In the present study, researchers successfully detected subfamily 3 group C nuclear hormone receptors and the pharmacodynamic measurement of receptor occupancy by cognate drugs in vivo using PET imaging

The glucocorticoid receptor (GR) is a nuclear hormone receptor that regulates many cellular processes, including catabolism and apoptosis. The transcriptional activity of GR in peripheral tissues is activated by binding to corticosteroids, which are synthesized and secreted by the adrenal cortex.

Corticosteroid production is controlled by a well understood negative feedback endocrine loop termed the hypothalamus-pituitary-adrenocortical axis. In healthy organisms, a pulse of high corticosteroid production and secretion typically occurs transiently after periods of stress, after that homeostasis is restored by corticosteroid metabolism in peripheral tissues.

While there is currently no gold standard non-invasive diagnostic assay for identifying GR-expressing tumors, the tumor-autonomous expression of other nuclear hormone receptors within the same subfamily has been successfully detected in patients with radiolabeled agonists and positron emission tomography (PET). On this basis, researchers sought to develop a radioligand that could detect GR expression levels in tumors.

Researchers developed a fluorine-18 labeled corticosteroid termed GR02 that potently binds the endogenous ligand binding pocket on full-length GR. Binding of 18F-GR02 was suppressed in many normal tissues by co-treatment with mifepristone, a GR antagonist in human use, and was elevated in many normal tissues among mice lacking circulating corticosteroids due to adrenalectomy. 

8F-GR02 also accumulated in GR positive subcutaneous and subrenal capsule prostate cancer models, and uptake in tumors was competed by mifepristone. Combined with a straightforward and high yielding radiosynthesis, these data establish the foundation for near-term clinical translation of 18F-GR02.

This manuscript outlines the synthesis and preliminary pharmacology of 18F-GR02, an experimental radioligand that may provide a more holistic view of GR expression levels in vivo with PET. The precursor synthesis was high yielding, the radiochemistry can be automated, and the preparation of 18F-GR02 utilizes radiochemistry that is safe for human translation.

Small animal PET/CT and biodistribution studies showed that 18F-GR02 detected GR rich tissues in intact immunocompetent mice with circulating endogenous corticosteroids. Tissue uptake of the radiotracer was competed by pre-dosing mice with mife., a potent GR antagonist in clinical trials for the treatment of cancer.

Radiotracer uptake also increased substantially in many normal tissues within anx mice compared to intact, and radiotracer accumulation in adx mice was blocked with mife. Lastly, 18F-GR02 accumulated in a mife.-dependent fashion in PC3 and DU145, two human prostate cancer models with endogenous GR expression (PC3 is also PR null).