Unique Distribution of Aromatase in the
Human Brain: In Vivo Studies With PET
ANAT BIEGON,1* SUNG WON KIM,2DAVID L. ALEXOFF,1MILLARD JAYNE,1PAULINE CARTER,1
BARBARA HUBBARD,1PAYTON KING,1JEAN LOGAN,1LISA MUENCH,2DEBORAH PARETO,3
DAVID SCHLYER,1COLLEEN SHEA,1FRANK TELANG,1GENE-JACK WANG,1,4
YOUWEN XU,1AND JOANNA S. FOWLER1,4,5
1Medical Department, Brookhaven National Laboratory, Upton, New York
2National Institute on Alcoholism and Alcohol Abuse, Bethesda, Maryland
3Institut Alta Tecnologia, CIBER BBN, Barcelona, Spain
4Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
5Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York
estrogen; testosterone; androgens; steroidogenesis; imaging
matase 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-11C]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 radio-
tracer 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 (VT) values in both men and women followed the fol-
lowing rank order: thalamus > amygdala 5 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 noninvasive assessment of aromatase involvement in various physiologi-
cal and pathological processes affecting the human brain. Synapse 64:801–807,
Aromatase catalyzes the last step in estrogen biosynthesis. Brain aro-
C2010 Wiley-Liss, Inc.
Aromatase, a member of the cytochrome P450
(CYP450) protein superfamily (Danielson, 2002), is a
unique gene product of the CYP19 gene. Aromatase
regulates the last step of estrogen biosynthesis, aro-
matizing the A ring of androgens such as androstene-
dione and testosterone to estrone and estradiol,
organs including the brain (Roselli, 2007; Simpson
et al., 2002). Low levels of aromatase were found
throughout the rat and monkey brain, with high lev-
els present only in the preoptic area, ventromedial
nucleus of the hypothalamus, medial amygdala, and
the bed nucleus of the stria terminalis (Roselli et al.,
2001; Takahashi et al., 2006). As for the human
brain, aromatase enzymatic activity, immunoreactiv-
ity, and gene expression (mRNA) were reported in
studies of specific brain regions, including the tempo-
ral cortex (Steckelbroeck et al., 1999), hypothalamic
Contract grant sponsor: US Department of Energy OBER; Contract grant
number: DE-AC02-98CH10886; Contract grant sponsor: NIH; Contract grant
numbers: R01 NS050285 (to AB), K05DA020001 (to JSF); Contract grant
sponsor: General Clinical Research Center of Stony Brook University (NIH);
Contract grant number: MO1RR10710.
*Correspondence to: Anat Biegon, PhD, Medical Department, Brookhaven
National Laboratory, Upton, New York 11973, USA. E-mail: firstname.lastname@example.org
Received 13 October 2009; Accepted 11 November 2009
Published online 29 March 2010 in Wiley Online Library (wileyonlinelibrary.
C2010 WILEY-LISS, INC.
SYNAPSE 64:801–807 (2010)
and ventral forebrain nuclei (Ishunina et al., 2005),
hippocampus (Stoffel-Wagner et al., 1999), and thala-
mus (Sasano et al., 1998). To date, there have been no
published studies of aromatase distribution or regula-
tion throughout the human brain, while animal stud-
ies suggest that brain aromatase activity is higher in
adult males than in adult females and is modulated
by changes in testosterone levels but not the phase of
the female estrus cycle (Abdelgadir et al., 1994; Rose-
lli et al., 1984; Rosselli and Resko, 2001).
Aromatase, along with specific estrogen receptors,
has been implicated in cellular proliferation, repro-
memory, and neuroprotection in various animal spe-
cies (Garcia-Segura, 2008; Roselli, 2007; Saldahana
et al., 2009). Changes in aromatase activity are also
implicated in a wide range of human diseases,
including Alzheimer’s disease (AD; Hiltunen et al.,
2006), brain injury (Roselli, 2007), breast cancer
(Bulun and Simpson, 2008), endometriosis (Fedele
et al., 2008), and hepatic cancer (Miceli et al.,
Aromatase inhibitors (AI) are a relatively new class
of drugs that are gaining ground in the treatment of
breast cancer (Budzar and Howell, 2001). AI are also
used by body builders who self-administer these drugs
to avoid feminizing effects of excess testosterone, the
precursor to estrogen (Hartgens and Kuipers, 2004).
