Binding of Pramipexole to Extrastriatal Dopamine D2/D3 Receptors in the Human Brain: A Positron Emission Tomography Study Using 11C-FLB 457
Ishiwata K (2011) Binding of Pramipexole to Extrastriatal Dopamine D2/D3 Receptors in the Human Brain: A
Positron Emission Tomography Study Using 11C-FLB 457. PLoS ONE 6(3): e17723. doi:10.1371/journal.pone.0017723
Binding of Pramipexole to Extrastriatal Dopamine D2/D3 Receptors in the Human Brain: A Positron Emission 11 Tomography Study Using C-FLB 457
Kenji Ishibashi 0
Kenji Ishii 0
Keiichi Oda 0
Hidehiro Mizusawa 0
Kiichi Ishiwata 0
Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan
0 1 Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan, 2 Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University , Tokyo , Japan
The purpose of this study was to determine the binding sites of pramipexole in extrastriatal dopaminergic regions because its antidepressive effects have been speculated to occur by activating the dopamine D2 receptor subfamily in extrastriatal areas. Dynamic positron emission tomography (PET) scanning using 11C-FLB 457 for quantification of D2/D3 receptor subtype was performed on 15 healthy volunteers. Each subject underwent two PET scans before and after receiving a single dose of pramipexole (0, 0.125, or 0.25 mg). The study demonstrated that pramipexole significantly binds to D2/D3 receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus at a dose of 0.25 mg. These regions have been indicated to have some relation to depression and may be part of the target sites where pramipexole exerts its antidepressive effects.
Pramipexole is a dopamine D2 receptor (D2R) subfamily
agonist. It was introduced for treating motor symptoms in patients
with idiopathic Parkinsons disease (PD)  and has been shown to
be effective by various clinical trials [2,3]. In addition, various
studies have recently found antidepressive effects of pramipexole
not only in patients with PD complicated by depressive state
[4,5,6,7], but also in depressive patients without parkinsonian
symptoms [8,9,10,11,12,13,14,15,16]. Its antidepressive effects
have been also shown in animal experiments [17,18].
The D2R subfamily consists of D2, D3, and D4 receptor
subtypes . Pramipexole is active mainly at D2 and D3
receptors, and compared with other dopamine agonists, it is
unique in that the binding affinity for D3 receptors is higher than
that for D2 receptors [20,21,22,23]. Kvernmo et al. reported that
binding affinities (inhibition constant; Ki) for cloned human D2
and D3 receptors of pramipexole were 3.9 and 0.5 nmol/L,
respectively . The distribution of D3 receptors in the brain is
different from that of D2 receptors [24,25,26,27,28,29]. Compared
with D2 receptors, D3 receptors are predominantly located in
extrastriatal regions including the mesolimbic dopamine system
involved in mood and behavior. On the other hand, although both
D2 and D3 receptors in the striatum are much more abundant
than those in other regions, the D2 receptor density is higher than
the D3 receptor density in the striatum. Stimulation of D2 and D3
receptors appears to induce different effects.
There are growing evidences that D3 receptors may play a role
in the pathogenesis of depression because of their pharmacology
and distribution in the brain [26,30,31], although the exact
mechanism remains unknown. The mechanism of antidepressive
effects and extrastriatal binding sites of pramipexole are also
unknown, and no study has investigated this issue. These effects
have been speculated to occur by means of activation of D2R
subfamily, especially the D3 receptor subtype, in the mesolimbic
dopamine system . Therefore, we aimed to determine the
binding sites of pramipexole in the extrastriatal dopaminergic
regions by using 11C-FLB 457 positron emission tomography
(PET) scanning for quantification of D2/D3 receptors in
extrastriatal brain regions. In addition, we discussed whether the
regional sites occupied by pramipexole may be target sites where
pramipexole exerts its antidepressive effects on the basis of
previous anatomical and functional reports on depression.
Materials and Methods
This study protocol was approved by the Ethics Committee of
the Tokyo Metropolitan Institute of Gerontology. Written
informed consent was obtained from all participants. A total of
15 healthy volunteers (7 men and 8 women; mean age = 50.2
years, SD = 11.7, range = 3077) participated in the study. All
subjects underwent two 11C-FLB 457 PET scans and magnetic
resonance imaging (MRI) of the brain. They were classified into 3
groups according to the dose of pramipexole (0.25, 0.125, or
0 mg). The 5 subjects in the high-dose group (2 men and 3
women, 57.2612.8 years) received a single oral 0.25 mg dose of
pramipexole. Another 5 subjects in the low-dose group (2 men and
3 women, 51.469.4 years) received a single oral 0.125 mg dose of
pramipexole. The drug was administered between the two PET
scans. The other 5 subjects were in the control group (3 men and 2
women, 42.066.3 years) and received no medication. Significant
difference was not found in age between the 3 groups with
oneway ANOVA test. All volunteers were free of any current or past
mental disorders, and defined as healthy on the basis of their
medical history, the results of their physical and neurological
examinations and routine mental health interview performed by a
neurologist, and the findings of the MRI. None had been receiving
any other medications at the time of this study.
