Androgen receptor PET imaging
Testosterone and the more potent 5α-dihydrotestosterone (5α-DHT) are the natural ligands for androgen receptor. Testosterone is the principal male sex hormone, which regulates sexual characteristics and body composition. In adult females, testosterone concentrations are ∼15-fold lower, and androgens are converted to estrogens. Low testosterone levels in ageing men are associated with sexual dysfunction, reduced skeletal muscle mass and strength, decreased bone mineral density, increased cardiovascular risk, and alterations of the glycometabolic profile. Testosterone replacement therapy (TRT) restores normal levels of serum testosterone in men, increasing libido and producing beneficial effects on bone density and muscle strength and cardioprotective effects. Acting via AR, androgens have an important role in the development and maintenance of normal brain function.
Steroid hormones in blood stream are bound to sex hormone binding globulin (SHBG, SBP) and albumin. SHBG binding protects androgens from metabolism in liver, where steroid hormones are conjugated to glucuronides. SHBG binding also helps in hormone transport into target cells through membrane receptors for SHBG.
Synthesis starts with cholesterol that is converted to pregnenolone, then to dehydroepiandrosterone (DHEA), further to androstenedione, and to testosterone (Lefebvre-Lacœuille et al., 2015). Testosterone is produced primarily in testicular Leydig cells in men, while in women precursors are biosynthesised in the adrenal cortex and ovaries and converted into testosterone in peripheral tissues.
In prostate cancer, Androgen-deprivation therapy (ADT) can be used to reduce androgen synthesis or to inhibit androgen receptors.
Androgen receptor (AR) is a member of the nuclear steroid receptor family. The classic action of androgens on target organs is mediated through the intracellular androgen receptor, which regulates nuclear receptor gene transcription. The androgen-androgen receptor complex interacts also with membrane proteins and can rapidly activate signalling cascades. AR mediates normal prostate function, and is implicated in development and growth of prostate cancer. AR expression does not indicate any predictive or prognostic value in determining the response to (ERα-based) endocrine therapy (Allott et al., 2015).
Androgen receptor radioligands, such as [18F]fluorodihydrotestosterone ([18F]FDHT) have been used to follow metastases in advanced prostate cancer and in treatment evaluation (Larson et al., 2005; Fox et al., 2018; Vargas et al., 2018; Kramer et al., 2019). The AR is expressed in breast cancer, and steroidal androgens have been used to treat metastatic breast cancer. The effect of selective AR modulators can be assessed using AR radioligands, such as [18F]FDHT (Boers et al., 2021; Jacene et al., 2022).
16β-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT) has high affinity for AR and low affinity for progesterone receptor. High affinity for SHBG in plasma protects [18F]FDHT from metabolism (Bonasera et al., 1996), and [18F]FDHT pre-bound to SHBG before significantly increased tumour uptake in murine models than administration of free [18F]FDHT (Larimer et al., 2018). [18F]FDHT half-life in blood is 6-7 min, and SUV in prostate cancer lesions reaches a plateau within 20 min from tracer administration (Beattie et al., 2010). The effective dose equivalent is 0.00177±0.000152 cSv/MBq, and the maximum absorbed dose occurred for the urinary bladder wall (Zanzonico et al., 2004). Excretion via kidneys into urine may hamper the detection of tumours close to prostate.
Beattie et al (2010) have compared different compartmental models in analysis of prostate cancer PET data, and found that irreversible 1TCM and 2TCM with blood volume fraction fitted data seemingly as well, but results from 2TCM were less robust and also Bayesian information criterion (BIC) supported 1TCM over 2TCM. More complex models including tissue compartment for radioactive metabolites did not provide robust results, but the analyses were based on population-mean blood curve and metabolite analysis from venous sampling. SUV correlated with Ktrap (from 1TCM), with R2=0.60 (Beattie et al., 2010). With arterial sampling, Kramer et al (2019) achieved good fits and mostly robust results using irreversible 2TCM in metastatic prostate cancer lesions. Excellent correlation was found between Ki values from compartmental model and Patlak plot; also FUR (SUV normalized to AUC of parent plasma input curve) correlated well with Kis. Using image-derived input function in combination with venous samples provided similar Ki results as obtained using arterial sampling. Performance of SUVbw and SUVLBM was poorer, but correction of SUVbw for serum SHBG levels improved correlation to Ki (Kramer et al., 2019).
Imaging of AR availability in the brain of rats is not feasible with [18F]FDHT, possibly due to low AR expression and rapid metabolism (Khayum et al., 2015).
Enzalutamide is an AR signalling inhibitor currently used in different stages of prostate cancer. In a mouse model, [18F]Enzalutamide has shown higher tumour uptake and better metabolic stability than [18F]FDHT (Antunes et al., 2021).
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.
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.
Updated at: 2023-01-08
Created at: 2023-01-02
Written by: Vesa Oikonen