Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists

Toshiki Kobayashi; Yuki Furusawa; Shoya Yamada; Masaru Akehi; Fumiaki Takenaka; Takanori Sasaki; Akiya Akahoshi; Takahisa Hanada; Eiji Matsuura; Hiroyuki Hirano; Akihiro Tai; Hiroki Kakuta

doi:10.1021/ml500511m

Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists

Toshiki Kobayashi, Yuki Furusawa, Shoya Yamada, Masaru Akehi, Fumiaki Takenaka, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Eiji Matsuura, Hiroyuki Hirano, Akihiro Tai, Hiroki Kakuta

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

18 Citations (Scopus)

Abstract

RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC₅₀ = 169 nM, E_max = 55%) showed a blood concentration higher than its E_max after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A^y mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [¹¹C]1a, [¹¹C]2a and fluorinated derivatives [¹⁸F]1b, [¹⁸F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.

Original language	English
Pages (from-to)	334-338
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	3
DOIs	https://doi.org/10.1021/ml500511m
Publication status	Published - Mar 12 2015

Keywords

Nuclear receptors
PET imaging
RXR
pharmacokinetics

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/ml500511m

Cite this

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title = "Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists",

abstract = "RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, Emax = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-Ay mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [11C]1a, [11C]2a and fluorinated derivatives [18F]1b, [18F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.",

keywords = "Nuclear receptors, PET imaging, RXR, pharmacokinetics",

author = "Toshiki Kobayashi and Yuki Furusawa and Shoya Yamada and Masaru Akehi and Fumiaki Takenaka and Takanori Sasaki and Akiya Akahoshi and Takahisa Hanada and Eiji Matsuura and Hiroyuki Hirano and Akihiro Tai and Hiroki Kakuta",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

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doi = "10.1021/ml500511m",

language = "English",

volume = "6",

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T1 - Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists

AU - Kobayashi, Toshiki

AU - Furusawa, Yuki

AU - Yamada, Shoya

AU - Akehi, Masaru

AU - Takenaka, Fumiaki

AU - Sasaki, Takanori

AU - Akahoshi, Akiya

AU - Hanada, Takahisa

AU - Matsuura, Eiji

AU - Hirano, Hiroyuki

AU - Tai, Akihiro

AU - Kakuta, Hiroki

PY - 2015/3/12

Y1 - 2015/3/12

N2 - RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, Emax = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-Ay mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [11C]1a, [11C]2a and fluorinated derivatives [18F]1b, [18F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.

AB - RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, Emax = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-Ay mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [11C]1a, [11C]2a and fluorinated derivatives [18F]1b, [18F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.

KW - Nuclear receptors

KW - PET imaging

KW - RXR

KW - pharmacokinetics

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Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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