INSERM U 334, Service Hospitalier Frédéric Joliot
A. Chenevier Hôpital, Créteil, and INSERM U 334, Service Hospitalier Frédéric Joliot, Orsay
INSERM U 334, Service Hospitalier Frédéric Joliot, Orsay
Pitié-Salpêtrière Hôpital, Paris, France
Correspondence: Jean-Luc Martinot, INSERUM U 334, SHFJ, CEA, 4 Place Gl. Leclerc, 91401 Orsay, France. E-mail: martinot{at}shfj.cea.fr
Declaration of interest The Fondation pour la Recherche Médicale and the Fondation Lilly France supported X.X. in part during the study.
* Presented in part at the VIIth International Congress on Schizophrenia
Research, Santa Fe, New Mexico, USA, 17-21 April 1999.
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ABSTRACT |
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Aims To investigate this hypothesis with the D2/D3-selective positron emission tomography (PET) probe [76Br]-FLB457.
Method PET scans were performed on 6 controls and 18 patients with schizophrenia treated with haloperidol or with risperidone, clozapine, amisulpride or olanzapine.
Results The D2 dopamine receptor blockade was high in the temporal cortex with both haloperidol and atypical antipsychotics. The atypicals, however, induced a significantly lower D2 binding index than haloperidol in the thalamus and in the striatum.
Conclusions Results suggest that cortical D2 dopamine receptors are a common target of traditional and atypical antipsychotics for therapeutic action. Higher in vivo binding to the D2 receptors in the cortex than in the basal ganglia is suggested as an indicator of favourable profile for a putative antipsychotic compound.
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INTRODUCTION |
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METHOD |
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Brain imaging
Brain imaging, image analysis and determination of the D2
dopamine blockade by the computation of a binding index were performed
according to a methodology described previously
(Xiberas et al,
2001). Briefly, for each subject a 1.5 T Signa Imager (General
Electric, Milwaukee, WI) provided 128 anatomical slices parallel to the
orbito-meatal line. Afterwards, 63 cerebral slices parallel to the
orbito-meatal line were acquired with a Siemens HR+ positron tomograph (of
spatial resolution 2.5 mm; Knoxville, TX). Just before injecting the
[76Br]-FLB457, venous blood was sampled for plasma concentration of
the antipsychotic drug. Approximately 1 mCi of [76Br]-FLB457 was
injected into each subject (mean (s.d.)=0.98 (0.20) mCi for healthy subjects
and 1.03 (0.23) mCi for patients, MannWhitney U=53.5,
P=0.82), with a high specific activity of 264±164 µCi/nmol
for healthy subjects and 481±299 µCi/nmol for patients
(MannWhitney U=29, P=0.08). Afterwards, a first image
series was acquired: two 5-min images, two 10-min images and two 15-min
images. Then the subjects were removed from the tomograph for 60 min and
afterwards placed in the same position using a thermoplastic-modelled mask as
well as skin marks with respect to a laser beam system, in order to acquire a
late image series: one 30-min and one 15-min image. Finally, a second
transmission scan was performed for co-registration purposes.
Image analysis
For each subject, the first PET image series was co-registrated on the
magnetic resonance image (MRI) using the first transmission scan
(Mangin et al, 1994).
Because the radioactivity concentrated mainly in the striatum in the late
image series, the cortical structures could not be used for registration.
Therefore, the second transmission scan was used for PET to MRI
co-registration. Regions of interest (ROIs) were drawn on the co-registrated
MRI slices, following the visible borders of the structures in each
hemisphere. Caudate and putamen were defined on five slices, thalamus on four
slices and temporal cortices on four slices below the lowest striatum slice;
finally; ROIs were defined in the cerebellar grey matter on four slices.
Regional radioactivity concentrations for each region (injected dose- and decay-corrected) were computed by pooling the corresponding ROI values and by summing the left and right regional values.
Determination of D2 dopamine receptor blockade: binding
index computation
Regional radioactivity was measured for each sequential scan and plotted
against time. Specific binding in the ROIs was defined as the difference
between radioactivities in the ROIs and the cerebellum. The activity measured
(Am) in the ROIs represents the sum of the free (and
non-specific binding) and bound radioligand concentrations:
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Plasma drug concentration determination
Haloperidol
After extraction from alkalinised plasma by a mixture of hexane/isoamylic
alcohol, haloperidol was purified from a Kromasil C8 column (5 µm, 250
x 4.6 mm) using a 73/23 mixture of phosphate buffer (pH 3) and
acetonitrile as mobile phase. The wavelength was set at 280 nm. The detection
limit was 1.0 µg/l.
Risperidone
After extraction from alkalinised plasma by a mixture of
hexane/ethylacetate, the risperidone was purified from a Kromasil C8 column
with the same characteristics as those described for haloperidol.
Clozapine
After extraction from alkalinised plasma by a mixture of hexane/isoamylic
alcohol, the clozapine was purified from a Spherisorp C8 column (5 µm, 250
x 4.6 mm) using a 55/40/5 mixture of phosphate buffer (pH 3),
acetonitrile and methanol as mobile phase. The wavelength was set at 230 nm.
The detection limit was 2.5 µg/l.
Amisulpride
After extraction from alkalinised plasma by a mixture of diethyl ether and
chloroform, the amisulpride was purified from a µBondapak C18 column (5
µm, 150 x 4.6 mm) using a 90/10 mixture of phosphate buffer (pH 3)
and acetonitrile as mobile phase. Detection was performed using a fluorimetric
detector set at ex=280 nm and
em=370 nm.
The detection limit was 0.5 µg/l.
Olanzapine
Owing to technical reasons, plasma drug concentration determinations were
not available.
