A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography.
Yangjie HuangNing ZhaoYung-Hua WangCharles TruilletJunnian WeiJoseph E BlechaHenry F VanBrocklinYoungho SeoMohd SayeedBrian J FeldmanRahul AggarwalSpencer C BehrHao ShaoDavid M WilsonJavier E Villanueva-MeyerJason E GestwickiKenneth W BaylesPublished in: ACS chemical biology (2020)
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.
Keyphrases
- positron emission tomography
- computed tomography
- adipose tissue
- pet ct
- poor prognosis
- gene expression
- pet imaging
- insulin resistance
- small molecule
- drug discovery
- endothelial cells
- squamous cell carcinoma
- low dose
- skeletal muscle
- multiple sclerosis
- blood brain barrier
- early onset
- photodynamic therapy
- neoadjuvant chemotherapy
- resting state
- molecular dynamics simulations
- fatty acid