The AI fall under two categories: (1) steroidal AI such
as formestane and exemestane, which bind irreversibly
to the active site in aromatase, and (2) nonsteroidal AI
such as aminoglutethimide, fadrozole, anastrozole,
letrozole, and vorozole, which bind competitively and
reversibly (Budzar and Howell, 2001). Among the
AI, vorozole ((S)-6-[(4-chlorophenyl)(1H-1,2,4-triazol-
1-yl)methyl]-1-methyl-1H-benzotriazole), Ki5 0.7 nM
(Vanden Bossche et al., 1990), and letrozole (Cohen
et al., 2002; Iveson et al., 1993) have been labeled with
carbon-11 using [11C]methyl iodide and evaluated as
radiotracers for in vivo imaging of brain aromatase in
primates (Kil et al., 2009; Kim et al., 2009; Lidstrom
et al., 1998; Takahashi et al., 2006). While [11C]letro-
zole failed to show specific displaceable binding in
vivo (Kil et al., 2009), [11C]vorozole brain scans
revealed high specific binding in the rhesus amygdala,
similar to results obtained with autoradiography of
the rat brain (Takahashi et al., 2006). We have
recently reinvestigated and modified the radiosynthe-
sis and purification of [11C]vorozole (Kim et al., 2009).
We found that the previously published method
resulted in three labeled compounds, not two as origi-
nally reported. [11C]vorozole and another labeled iso-
mer were not separated in the prior work, and thus
we developed an improved purification method that
yielded pure [11C]vorozole (Kim et al., 2009). The pure
labeled vorozole was tested and validated in female
baboons, with the highest binding occurring in the
amygdala and hypothalamic/preoptic area (Kim et al.,
Despite the importance of aromatase in physiologi-
cal and pathological processes and the increasing use
of AI, there are no published quantitative, noninva-
sive studies of the distribution and regulation of aro-
matase in living humans. We hereby show that
[11C]vorozole is a useful ligand for studies of aroma-
tase in the human brain with a unique pattern of
Six young, healthy nonsmoking subjects, three men
and three women, were included in the study, which
was approved by the Institutional Review Board and
the Radioactive Drug Research Committee of Stony
Brook University/Brookhaven National Laboratory. All
subjects gave written informed consent. The study
inclusion criteria were age 21–40, good health, and
excluded for recent or current use of steroids (including
contraceptives), recreational drugs and medications
affecting brain function, neurological/psychiatric/meta-
bolic disorders, and pregnancy in females.
During the screening visit, women were asked to
report the date of their last menstrual period and
their PET studies were scheduled to coincide with the
nearest midcycle, when plasma estrogen levels are at
their highest, or during the menstrual/early follicular
phase, when estrogen levels are lower. Men were
scanned at baseline, ?2 weeks later (retest) and again
(blocking study) 2 h after ingesting an oral dose (2.5
mg) of letrozole (Femara, e.g., Cohen et al., 2002).
Blood samples were withdrawn from all subjects on
the day of the PET study and gonadal hormone levels
measured in the plasma in a commercial laboratory
Pure [11C]vorozole was synthesized and purified as
recently described (Kim et al., 2009). Briefly, to (S)-
norvorozole (1 mg) in DMSO (300 ll) was added KOH
(5 M, 1 ll). After vortexing for 30 s, the reaction mix-
ture was transferred into a V-shape reaction vessel.
[11C]methyl iodide was purged into this solution at
room temperature and peak trapping was observed by
a pin-diode detector. After the vessel was heated to
908C for 3 min, the reaction mixture was cooled and
diluted with high-performance liquid chromatography
(HPLC) eluent. The crude product in DMSO was
chromatographed using a solvent mixture of water
(pH 5 3.0, adjusted with formic acid)/methanol
A. BIEGON ET AL.
(45/55) at a flow rate 1 ml/min on a Luna PFP(2)
(Phenomenex, 250 mm 3 10 mm, 5 lm). [N-meth-
yl-11C] vorozole eluted at 24.5 min was collected. The
HPLC solvent was removed by azeotropic evaporation
with acetonitrile using a rotary evaporator under
reduced pressure. The residue was taken up by saline
(4 ml) and filtered through a 0.22 lm Millipore1filter
(Millipore, Billerica, MA) into a sterile vial. The
radiochemical purity for [11C]vorozole was >99%,
measured by analytical HPLC using aqueous formic
acid solution (pH 5 3.0)/methanol (1/2) at a flow rate
of 1 ml/min on a Luna PFP(2) (250 mm 3 4.6 mm,
5 lm; Phenomenex, Torrance, CA). Specific activity
was calculated from the radioactivity and mass
detected (UV-254 nm) during preparative HPLC and
reported as the ratio of radioactivity/mass (Ci/lmol).