Doses of pramipexole
Previous studies have shown that administration of more than
approximately 1 mg of pramipexole exerts antidepressive effects
[4,5,6,7,8,9,10,11,12,13,14,15,16]; compared with these studies,
the doses of pramipexole used in our study were low. We chose
these low doses to ensure the safety of the participants in this study.
According to unpublished data on file in Nippon Boehringer
Ingelheim (Tokyo, Japan), a single administration of pramipexole
0.4 mg caused orthostatic hypotension in an early clinical trial of
German volunteers. On the basis of these results, the doses of
pramipexole were set at 0.1, 0.2, and 0.3 mg in the Phase one
clinical trial of Japanese volunteers, and no one developed more
than moderate adverse effects. After oral administration of a single
dose of pramipexole 0.1 mg, Cmax, Tmax, and t1/2 were
294.6646.3 pg/mL, 1.560.5 h and 7.7161.90 h (mean 6 SD),
respectively. After administration of pramipexole 0.2 mg, the
values were 583.2669.9 pg/mL, 1.460.5 h, and 6.3661.46 h,
respectively; after a dose of 0.3 mg, the values were
766.3688.8 pg/mL, 2.361.2 h, and 6.9461.09 h, respectively.
One tablet of pramipexole equals 0.125 mg. Therefore, the doses
of pramipexole were set at 0.25 and 0.125 mg in this study.
11C-FLB 457 PET imaging
Each volunteer participated in two 11C-FLB 457 PET scans on
the same dayone in the morning and another in the afternoon.
Of 15 subjects, 10 were administered with either 0.25 or 0.125 mg
of pramipexole after the first PET scan; the second PET scan took
place 11.5 h later because the concentration of pramipexole in
plasma reaches its peak in approximately 12 hours as described
PET imaging was performed at the Positron Medical Center,
Tokyo Metropolitan Institute of Gerontology, with a SET-2400W
scanner (Shimadzu, Kyoto, Japan). The spatial resolution was
4.4 mm full width at half maximum in the transverse direction and
6.5 mm full width at half maximum in the axial direction. Images
with 50 slices were obtained with a 26263.125-mm voxel size and
a 1286128 matrix size. The transmission data were acquired by
using a rotating 68Ga/68Ge rod as a source for attenuation
correction. 11C-FLB 457 was prepared as described previously
In the first PET experiment, the injected dose, specific activity,
and mass of injected ligand were 283624 MBq, 118645 GBq/
mmol, and 3.061.7 mg (mean 6 SD), respectively. The respective
values in the second PET experiment were 285619 MBq,
110638 GBq/mmol, and 3.262.0 mg. The time interval between
the first and second injections of 11C-FLB 457 was 44.5 hours.
The mass of injected ligand in each second scan was carefully
adjusted to that in each first scan because of potential occupancy
effects by unlabelled ligand itself [33,34], and no significant
difference was found in the mass of injected ligand as well as the
injected dose and specific activity between the first and second
scans in each group, using paired Student t test.
A dynamic series of decay-corrected PET data acquisition was
performed in the 3D mode for 90 minutes starting at the time of
the intravenous injection of 11C-FLB 457. The frame arrangement
was 20 s 66 frames, 60 s 62 frames, 180 s 62 frames, and 300 s
For the 5 subjects in the high-dose group, arterial blood samples
were also obtained. Immediately after the intravenous injection of
11C-FLB 457, 18 arterial blood samples were collected at 10-s
intervals over 3 min; the next 2 samples were collected at 60-s
intervals over 2 min, and the remaining 10 samples were collected
at longer intervals, for a total of 30 samples. All samples were
manually drawn. Plasma was separated, weighed, and measured
for radioactivity with a sodium iodide (Tl) well scintillation
counter. Six samples collected at 3, 10, 20, 30, 40, and 60 minutes
were further processed by high-performance liquid
chromatography to determine the fractions of plasma radioactivity
corresponding to unchanged 11C-FLB 457 and labeled metabolites, as
described previously .
