Benzyl [11C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice

Tatsuya Kikuchi; Toshimitsu Okamura; Maki Okada; Masanao Ogawa; Chie Suzuki; Hidekatsu Wakizaka; Joji Yui; Toshimitsu Fukumura; Antony D. Gee; Ming Rong Zhang

doi:10.1021/acs.jmedchem.6b00454

Benzyl [¹¹C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice

Tatsuya Kikuchi^*, Toshimitsu Okamura, Maki Okada, Masanao Ogawa, Chie Suzuki, Hidekatsu Wakizaka, Joji Yui, Toshimitsu Fukumura, Antony D. Gee, Ming Rong Zhang

^*Corresponding author for this work

Imaging Chemistry & Biology

National Institute of Radiological Sciences Chiba
SHI Accelerater Service Co. Ltd.
Hamamatsu University
Fédération d'anesthésiologie-réanimation et de médecine hyperbare, hôpital d'instruction des armées du Val-de-Grâce, 75005 Paris, France; Inserm U676, hôpital Robert-Debré, 48, boulevard Sérurier, 75019 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMRS 676, 75013 Paris, France; Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, London, Royaume-Uni. Electronic address: [email protected].

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7 Citations (Scopus)

Abstract

Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several ¹¹C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding ¹¹C-labeled organic acids in target tissues. Among the compounds screened, benzyl [¹¹C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3^-/- and Mrp4^-/- mice, respectively, compared with that of control mice after the intravenous administration of benzyl [¹¹C]hippurate. Benzyl [¹¹C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively.

Original language	English
Pages (from-to)	5847-5856
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	12
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00454
Publication status	Published - 23 Jun 2016

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Kikuchi, T., Okamura, T., Okada, M., Ogawa, M., Suzuki, C., Wakizaka, H., Yui, J., Fukumura, T., Gee, A. D., & Zhang, M. R. (2016). Benzyl [¹¹C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice. Journal of Medicinal Chemistry, 59(12), 5847-5856. https://doi.org/10.1021/acs.jmedchem.6b00454

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title = "Benzyl [11C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice",

abstract = "Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several 11C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding 11C-labeled organic acids in target tissues. Among the compounds screened, benzyl [11C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3-/- and Mrp4-/- mice, respectively, compared with that of control mice after the intravenous administration of benzyl [11C]hippurate. Benzyl [11C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively.",

author = "Tatsuya Kikuchi and Toshimitsu Okamura and Maki Okada and Masanao Ogawa and Chie Suzuki and Hidekatsu Wakizaka and Joji Yui and Toshimitsu Fukumura and Gee, {Antony D.} and Zhang, {Ming Rong}",

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doi = "10.1021/acs.jmedchem.6b00454",

language = "English",

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Kikuchi, T, Okamura, T, Okada, M, Ogawa, M, Suzuki, C, Wakizaka, H, Yui, J, Fukumura, T, Gee, AD & Zhang, MR 2016, 'Benzyl [¹¹C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice', Journal of Medicinal Chemistry, vol. 59, no. 12, pp. 5847-5856. https://doi.org/10.1021/acs.jmedchem.6b00454

Benzyl [¹¹C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice. / Kikuchi, Tatsuya; Okamura, Toshimitsu; Okada, Maki et al.
In: Journal of Medicinal Chemistry, Vol. 59, No. 12, 23.06.2016, p. 5847-5856.

Research output: Contribution to journal › Article › peer-review

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T1 - Benzyl [11C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice

AU - Kikuchi, Tatsuya

AU - Okamura, Toshimitsu

AU - Okada, Maki

AU - Ogawa, Masanao

AU - Suzuki, Chie

AU - Wakizaka, Hidekatsu

AU - Yui, Joji

AU - Fukumura, Toshimitsu

AU - Gee, Antony D.

AU - Zhang, Ming Rong

PY - 2016/6/23

Y1 - 2016/6/23

N2 - Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several 11C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding 11C-labeled organic acids in target tissues. Among the compounds screened, benzyl [11C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3-/- and Mrp4-/- mice, respectively, compared with that of control mice after the intravenous administration of benzyl [11C]hippurate. Benzyl [11C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively.

AB - Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several 11C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding 11C-labeled organic acids in target tissues. Among the compounds screened, benzyl [11C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3-/- and Mrp4-/- mice, respectively, compared with that of control mice after the intravenous administration of benzyl [11C]hippurate. Benzyl [11C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively.

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ER -

Benzyl [¹¹C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice

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