PET images were acquired over a 90-min period
using a whole body, high-resolution positron emission
tomograph (Siemen’s HR1, 4.5 3 4.5 3 4.8 mm, mo3
at the center of field of view) in 3D dynamic acquisi-
tion mode as previously described (Kim et al., 2009).
For each of the PET scans, subjects received an injec-
tion of [11C]vorozole (3–8 mCi; specific activity >0.1
mCi/nmol at the time of injection). An arterial plasma
input function for [11C]vorozole was obtained from ar-
terial blood samples withdrawn every 2.5 s for the
first 2 min (Ole Dich automatic blood sampler), then
at 3, 4, 5, 6, 8, 10, 15, 20, 30, 45, 60, and up to 90
min (end of study). All samples were centrifuged to
obtain plasma which was counted, and selected sam-
ples were assayed for the presence of unchanged
Assay of unchanged [11C]vorozole in plasma
The fraction of [11C]vorozole remaining in plasma
was determined by automated solid phase extraction
(Alexoff et al., 1995) after validating by HPLC using
conditions described previously (Kim et al. 2009). The
automated assay consisted of the following steps.
Plasma (0.4 ml) was added to 3 ml phosphate buffer
(pH 7 ) and applied to a previously conditioned C18
cartridge (Varian BondElut LRC 500 mg, Varian, Wal-
nut Creek, CA), which was then washed sequentially
with 33 5 ml of water. All wash fractions and the
C18 cartridge were counted. The ratio of the radioac-
tivity remaining on the C18 cartridge to that of the
total radioactivity recovered is the percent unchanged
tracer, after corrections for radioactive decay, back-
ground, and geometry-dependent counting efficiency
(Alexoff et al., 1995). Radioactivity recovery was
Time frames were summed over the 90-min scan-
ning period. The summed PET images were coregis-
tered with structural 3D MR image of the same
subject using PMOD software (PMOD Technologies,
Zurich, Switzerland) when available to confirm the an-
atomical location of tracer accumulation. Regions of in-
terest (ROIs), including amygdala, cerebellum, cortex,
medulla, preoptic area, putamen, thalamus, and corti-
cal white matter, were placed on the summed image
and then projected onto the dynamic images to obtain
time activity curves. Regions occurring bilaterally
were averaged. C-11 concentration in each ROI was di-
vided by the injected dose to obtain the % dose/cm3.
A two-compartment model (Gunn et al., 2001) was
used to estimate the total tissue distribution volume,
VT, which includes free and nonspecifically bound
tracer as well as specifically bound tracer (Innis
et al., 2007). In terms of a two compartment model
VT5 k1/k2(1 1 k3/k4). The four model parameters of
the two-compartment model were optimized to obtain
the best fit to the ROI data using routines from
Numerical Recipes (Press et al., 1990).
Plasma levels of [N-methyl-11C]vorozole rose very
quickly (less than 1 min to peak), followed by a mono-
phasic decrease. Tracer metabolism in plasma was
unchanged vorozole after 30 min and ?60% after 90
min with no apparent effect of sex or letrozole
pretreatment (Fig. 1). The tracer showed fast brain
Analysis was performed on plasma samples from three men and
three women injected IV with [11C]vorozole. The graph depicts
means (SD) of % radioactivity identified as [11C]vorozole at the
specified time points.
Metablic stability of [11C]vorozole in human plasma.
IMAGING HUMAN BRAIN AROMATASE
penetration reaching peak values within less than 2
min, followed by a fast clearance stage and selective
retention in specific regions such as thalamus and
amygdala, where levels of radioactivity (decay cor-
rected) were stable or even increased during the last
30 min of PET data acquisition (Fig. 2). This region-
specific retention was completely blocked by pretreat-
ment with letrozole (Fig. 2). Tracer distribution in the
late (50–90 min post-tracer injection) time-frames
was highly heterogeneous, with the highest levels
seen in thalamus. Thalamic distribution was hetero-
geneous as well, with the highest levels in the para-
ventricular, dorsomedial, and pulvinar nuclei and
lower binding in lateral and ventral thalamic nuclei
(Figs. 2 and 3). Moderate levels of radioactivity were
noted in amygdala and preoptic area/anterior hypo-
thalamus and in the medulla (inferior olive). Cortical
and basal ganglia levels were relatively low, with hip-
pocampus indistinguishable from the temporal cortex.
Accumbens levels in the basal ganglia were higher
than those in caudate and putamen (Fig. 3).
