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

14 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

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10.1021/ml500511m

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Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists. / Kobayashi, Toshiki; Furusawa, Yuki; Yamada, Shoya; Akehi, Masaru; Takenaka, Fumiaki; Sasaki, Takanori; Akahoshi, Akiya; Hanada, Takahisa; Matsuura, Eiji; Hirano, Hiroyuki; Tai, Akihiro; Kakuta, Hiroki.

In: ACS Medicinal Chemistry Letters, Vol. 6, No. 3, 12.03.2015, p. 334-338.

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

Kobayashi, Toshiki ; Furusawa, Yuki ; Yamada, Shoya ; Akehi, Masaru ; Takenaka, Fumiaki ; Sasaki, Takanori ; Akahoshi, Akiya ; Hanada, Takahisa ; Matsuura, Eiji ; Hirano, Hiroyuki ; Tai, Akihiro ; Kakuta, Hiroki. / Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists. In: ACS Medicinal Chemistry Letters. 2015 ; Vol. 6, No. 3. pp. 334-338.

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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.",

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AU - Sasaki, Takanori

AU - Akahoshi, Akiya

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