1, 2020, 375 (3) 451-462; DOI: https://doi.org/10.1124/jpet.120.000235
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