Image manipulations were performed using Dr. View version
R2.0 (AJS, Tokyo, Japan) and statistical parametric mapping 2
(SPM2; Functional Imaging Laboratory, London, UK)
implemented in MATLAB version 7.0.1 (The MathWorks, Natick,
MA). First, individual two dynamic 11C-FLB 457 images and MRI
images were coregistered. Next, regions of interest (ROIs) were
defined over the prefrontal, parietal, lateral temporal and anterior
cingulate cortices, medial and lateral parts of the thalamus,
amygdala, hippocampus, and cerebellum on the individual
coregistered MRI. These ROIs were spatially moved on the
corresponding coregistered dynamic 11C-FLB 457 images.
11C-FLB 457 binding to extrastriatal D2/D3 receptors was
calculated as the binding potential (BP) by the simplified reference
tissue model (SRTM) using cerebellum as a reference tissue .
BP derived with this method is referred to as BPND_SRTM (ND:
nondisplaceable). For the high-dose group with arterial blood
samples, the binding was also analyzed by using the linear graphic
analysis by Logan et al. . The slope of the linear phase of the
obtained plot corresponds to the total distribution volume (VT) of
the ligand plus the plasma volume. The regional VT was
determined from the slope, and the BP with this method was
calculated as follows using cerebellum as a reference region:
BPND_Logan = (VT on ROI/VT on cerebellum) - 1.
D2/D3 occupancy rate by pramipexole was calculated for each
ROI by using the following equation: occupancy rate (%) = 1006
(BP at baseline BP at pramipexole-loading)/BP at baseline. BP at
baseline and BP at pramipexole-loading are obtained from first
and second PET scans, respectively. Data were expressed as mean
The differences between first and second PET scans were tested
by paired Students t-test. Correlations between BPND_SRTM and
BPND_Logan in high-dose group were assessed by means of linear
regression analysis with Pearsons correlation test. P values,0.05
were considered statistically significant.
For the high-dose group, BPND_SRTM was found to be
significantly correlated with BPND_Logan (r = 0.97; P,0.01) using
data of both the first and second experiments, as shown in Figure 1.
Although the slope of the regression line was slightly less than one,
the BPND_SRTM and BPND_Logan had almost a one-to-one
Each regional BPND of first and second PET scans for each dose of
pramipexole is shown in Figure 2. After administration of
pramipexole 0.25 mg, BPND_Logan in the prefrontal cortex
(P = 0.03, t = 3.15), medial (P = 0.01, t = 4.56) and lateral (P = 0.01,
t = 3.78) thalamus, and amygdala (P = 0.02, t = 3.32) and BPND_SRTM
in medial (P = 0.01, t = 4.51) and lateral (P = 0.02, t = 3.33) thalamus
decreased significantly. D2/D3 occupancy rates estimated with
BPND_Logan in the prefrontal cortex, medial and lateral thalamus,
and amygdala were 10.3%66.8%, 16.7%66.9%, 14.9%68.9%,
and 20.4%68.6%, respectively. Occupancy rates estimated with
BPND_SRTM in the medial and lateral thalamus were 10.3%65.0%
and 10.8%66.4%, respectively. No significant difference was found
in occupancy rates estimated with either BPND_Logan or BPND_SRTM
between the medial and lateral thalamus, using paired Student t test.
In the low-dose group with 0.125 mg of pramipexole and in the
control group, there was no significant correlation between
BPND_SRTM of the two PET scans in all regions.
The time-activity curves of representative regions before and
after administration of pramipexole 0.25 mg are displayed in
Figure 3. Visually, the radioactivity levels of the putamen, entire
thalamus and amygdala seemed to decrease after administration of
pramipexole 0.25 mg. On the other hand, the radioactively level
of the cerebellum seemed mostly unchanged between the first and
second scans. Actually, VT on the cerebellum estimated by Logan
plot method in the first and second PET scans was 4.5560.68 and
4.6760.97, respectively, and no significant difference was found
between the two.
