Glucocorticoid receptor PET imaging


Glucocorticoids (cortisol in humans, and corticosterone in rodents and many other animals) are synthesized in the cortical zona fasciculata of adrenal glands and released into circulation as a response to adrenocorticotropic hormone (ACTH). ACTH is secreted from the anterior lobe of the pituitary gland in response to corticotropin-releasing hormone (CRH) and vasopressin, which are secreted from the hypothalamus. Glucocorticoids inhibit the secretion of these hormones in the hypothalamus and pituitary gland in this neuroendocrine system called hypothalamus-pituitary-adrenocortical axis (HPA axis). Glucocorticoids are also degraded in peripheral tissues, helping to quickly restore homeostasis after a stress-induced pulse in HPA axis activity.

Circulating glucocorticoids are bound to transcortin (CBG, serpin A6) and albumin. Transcortin in synthesized in the liver and adrenal glands. Protein binding protects glucocorticoids from metabolism in liver.

Cortisol is rapidly removed from the brain by p-glycoprotein, suggesting that circulating cortisol is not the main source of cortisol in CNS. Instead, cortisol can be produced intracellularly from cortisone that can readily pass the blood-brain barrier (BBB).


Cortisone is an inactive metabolite of cortisol (hydrocortisone), and circulating cortisone is formed by corticosteroid 11-beta-dehydrogenase isozyme 2 (HSD11B2, 11β-HSD2) mainly in the kidneys. This enzyme is highly expressed in tissues that express mineralocorticoid receptor, which binds cortisol and aldosterone with similar affinities; since plasma cortisol concentration is much higher than concentration of aldosterone, cortisol would otherwise out-compete aldosterone at these sites.

Cortisone can be converted back to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1, 11β-HSD1), which is highly expressed in the liver, adipose tissue, and CNS. Unlike cortisol, cortisone can easily travel across the BBB. Intracellular conversion of cortisone to cortisol by 11β-HSD1 is main source of cortisol in the brain. 11β-HSD1 may modulate the HPA axis via cortisol and glucocorticoid receptors in cortical and limbic brain regions, and therefore 11β-HSD1 is a potential drug target. [18F]AS2471907 can be used to assess 11β-HSD1 in vivo in the brain (Baum et al., 2019; Bhatt et al., 2020 and 2021).

Cortisol Corticosterone Cortisone

Cortisol, corticosterone, and cortisone.

Glucocorticoid receptor

Glucocorticoid receptor (GCR, GR) is a member of the nuclear steroid receptor 3C subfamily along with mineralocorticoid receptor, progesterone receptor, and androgen receptor. GCRs are activated by corticosteroids that are secreted from the cortex of adrenal glands.

Cancer cells may overexpress GCR, making them more resistant to chemotherapy, but expression is highly variable (Truillet et al., 2018).

The glucocorticoid-based PET radioligands have generally been metabolized too rapidly to be useful in in vivo imaging and do not have sufficient BBB permeability or specific binding for brain imaging (Steiniger et al., 2008). Instead, non-steroidal radioligands (±)-[11C]YJH08 and (±)-[18F]YJH08 have shown promising results in animal studies (Huang et al., 2020 and 2021; Kim et al., 2022).

See also:


Moraga-Amaro R, Doorduin J, Dierckx RAJO, de Vries EFJ. PET and SPECT imaging of steroid hormone receptors in the brain. In: PET and SPECT of Neurobiological Systems, Springer, 2021, p. 483-520. doi: 10.1007/978-3-030-53176-8_14.

Parent EE, Fowler AM. Nuclear receptor imaging in vivo - Clinical and research advances. J Endocr Soc. 2023; 7(3): 1-12. doi: 10.1210/jendso/bvac197.

Russell G, Lightman S. The human stress response. Nat Rev. 2019; 15: 525-534. doi: 10.1038/s41574-019-0228-0.

Steiniger B, Kniess T, Bergmann R, Pietzsch J, Wuest FR. Radiolabeled glucocorticoids as molecular probes for imaging brain glucocorticoid receptors by means of positron emission tomography (PET). Mini Rev Med Chem. 2008; 8(7): 728-739. doi: 10.2174/138955708784567403.

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Updated at: 2023-02-22
Created at: 2023-02-22
Written by: Vesa Oikonen