RT Journal Article
SR Electronic
T1 18F-YJH08, a novel radioligand targeting the glucocorticoid receptor to understand the pathobiology of cancer and major depressive disease.
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 261
OP 261
VO 61
IS supplement 1
A1 Michael Evans
A1 Yangjie Huang
A1 Ning Zhao
A1 Yung-Hua Wang
A1 Youngho Seo
A1 David Wilson
A1 Joseph Blecha
A1 Henry VanBrocklin
A1 Spencer Behr
YR 2020
UL http://jnm.snmjournals.org/content/61/supplement_1/261.abstract
AB 261Objectives: 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 the first non-invasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJH08 potently binds GR (Kd ~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 starting [18F]fluoride ion. We applied treatment with the tissue-wide GR agonist dexamethasone, 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, specific 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 conventional screening 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.