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br In vivo visualization of aromatase with positron emission
In vivo visualization of aromatase with positron emission tomography (PET)
Positron emission tomography (PET) utilizes the high IWP-2 synthesis photons formed during the annihilation of positrons to detect the changes in the amount and localization of injected radiopharmaceuticals in the living body (recently reviewed in Zanzonico, 2012). Radiolabeled molecules with known affinity and selectivity for specific tissue constituents (e.g. receptors, transporters and enzymes) are used to assess the anatomical distribution and temporal changes in target availability by measuring the amount of radioactivity in different tissues over time relative to the amount injected; or, using mathematical modeling, relative to the amount present in plasma over the same time period, corrected for metabolites. The first method, used in most clinical applications, yields standardized uptake values (SUV); where SUV (t)=measured radioactivity in tissue (Bq/ml)/injected activity (Bq)/body weight. SUV is a dimensionless number; assuming a mass density of 1kg/L (see recent review by Kinahan and Fletcher, 2010).
The 2nd method, in conjunction with various theoretical models, can be used to derive a number of kinetic parameters; the most commonly used being the total volume of distribution, VT (Innis et al., 2007). VT represents the distribution volume of total radiopharmaceutical uptake in tissue relative to total concentration in plasma, and is a dimensionless entity under the same assumption (1mL=1gr in tissue and blood). Both SUV and VT increases are proportional to the concentration of target available for binding the tracer; and decrease when the target is occupied by physiological or pharmacological agents which occupy the target.
Relationship between in vivo and in vitro studies of aromatase distribution in animals and humans
The results of in vivo studies of aromatase distribution under baseline conditions as well as following hormonal and pharmacological manipulations are generally consistent with in vitro studies. For example, higher aromatase levels in male relative to female brains observed in vivo are consistent with the findings of Takahashi et al., 2007, Takahashi et al., 2008 who demonstrated that androgenic–anabolic steroids increased aromatase concentration in the bed nucleus of stria terminalis and preoptic area in rat brain, as evaluated using autoradiography with [11C]vorozole. A follow-up study examined whether the increase in aromatase binding is mediated via androgen receptors and whether this increase occurs in neurons or glial cells (Takahashi et al., 2008). Treatment with the androgen receptor antagonist Flutamide decreased [11C]vorozole binding in the bed nucleus of the stria terminalis, preoptic area, and medial amygdala, which was increased by the agonist nandrolone. Immunohistochemical examination demonstrated that androgen-mediated upregulation of aromatase expression occurred in neurons. These findings are also compatible with earlier studies showing androgen regulation of aromatase mRNA in rat brain (Abdelgadir et al., 1994).
A comparison of findings from different species yields some similarities but also significant differences in aromatase distribution. Relatively high aromatase levels in the ovary, especially around the time of ovulation, were observed in rats, monkeys and women. Prominent liver uptake was also seen across species. However, the high uptake in rat stomach reported by Ozawa et al. (2011) was not seen in baboons or humans. Tracer uptake in the majority of most other peripheral organs, including bone, kidney, muscle, heart and lung, was uniformly low across species.
Comparison of brain distribution across species reveals a similar rank order of tracer uptake in rats, rhesus monkeys and baboons, with highest levels in amygdala. However, the distribution pattern in the human brain is starkly different, with the highest levels of aromatase detected in thalamic nuclei (mediodorsal and pulvinar); and moderate levels in the amygdala, preoptic area and medulla (Biegon et al., 2010a, Biegon et al., 2010b, Biegon et al., 2012a, Biegon et al., 2012b, Biegon et al., 2015). Low levels of aromatase are found in all other cortical and subcortical regions of all species examined (Takahashi et al., 2006, Takahashi et al., 2014, Kim et al., 2009a, Kim et al., 2009b, Biegon et al., 2010a, Biegon et al., 2010b).