The regional distribution pattern illustrated in Fig-
ure 3 was observed in all of the subjects and scans in
which the tracer was injected alone. The distribution
volume (VT) values derived from a two-compartment
model in both men and women (regardless of men-
strual cycle) followed the following rank order: thala-
mus > amygdala 5 preoptic area > medulla (inferior
olive) cortex, putamen, cerebellum, and white matter
(Figs. 4 and 5). Baseline and retest studies demon-
strated the same regional rank order of tracer accu-
mulation, with a trend toward lower VT values in
retest studies compared to baseline (Fig. 4).
Individual plasma testosterone and estrogen levels
were within the established normal range for young
men and women, with testosterone levels ranging
from 250 to 570 ng/ml in men and <20–32 ng/ml in
women and estrogen levels ranging from <50 to
114 pg/ml in men and 84–250 pg/ml in women.
Pretreatment with letrozole reduced VT in all of
the regions examined, resulting in a homogenous
distribution across regions (Fig. 4). The size of the
reduction was region-dependent, ranging from ?70%
blocking in thalamus and preoptic area to ?10% in
cerebellum (Fig. 4).
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 h after oral administration of letrozole
Time-activity curves of [11C]vorozole in human brain
Figure shows coronal PET images (summed frames over 60–90 min,
pseudocolored using the rainbow spectrum) overlaid on structural
MRI (gray levels) of same subject. A 5 level of nucleus accumbens,
B 5 level of anterior hypothalamus/preoptic area, C 5 level of
Anatomical distribution of [11C]vorozole in human brain.
amygdala, D 5 level of dorsomedial thalamus, E 5 level of pulvinar
nucleus of thalamus, F 5 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–C) and
hippocampus (Levels D and E).
A. BIEGON ET AL.
The results of the studies reported here suggest
that [N-methyl-11C]vorozole is a useful radiotracer for
the noninvasive measurement of brain aromatase in
humans, demonstrating anatomical and pharmacolog-
ical specificity. Thus, the regional distribution pattern
of the tracer was highly heterogeneous, with the
highest levels found in distinct (dorsomedial, pulvi-
nar, and paraventricular) thalamic nuclei, followed by
moderately high levels in amygdala, preoptic area,
and medulla and low levels in cortex, putamen, cere-
bellum, and cortical white matter. Tracer accumula-
tion in all regions was reduced by oral pretreatment
with the aromatase inhibitor letrozole (2.5 mg) given
2 h before tracer injection. This is in line with pub-
lished studies performed in healthy volunteers, where
the same dose of letrozole resulted in a near-complete
decrease in plasma estrogen levels (Iveson et al.,
1993). The time interval between pretreatment and
tracer injection was also based on previous studies of
peripheral inhibition of aromatase, where the effect of
the drug peaked within 2–4 h of administration and
lasted for more than 24 h (Iveson et al., 1993).
Previous PET studies with [11C]vorozole (Lidstrom
et al., 1998; Takahashi et al., 2006) did not report ki-
netic modeling of the tracer uptake but rather relied
on region to cerebellum ratios at late time points.
This approach, as well as a tissue reference model,
was deemed inappropriate, since all gray matter
regions, including the cerebellum, appeared to contain
displaceable [11C]vorozole binding in our baboon stud-
ies (Biegon et al., 2010; Kim et al., 2009) as well as in
the present studies of the human brain. A comparison
of one- and two-compartment models to the model-in-
dependent graphical approach (Logan et al., 2003)
demonstrated a better fit of the two-compartment
model, since the one-compartment model consistently
underestimated the volume of distribution derived
from the graphical analysis in baboons (Biegon et al.,
2010). Therefore, we have used the two-compartment
model to estimate the regional distribution volumes
of [11C]vorozole in the human brain. The regional
rank order of VTwas similar to the %ID/CC observed
at late (>50 min) but not early times after tracer
The regional distribution pattern of aromatase in
the human brain is strikingly different from the dis-
tribution reported in rodents and primates (baboon
and rhesus), in which the highest levels were found
in the amygdala and preoptic area while the levels in
thalamus and medulla were unremarkable (Kim
et al., 2009; Lidstrom et al., 1998; Takahashi et al.,
2006). While difference between rodents and primates
in brain receptor and enzyme distribution are com-
mon, primate and human brain usually show similar
regional distribution patterns (e.g., Osterlund et al.,
2001) making this an unexpected finding and suggest-
ing a unique role for thalamic and medullar aroma-
tase in humans.
