Unique distribution of aromatase in the human brain: In vivo studies with PET and [N‐methyl‐¹¹C]vorozole

Abstract

Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-11 C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, 3 men and 3 women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90 min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (VT) values in both men and women followed the rank order: thalamus>amygdala=preoptic area>medulla(inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region dependent; ranging from ~70% blocking in thalamus and preoptic area to ~10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the non-invasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

11C-Cetrozole: An Improved C-11C-Methylated PET Probe for Aromatase Imaging in the Brain

“…These results indicated that 11 C-cetrozole may be a more preferable tracer than 11 C-vorozole for the quantitative measurement of aromatase in the brain. Even in a human PET study (18), the time-activity curve of 11 C-vorozole in the brain was almost the same as that of the monkey: specifically, that increased radioactivity was also observed in the late phase.…”

“…11 C-labeled vorozole, the first aromatase inhibitor-type PET probe developed at the Uppsala University PET Centre, allowed imaging of the dynamic status of aromatase in the living body including the brain (15). PET studies using this probe clarified the distribution of aromatase in living rhesus monkeys (16,24,27), baboons (17), and also humans (18), strongly suggesting a role for aromatase in brain functions. For example, an increase in aromatase expression was detected in the hypothalamic nuclei of rats and rhesus monkeys by the repeated administration of anabolic androgenic steroids for 3 wk daily, inducing psychologic adverse effects (27).…”

“…A method for isolating 11 C-vorozole labeled in the right position was established later on (17). Up to now, using 11 Cvorozole, the distribution of aromatase in the brain of rats, rhesus monkeys (16), baboons (17), and humans (18) and the effect of anabolic-androgenic steroids on aromatase (19,20) have been demonstrated. Although 11 C-labeled sulfonanilide analogs (21), 11 C-labeled sulfamate derivatives (dual aromatase-steroid sulfatase inhibitors) (22), and 11 C-letrozole (23) have also been developed as aromatase imaging PET probes, 11 C-vorozole is still the most popular probe for imaging brain aromatase.…”

Aromatase Imaging with [N-Methyl-11C]Vorozole PET in Healthy Men and Women

“…Aromatase regulates the last step of estrogen biosynthesis, aromatizing the A ring of androgens such as androstenedione and testosterone to estrone and estradiol, respectively. Aromatase is expressed in various peripheral organs as well as in the brain of rodents, nonhuman primates, and humans (2)(3)(4)(5). To date, there have been no published studies of aromatase distribution throughout the human body or its regulation by sex and hormonal status, although animal studies suggest that brain aromatase activity is higher in males than in females and is modulated by changes in testosterone levels but not in the phase of the female estrus cycle (3,6,7).…”

PET of Aromatase in Gastric Parietal Cells Using 11C-Vorozole

“…11 C-labeled vorozole, (S)-11 C-6-[(4-chlorophenyl)(1H-1,2,4-triazole-1-yl)methyl]-1-methyl-1H-benzotriazole (12), was developed as a PET tracer to investigate the in vivo distribution of aromatase in living animals and humans (13,14). Consistent with previous reports, we have shown that the accumulation of 11 C-vorozole was increased in several brain regions of rats and monkeys treated with anabolic steroids (15)(16)(17)(18), indicating that 11 C-vorozole is a useful molecular probe for aromatase imaging.…”