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

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

Access to Document

10.1021/ml500511m

Fingerprint Dive into the research topics of 'Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists'. Together they form a unique fingerprint.

Cite this

Kobayashi, T., Furusawa, Y., Yamada, S., Akehi, M., Takenaka, F., Sasaki, T., Akahoshi, A., Hanada, T., Matsuura, E., Hirano, H., Tai, A., & Kakuta, H. (2015). Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists. ACS Medicinal Chemistry Letters, 6(3), 334-338. https://doi.org/10.1021/ml500511m

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

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.

@article{e52f0edfe64348b5abf7f3ebd1d3d72d,

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",

year = "2015",

month = mar,

day = "12",

doi = "10.1021/ml500511m",

language = "English",

volume = "6",

pages = "334--338",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "3",

}

TY - JOUR

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

UR - http://www.scopus.com/inward/record.url?scp=84924744768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924744768&partnerID=8YFLogxK

U2 - 10.1021/ml500511m

DO - 10.1021/ml500511m

M3 - Article

AN - SCOPUS:84924744768

VL - 6

SP - 334

EP - 338

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 3

ER -