Pramipexole is a synthetic aminobenzothiazole derivative with
selective actions mainly on D2 and D3 receptors, and it binds with
the highest affinity to D3 receptors [20,21,22,23]. In the brain, the
distribution of D3 receptors is known to be different from that of
D2 receptors [24,25,26,27,28,29], although there are some
differences in the relative proportion of D2 and D3 receptors
between the previous studies. The D2 binding sites are widely
detected with the highest concentration found in the striatum,
followed by the nucleus accumbens, external segment of the globus
pallidus, substantia nigra and ventral tegmental area. The
distribution of D3 receptors is relatively restricted and D3 binding
sites are enriched in the amygdala, nucleus accumbens, ventral
Figure 2. Changes in BPND between first and second PET scans in each extrastriatal region. For 0.25 mg dose group, each BPND was
estimated by the Logan plot method and simplified reference tissue model method. For 0.125 mg and 0 mg dose groups, each BPND was estimated
only by the simplified reference tissue model method. Pramipexole was orally administered 11.5 h before second PET scanning at doses of 0.25 mg,
0.125 mg. Each P value was estimated by paired Students t-test between first and second PET scans. Significant differences were found only in the
high-dose group (* P,0.05). BP: binding potential, ND: nondisplaceable.
Figure 3. Average time-activity curves of representative regions of five subjects before (left) and after (right) administration of
pramipexole 0.25 mg. Each point was normalized to the radioactivity of 185 MBq. The time-activity curve of the putamen is displayed for
reference. Thalamus (&) represents the entire thalamus.
striatum, substantia nigra, anteroventral nucleus of the thalamus
and internal segment of the globus pallidus. Thus, D2 or D3
binding sites are located in the synapse of the afferent structures as
well as the neurons of the efferent structures such as substantia
nigra and ventral tegmental area. D2 or D3 receptors in the
efferent structures are thought to act as autoreceptors, which could
play an important role in regulating the activity of dopaminergic
On the other hand, in this study, the BPND in the substantia
nigra or ventral tegmental area could not be quantified with
reliability, because the structures were too small for usual ROI
analysis of the dynamic data on the basis of the resolution of the
PET scanner and the number of subjects was relatively small. For
the same reasons, the ROIs were drawn over not each small
nucleus but medial and lateral parts of the thalamus although the
thalamus is known to have a great deal of regional heterogeneity in
D2 and D3 expression. Also, the BPND in the striatal and its closely
neighbor regions such as the ventral striatum and globus pallidus
could not be quantified using 11C-FLB 457 because a long time
more than a few hours is needed for reaching equilibration in the
striatum . Based on the distribution of D2 and D3 receptors
and the technical matters as described above, we investigated the
binding sites of pramipexole especially in the limbic system,
thalamus and cortical regions. To our knowledge, this is the first in
vivo study that has investigated the relationship between a
dopamine agonist and its binding sites in extrastriatal regions.
This study showed that a single dose of pramipexole 0.25 mg
decreased BPND_Logan significantly in the prefrontal cortex,
amygdala, and thalamus. The mesolimbic pathway begins in the
ventral tegmental area of the midbrain and projects to the limbic
areas, including the nucleus accumbens in the ventral striatum,
amygdala, and hippocampus; it also projects to the cortical areas,
including the prefrontal and cingulate cortices. The latter cortical
pathway is called as the mesocortical pathway. Both pathways are
known to be involved in the depressive state [38,39,40,41]. Indeed,
the amygdala is important for emotional processing and its
functional abnormalities are associated with depression [42,43,44],
and frontal cortical dopamine function has been reported to be
involved in depression [45,46,47]. In the mesolimbic pathway, D2
and D3 binding sites are predominant in the hippocampus and
amygdala, respectively [24,25,27], and this difference may be one
of the reasons that significant decrease of BPND_Logan was not
found in the hippocampus. The mesocortical pathway also has D3
receptors as well as D2 receptors [27,29], although there is no
detail report on the relative proportion of D2 and D3 receptors in
that area. The thalamic dopaminergic system has been recently
identified; this system is speculated to have a prominent role in
depression, especially in regard to emotion, attention, cognition,
and complex somatosensory and visual processing [44,48,49,50].
Although this study could not find the significant difference
between medial and lateral parts of the thalamus, D3 binding sites
are relatively abundant and especially tend to be concentrated
along the midline in the thalamus, while D2 binding sites are more
homogeneously distributed [24,27]. On the basis of the
relationship between the occupied sites by pramipexole, the distribution of
D2 and D3 receptors and previous anatomical and functional
reports on depression, it is reasonable to suggest that pramipexole
may exert its antidepressive effects by activating D2R subfamily,
especially the D3 receptor subtype, in these regions (prefrontal
cortex, amygdala, and thalamus).