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RESULTS |
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Striatal and thalamic binding indices
Striatal and thalamic binding indices clearly distinguished
haloperidol-treated from atypical antipsychotic-treated patients: indices were
lower with atypical antipsychotics. In the thalamus, the D2 binding
indices induced by clozapine, amisulpride and olanzapine were lower than that
induced by haloperidol. Analogous trends were detected in the thalamus and
striatum of risperidone-treated patients.
Temporal binding indices
Binding indices in the temporal cortex were similarly high, whatever the
antipsychotic compound.
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DISCUSSION |
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Methodological considerations
Long-time-frame PET imaging
For each patient, a binding index of the antipsychotic drug was derived
from the patient's measured regional radioactivity concentrations in the
striatum, the extrastriatal regions (thalamus, temporal cortex) and the
cerebellum 165 min after injection (Fig.
1), using the measures in control subjects as a baseline. The time
was chosen from modelling studies in primates, because it tallies with the
duration required for the radioligand's equilibrium in the extrastriatal
regions (Delforge et al,
1999). However, according to the same model, equilibrium is
reached only at t=300 min after injection in striatal regions. In one
control subject, we measured the concentration of the radioactivity in the
striata at 165 and 315 min after injection: an increase of 10% only (139
v. 152 nCi/ml) was observed at 315 min. Thus, the binding in the
striatum is probably slightly underestimated and values reported for striatal
regions should not be considered as effective D2 receptor occupancy
figures but as approximate values. They are, nevertheless, useful to compare
the striatal D2 receptor blockade induced in vivo by
various antipsychotic drugs.
Picomolar affinity radioligand
The picomolar affinity of [76Br]-FLB457 for D2
receptors accounts for the detection of a decrease of cerebellar radioactivity
values in treated patients, which is likely to reflect some degree of
occupancy of the small concentration of cerebellar D2 receptors.
This was not detected in previous studies using lower-affinity D2
radioligands. Although the cerebellar radioactivity cannot be considered as
solely reflecting non-specific binding of the [76Br]-FLB457, in the
conditions of the present study the use of a subtractive operator in the
binding index computation (i.e. regional Am
C) limits the incidence of the cerebellar specific binding for
comparison of the binding index under various antipsychotic treatments.
Indeed, by using the mean cerebellar value observed in the healthy subjects as
a reference, underestimation of binding index values was below 5% in
the striatum but ranged from 4% (haloperidol) to 12% (clozapine) in the
temporal cortex.
This underestimation, more marked in cortical than in striatal structures, strengthens the observation of a high binding index in cortical regions with all antipsychotics and the differential binding index values between haloperidol and atypical compounds in the basal ganglia. This observation is in keeping with a modelling study, correlating the affinity of a ligand with the Bmax in the structure studied. According to that modelling, the apparent affinity of a radioligand is correlated with the Bmax in the structure: when the Bmax is low, the apparent affinity of the radioligand to its receptor increases (Delforge et al, 1999).
Consistency with previous ex vivo findings in animals
The high D2 blockade induced in the temporal cortex by each of
the five antipsychotic drugs is consistent with reports using different
methodologies. The topographical selectivity of atypical antipsychotics on
dopamine blockade has been reported previously from ex vivo
measurements in animals. For instance, studies have demonstrated a higher
affinity of amisulpride for D2 dopamine receptors in the temporal
regions than in striatum (Schoemaker
et al, 1997). Also, chronic treatment with clozapine has
been shown specifically to upregulate cortical D2 mRNA turnover and
cortical D2 receptor binding, at variance with haloperidol, which
seems to upregulate both striatal and cortical D2 receptors
(Lidow & Goldman-Rakic,
1994). Atypical antipsychotics raise dopamine turnover more in
limbic structures than in striatum, whereas traditional antipsychotics affect
the dopamine turnover in both regions to the same degree
(Westerink et al,
1977). In addition, the c-fos-like immunoreactivity is
increased by atypical antipsychotics in limbic areas and in cortices, whereas
traditional antipsychotics also lead to an increased c-fos expression
in the dorsolateral striatum (Fink-Jensen
& Kristensen, 1994).
Consistency with previous in vivo findings in humans
Our results obtained with a quantitative imaging technique are in agreement
with previous in vivo reports using a radioligand with the same
picomolar affinity for D2 receptors [123I]-epidepride)
and single photon emission tomography to assess the occupancy of
D2 receptors by antipsychotic drugs in the striatum and temporal
cortex. Indeed, the elevated occupancy figures observed with traditional
compounds (haloperidol, fluphenazine, flupenthixol, pipotiazine, droperidol)
in both temporal (mean 82%) and striatal (mean 73%) regions
(Bigliani et al,
1999), and the small difference between striatal and temporal
cortex blockade were analogous to those determined in the haloperidol-treated
patients of the present study. Thus, although a relative temporal cortex
selectivity in D2 blockade
(Pilowsky et al,
1997; Bigliani et al,
2000) appears to characterise atypical antipsychotics, a similar
high D2 blockade in both temporal and striatal regions is induced
by usual antipsychotic doses of traditional antipsychotics.
On the whole, the convergence of ex vivo and in vivo data strongly suggests that cortical D2 dopamine receptors are a common target of both traditional and atypical antipsychotics for therapeutic action.
Finally, from a clinical point of view, our results are in keeping with the association of antipsychotic efficacy (attributed to an action on meso-cortico-limbic dopamine pathways) and lower extrapyramidal side-effects (attributed to an antidopaminergic activity in the dorsolateral striatum) with atypical antipsychotics than with traditional compounds. Searching for a high in vivo binding to the D2 receptors in the cortex co-occurring with a lower binding in the basal ganglia therefore could be suggested as an indicator of a favourable benefit/risk profile for a putative antipsychotic compound.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication February 13, 2001. Revision received June 29, 2001. Accepted for publication July 6, 2001.
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