Previous studies of human brain aromatase were
conducted postmortem or on biopsy material and
were confined to preselected, specific regions, such as
urability of [11C]vorozole in the brains of young men. Bars depict
mean (SEM) of VTfollowing the first injection of tracer (baseline),
tracer injection 2 h after letrozole (blocking), or tracer alone ?2
weeks after the first scan (retest). Amy, amygdala; cb, cerebellum;
med, medulla (inferior olive); occ, occipital cortex; poa, preoptic
area; put, putamen; temp, temporal cortex; thal, thalamus (pulvinar
and mediodorsal); wm, cortical white matter.
Regional volume of distribution, reproducibility, and sat-
brains of young women. Bars depict mean (SEM) of VT following
injection of tracer in three women who were scanned around mid-
cycle (12–17 days after onset of menses, when estrogen levels are at
their highest, hatched bars) or during the menstrual/early follicular
phase (27–4 days after onset of menses, when estrogen levels are
low, black bars). Amy, amygdala; cb, cerebellum; med, medulla (infe-
rior olive); occ, occipital cortex; poa, preoptic area; put, putamen;
temp, temporal cortex; thal, thalamus (pulvinar and mediodorsal);
wm, cortical white matter.
Regional volume of distribution of [11C]vorozole in the
IMAGING HUMAN BRAIN AROMATASE
the temporal cortex (Stoffler-Wagner et al., 1999) or
specific hypothalamic and ventral forebrain nuclei
(Ishunina et al., 2005). Our results are in line with
Sasano et al. (1998) who measured aromatase gene
expression in thalamus as well as eight other regions
and found high levels of aromatase gene expression
in thalamus, while confirming the presence of aroma-
tase in all other regions investigated. Although the
number of subjects in our study is too small for for-
mal statistical analysis, we did not find higher levels
in men compared to women, as expected from the
findings of Sasano et al. (1998), Steckelbroeck et al.
(1999), Stoffel-Wagner et al. (1999), and Ishunina
et al. (2005), who reported similar levels of brain aro-
matase activity and gene expression in men and
women. Conversely, results from animal studies dem-
onstrated higher levels of brain aromatase in males
and suggested testosterone was a positive modulator
of aromatasein the hypothalamic–preoptic
(Abdelgadir et al., 1994; Roselli et al., 1984). However,
brain aromatase did not appear to be significantly
regulated by the estrous cycle in rodents (Roselli
et al., 1984), matching our results in a small number
of women imaged at opposite phases of the menstrual
cycle. Taken together, our findings support the notion
that brain aromatase expression is regulated in a spe-
cies- and region-selective manner (Roselli et al.,
1984). Such specific regulation may be the result of
tissue-specific aromatase promoters, which were iden-
tified in animal and human tissues (Golovine et al.,
2003; Jones et al., 2006). Since other promoters
besides the brain specific exon 1.f (Sasano et al.,
1998) are expressed in the human brain, this hetero-
geneity may provide the basis for brain region-specific
regulation and expression of aromatase in humans.
At present, we do not know which brain functions
are served by the estrogen produced locally in the
thalamus and inferior olive or the identity of the rele-
vant estrogen receptor subtypes. Although the exact
functions subserved by the human inferior olive are
not clear, available information implicates this nu-
cleus as well as specific thalamic nuclei in cognitive
aspects of sensory and motor information processing,
which may be modulated by estrogen (Liu et al.,
2008; Ward et al., 2007).
As for the estrogen receptors, both ERa and ERb
receptors are expressed in a subtype-specific manner
in the human brain, with ERa mostly restricted to
hypothalamus and amygdala while ERb expression is
more widespread and found also in hippocampus, cor-
tex, and thalamus (Osterlund et al., 2000). It is also
possible that estrogen synthesized in thalamus and
medulla interacts with the more recently character-
ized membranal estrogen receptors (Qiu et al., 2008;
Toran-Allerand, 2004), some of which are expressed
in regions lacking classical ERa and ERb such as
striatum and medulla in rats (Brailoiu et al., 2007).
However, the regional distribution of membranal
estrogen receptors in the human brain has not been
reported to date.
In summary, [N-methyl-11C]vorozole is a useful
tracer for aromatase in the human brain, showing
fast brain penetration and a unique pattern of bind-
ing in specific brain regions. These studies set the
stage for the noninvasive assessment of aromatase
involvement in various physiological, pathological,
and pharmacological processes affecting the human
We thank Michael Schueller for cyclotron opera-
tions, Donald Warner for PET operations, and Karen
Apelskog-Torres for study protocol preparation. We
are also grateful to the people who volunteered for
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IMAGING HUMAN BRAIN AROMATASE