With regard to the BPND_SRTM method, after administration of a
single dose of pramipexole 0.25 mg, binding in the medial and
lateral thalamus decreased significantly as shown in the BPND_Logan
method, and bindings in both the prefrontal cortex and amygdala
showed the tendency to decrease without significant difference. On
the other hand, there was no significant difference between first and
second PET scans in both the low-dose group and the control
group. On the basis of the difference between the high-dose group
and the other two groups, we speculate that the effects of
pramipexole may be dose dependent, although it is impossible to
confirm this finding only with our data. Despite the high correlation
between BPND_Logan and BPND_SRTM methods as shown in Figure 1,
the discrepancies between the both methods found in the high-dose
group could be explained by the interindividual and intraindividual
variability of each analytical method [51,52,53]. However,
BPND_Logan estimated with artery blood samples should be regarded
as more reliable and accurate than BPND_SRTM estimated without
artery blood samples, and the findings for the prefrontal cortex and
amygdala, where only the BPND_Logan method showed significance,
were considered to be meaningful.
Vilkman et al. conducted a test-retest analysis of 11C-FLB 457
PET scanning with 7 healthy volunteers (mean age 6
SD = 29.066.9) and suggested that coefficient of variation
(COV) of each extrastriatal region in BPND_Logan and BPND_SRTM
methods was about 20% and the reproducibility of both methods
was good . Consistent with Vilkman et al., our results of the
control group corresponding to a test-retest analysis showed no
significant difference in BPND_SRTM of each region between first
and second PET scans. In the control group, the COV of each
region between the first and second experiments was similar, and
the ranges of COV in the first and second experiments were
19.3%33.9% and 16.3%38.5%, respectively. Thus, the
reproducibility of the BPND_SRTM method in this study was good.
Compared with previous studies [51,52,53], the COV in our
control group was somewhat larger. A possible explanation for this
difference could be given by following two reasons. One is the
relatively smaller number of subjects, and the other is the relatively
larger variability in age because D2R subfamily in each
extrastriatal region is known to show age-related decline [54,55].
In vitro brain homogenate binding studies have demonstrated
that D2R subfamily exists in two affinity states, i.e., high and low
affinity states [56,57,58]. The high affinity state is thought to
represent the functional state, and agonists bind preferentially to
D2R subfamily in the high affinity state, while antagonists have
equal affinity for D2R subfamily in the high and low affinity states.
In vivo competition studies between endogenous dopamine and a
labeled agonist or antagonist ligand estimated the percentage of
high affinity state to be about 6070% [59,60]. On the other hand,
some recent in vivo studies indicated that most D2R subfamily is in
the high affinity state at living conditions because the binding of
exogenous unlabeled agonist to D2R subfamily in high or low
affinity states could not be differentiated with either a labeled
agonist or antagonist ligand [61,62]. Thus, the accurate
proportion of the two states remains controversial. In this study,
relatively low D2/D3 occupancy rates by pramipexole were mainly
due to low dose of pramipexole. However, based on the two states
theory, another reason may be because D2/D3 occupancy rates by
agonist pramipexole were estimated by antagonist ligand 11C-FLB
One of the drawbacks of this study may be that we used the
cerebellum as a reference region, in order to gain smaller
variability and better reproducibility for the analysis of the PET
data, compared with the two-tissue compartment four-rate
constant model . Asselin et al. reported that using the
cerebellum as a reference region could lead to underestimation of
BPND and occupancy rate . However, we showed no statistical
difference in VT on the cerebellum estimated by Logan plot
method before and after administration of pramipexole 0.25 mg,
and at least our data, especially in the high-dose group, would be
appropriate for the purpose of confirming the extrastriatal effects
of a dopamine agonist. Other drawbacks of this study may be that
we collected arterial blood samples only from the high-dose group,
the number of subjects was relatively small and a dose of
pramipexole was relatively low for safety, as described previously.
In conclusion, we demonstrated that pramipexole binds to D2/
D3 receptors in the prefrontal cortex, amygdala, and medial and
lateral thalamus. These regions have been indicated to have some
relation to depression and may be part of the target sites where
pramipexole exerts its antidepressive effects.
The authors are thankful to Ms. Hiroko Tsukinari and Mr. Kunpei
Hayashi for their technical assistance.
Conceived and designed the experiments: K. Ishibashi K. Ishii K. Ishiwata.
Performed the experiments: K. Ishibashi K. Ishii KO K. Ishiwata.
Analyzed the data: K. Ishibashi KO K. Ishiwat. Contributed reagents/
materials/analysis tools: K. Ishibashi K. Ishii KO HM K. Ishiwata. Wrote
the paper: K. Ishibashi K. Ishiwata. Discussed the results: K. Ishibashi K.
Ishii KO HM K. Ishiwata.
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