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

  • ACS Med Chem Lett. 2015 Jan 20;6(3):334-8. doi: 10.1021/ml500511m.
Toshiki Kobayashi  1 ,  Yuki Furusawa  1 ,  Shoya Yamada  2 ,  Masaru Akehi  3 ,  Fumiaki Takenaka  3 ,  Takanori Sasaki  3 ,  Akiya Akahoshi  3 ,  Takahisa Hanada  3 ,  Eiji Matsuura  3 ,  Hiroyuki Hirano  4 ,  Akihiro Tai  5 ,  Hiroki Kakuta  1
Affiliations
  • 1. Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
  • 2. Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan ; Research Fellowship Division, Japan Society for the Promotion of Science , Sumitomo-Ichibancho FS Bldg., 8 Ichibancho, Chiyoda-ku, Tokyo 102-8472, Japan.
  • 3. Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
  • 4. SHI Accelerator Service Ltd. 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
  • 5. Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima , 562 Nanatsuka-Cho, Shobara, Hiroshima 727-0023, Japan.
PMID: 25815156 DOI: 10.1021/ml500511m
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 [(11)C]1a, [(11)C]2a and fluorinated derivatives [(18)F]1b, [(18)F]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.