Fluorine-18 (18F)-labeled retinoid x receptor (RXR) partial agonist whose tissue transferability is affected by other RXR ligands. Issue 14 (15th July 2019)

• Record Type: Journal Article
• Authors: Takamura, Yuta; Shibahara, Osamu; Watanabe, Masaki; Fujihara, Michiko; Yamada, Shoya; Akehi, Masaru; Sasaki, Takanori; Hirano, Hiroyuki; Kakuta, Hiroki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 14(2019)
• Page Start: 3128
• Page End: 3134
• Publication Date: 2019-07-15
• Subjects: ARG autoradiography -- BNCT boron neutron complementary therapy -- BPA borono-l-phenylalanine -- CT computed tomography -- CTCL cutaneous T cell lymphoma -- HPLC high performance liquid chromatography -- hRXR human RXR -- LBD ligand-binding domain -- PBS phosphate buffered saline -- PET positron emission tomography -- p-TSA p-toluenesulfonic acid -- RA retinoic acid -- ROI regions of interest -- RT retention time -- r.t. room temperature -- RXR retinoid X receptor -- SEAP secreted alkaline phosphatase -- TLC thin layer chromatography; 18F -- Nuclear receptors -- PET imaging -- Pharmacokinetics -- Retinoids -- RXR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.05.045
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Bexarotene (1 ), a retinoid X receptor (RXR) agonist approved for the treatment of cutaneous T cell lymphoma (CTCL), was reported to migrate into baboon brain based on findings obtained by positron emission tomography (PET) with a 11 C-labeled tracer. However, co-administration of non-radioactive 1 had no effect on the distribution of [ 11 C]1, probably due to non-specific binding of 1 as a result of its high lipophilicity. Here, we report a fluorine-18 ( 18 F)-labeled PET tracer [ 18 F]6 derived from RXR partial agonist CBt-PMN (2 ), which has lower lipophilicity and weaker RXR-binding ability than [ 11 C]1 . The concomitant administration of 1 or 2 with [ 18 F]6 with resulted in decreased accumulation of [ 18 F]6 in liver, together with increased brain uptake and increased accumulation in kidney and muscle, as visualized by PET. A plausible explanation of these findings is the inhibition of [ 18 F]6 uptake into the liver by concomitantly administered 1 or 2, leading to an increase in blood concentration of [ 18 F]6 followed by increased accumulation in other tissues.