Progesterone receptor PET imaging

Progesterone

Progesterone is involved in differentiation of the endometrium, pregnancy, and mammary development (Obr & Edwards, 2012; Hilton et al., 2018). Progesterone and related synthetic drugs are used as contraceptives, for reducing the risk of preterm birth, and preventing endometrial cancer. Additionally, progesterone could be used in treatment of neurological diseases such as stroke, traumatic brain injury, spinal cord trauma, neuropathies, motoneuron degeneration, MS, and other neurodegenerative diseases (González et al., 2020).

In tissues, progesterone can be reduced to dihydroprogesterone (5-α-DHP) and allopregnanolone (3α,5α-tetrahydroprogesterone) with different properties as progesterone (González et al., 2020).

Biosynthesis

Synthesis starts with cholesterol that is converted to pregnenolone and then to progesterone.

Progesterone receptor

Progesterone receptor (PR, PgR) is a member of the nuclear steroid receptor family. It is encoded by PGR gene, which, through separate promoters, produces two functionally distinct ligand-activated transcription factors, PR-A and PR-B (Kastner et al., 1990; Richter et al., 2002; Jacobsen et al., 2005). In normal breast tissue, similar amounts of PR-A and PR-B are present, but in breast cancer a higher PR-A/PR-B ratio has been observed (Graham et al., 2005; Karigiana et al., 2008). Imbalanced PR isoform expression may affect the prognosis of breast cancer (Hopp et al., 2004), and predict the benefit from endocrine therapy (Mote et al., 2015). Ligand-bound PR dimerizes to form homo- or heterodimers A:A, A:B, or B:B, and recruits specific co-regulators and general transcription factors, to bind to progestin response elements (PREs) in the promoters of target genes.

Progesterone receptor expression is upregulated by estrogens (Horwitz & McGuire, 1978). Progestin-based radiopharmaceuticals, such as [¹⁸F]FFNP, can be used for PR imaging, which is an indicator of a functionally intact ERα signalling pathway (Buckman et al., 1995).

Progesterone can bind also to several membrane-associated receptors (mPRs), unrelated to PR, that activate G-protein coupled pathways and MAPK signalling cascades. Progesterone and/or its metabolites can bind and modulate the function of other receptors, such as sigma receptors, GABA receptors, NMDA receptors (González et al., 2020).

[¹⁸F]FFNP

[¹⁸F]F-furanyl-norprogesterone ([¹⁸F]FFNP) is a progestin-based radiopharmaceutical for PR PET imaging. It shows affinity also to glucocorticoid receptor (GR) and androgen receptor (AR) (Lee et al., 2010). Gallbladder is the dose-limiting organ, receiving an average radiation dose of 0.113 mGy/MBq; the whole-body dose was 0.015 mGy/MBq, with an effective dose of 0.020 mSv/MBq (Dehdashti et al., 2012).

[¹⁸F]FFNP has been used for imaging patients with breast cancer (Dehdashti et al., 2012). Preclinical studies have shown high [¹⁸F]FFNP uptake in the uterus and ovaries of estrogen-primed immature female rats (Buckman et al., 1995). In mouse model of human breast cancer, [¹⁸F]FFNP can detect estrogen-induced shifts in PR expression, with equivalent binding to PR-A and PR-B isoforms (Salem et al., 2019). Assessment of baseline [¹⁸F]FES uptake and initial changes in [¹⁸F]FFNP uptake could be used to identify responders and non-responders to endocrine therapy at an early stage (Fowler et al., 2012).

[¹⁸F]FPTP

[¹⁸F]fluoropropyl-Tanaproget ([¹⁸F]FPTP) as a racemic mixture has similar affinity to PR as [¹⁸F]FFNP, but affinity to GR and AR is lower (Lee et al., 2010).

Literature

Allott L, Smith G, Aboagye EO, Carroll L. PET imaging of steroid hormone receptor expression. Mol Imaging. 2015; 14(10): 534-550. doi: 10.2310/7290.2015.00026.

Grimm SL, Hartig SM, Edwards DP. Progesterone receptor signaling mechanisms. J Mol Biol. 2016; 428(19): 3831-3849. doi: 10.1016/j.jmb.2016.06.020.

Linden HM, Peterson LM, Fowler AM. Clinical potential of estrogen and progesterone receptor imaging. PET Clin. 2018; 13(3): 415-422. doi: 10.1016/j.cpet.2018.02.005.

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.

Tags: Steroids, Progesterone, Estrogen

Updated at: 2023-01-04
Created at: 2023-01-02
Written by: Vesa Oikonen