PT  - JOURNAL ARTICLE
AU  - Michael Evans
AU  - Yangjie Huang
AU  - Ning Zhao
AU  - Yung-Hua Wang
AU  - Youngho Seo
AU  - David Wilson
AU  - Joseph Blecha
AU  - Henry VanBrocklin
AU  - Spencer Behr
TI  - 18F-YJH08, a novel radioligand targeting the glucocorticoid receptor to understand the pathobiology of cancer and major depressive disease.
DP  - 2020 May 01
TA  - Journal of Nuclear Medicine
PG  - 261--261
VI  - 61
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/61/supplement_1/261.short
4100  - http://jnm.snmjournals.org/content/61/supplement_1/261.full
SO  - J Nucl Med2020 May 01; 61
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.