A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography
| Autor: | Yangjie Huang, Charles Truillet, Michael J. Evans, Javier Villanueva-Meyer, Spencer C. Behr, David M. Wilson, Jason E. Gestwicki, Youngho Seo, Brian J. Feldman, Joseph E. Blecha, Hao Shao, Henry F. VanBrocklin, Rahul Aggarwal, Mohd Sayeed, Ning Zhao, Yung-hua Wang, Junnian Wei |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist Male Fluorine Radioisotopes medicine.drug_class Knockout Adipose tissue Gene Expression Inbred C57BL 01 natural sciences Biochemistry Dexamethasone 03 medical and health sciences chemistry.chemical_compound Mice Receptors Glucocorticoid Glucocorticoid receptor Glucocorticoid In vivo Adipocyte Receptors Radioligand medicine Animals Glucocorticoids Mice Knockout 010405 organic chemistry Chemistry Organic Chemistry Articles General Medicine Biological Sciences 0104 chemical sciences Cell biology Mice Inbred C57BL 030104 developmental biology Nuclear receptor Positron-Emission Tomography Knockout mouse Chemical Sciences Quinolines Molecular Medicine Biomedical Imaging |
| Zdroj: | ACS chemical biology, vol 15, iss 6 ACS Chemical Biology |
| Popis: | The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR’s role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report 18F-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline (18F-YJH08), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJH08 potently binds GR (Ki ∼ 0.4 nM) with ∼100-fold selectivity compared to nuclear hormone receptors in the same subfamily. 18F-YJH08 was prepared via Cu(OTf)2(py)4-mediated radiofluorination of an arylboronic acid pinacol ester with ∼12% decay corrected radiochemical yield from the starting 18F-fluoride ion. We applied treatment with the tissue-wide GR agonist dexamethasone and adrenalectomy and generated an adipocyte specific GR knockout mouse to show that 18F-YJH08 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, 18F-YJH08 PET also revealed that JG231, a potent and bioavailable HSP70 inhibitor, selectively degrades GR only in the adipose tissue of mice, a finding that foreshadows how GR targeted PET might be integrated into drug discovery to screen for selective GR modulation at the tissue level, beyond the historical screening that was performed at the transcriptional level. In summary, 18F-YJH08 enables a quantitative assessment of GR expression levels in real time among multiple tissues simultaneously, and this technology is a first step toward unraveling the daunting complexity of GR signaling and rationally engineering tissue specific therapeutic modulators in vivo. |
| Databáze: | OpenAIRE |
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