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. 2010 Nov;64(11):801-7.
doi: 10.1002/syn.20791.

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

Anat Biegon  1 , Sung Won Kim, David L Alexoff, Millard Jayne, Pauline Carter, Barbara Hubbard, Payton King, Jean Logan, Lisa Muench, Deborah Pareto, David Schlyer, Colleen Shea, Frank Telang, Gene-Jack Wang, Youwen Xu, Joanna S Fowler
Affiliations

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

Anat Biegon et al. Synapse. 2010 Nov.

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, three men and three 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 (2.5 mg) 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 (V(T)) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced V(T) in all regions, though the size of the reduction was region-dependent, ranging from ∼70% blocking in thalamus andpreoptic 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 noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

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Figures

Figure 1
Figure 1. Metablic stability of [11C]vorozole in human plasma
Analysis was performed on plasma samples from 3 men and 3 women injected IV with [11C]vorozole . The graph depics means(SD) of %radioactivity identified as [11C]vorozole vorozole at the specified time points
Figure 2
Figure 2. Time-activity curves of [11C]vorozole in human brain regions
Representative time activity curves in thalamus, amygdala and cerebellum from one subject. Filled symbols depict a baseline (radiotracer only) scan and empty symbols depict a blocking study, with tracer injected 2 hrs after oral administration of letrozole 2.5mg.
Figure 3
Figure 3. Anatomical distribution of [11C]vorozole in human brain
Figure shows coronal PET images (summed frames over 60-90 minutes, pseudocolored using the rainbow spectrum) overlaid on structural MRI (grey levels) of same subject. A=level of nucleus accumbens B=level of anterior hypothalamus/preoptic area C=level of amygdala D=level of dorsomedial thalamus E=level of pulvinar nucleus of thalamus F=level of medulla/inferior olive. Note some radioactivity in cortical white matter but not in corpus callosum and relatively low levels in caudate and putamen (levels A,B,C) and hippocampus (levels D,E).
Figure 4
Figure 4. Regional volume of distribution, reproducibility and saturability of [11C]vorozole in the brains of young men
Bars depict mean (SEM) of VT following the first injection of tracer (baseline), tracer injection 2 hr after letrozole (blocking) or tracer alone approximately 2 weeks after the first scan (retest). Abbreviations: amy=amygdala, cb=cerebellum,med=medulla(inferior olive), occ=occipital cortex, poa=preoptic area, put=putamen, temp=temporal cortex, thal = thalamus (pulvinar and mediidorsal), wm=cortical white matter.
Figure 5
Figure 5. Regional volume of distribution of [11C]vorozole in the brains of young women
Bars depict mean (SEM) of VT following injection of tracer in three women who were scanned around midcycle (12-17 days after onset of menses, when estrogen levels are at their highest, open bars) or during the menstrual/early follicular phase (27-4 days after onset of menses, when estrogen levels are low, hatched bars). Abbreviations:Amy=amygdala, cb=cerebellum,med=medulla(inferior olive), occ=occipital cortex, poa=preoptic area, put=putamen, temp=temporal cortex, thal = thalamus (pulvinar and mediidorsal), wm=cortical white matter.
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