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Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts.

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VTin patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VTand clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [11C]raclopride binding to the D2- and D3-dopamine receptor and [11C]WAY100635 binding to the serotonin 5-HT1Areceptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3and 5-HT1Areceptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70–0.75) on neocortical 5-HT1Areceptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature–nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

To test the hypothesis that in mesial temporal lobe epilepsy (MTLE) there is involvement outside of mesial structures and that this involvement affects serotonin systems, thus suggesting a mechanism for affective symptoms in this population.

The main objective of the study was to evaluate with autoradiographic technique whether or not [11C]vinpocetine, a compound widely used in the prevention and treatment of cerebrovascular diseases (Cavinton®, Gedeon Richter Ltd., Budapest), binds to specific sites in the human brain in post mortem human brain sections. Binding was assessed under four conditions: the incubation was performed using Tris-HCl buffer with or without the addition of salts (0.1% (weight/vol) ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2and 1 mM MgCl2), with or without the addition of excess (10 mM) unlabelled vinpocetine. Measurements on digitized autoradiograms indicated that [11C]vinpocetine labelled all grey matter areas in the human brain to a similar extent and no significantly heterogeneous binding could be demonstrated among cortical or subcortical regions. The addition of excess unlabelled vinpocetine lowered the binding slightly in all regions. Although these results indicate that [11C]vinpocetine does not bind to human brain transmitter receptors or transporters with a high affinity (Ki < 10 nM), it cannot be ruled out that the compound binds to receptors and/or transporters with lower affinity.

The main objective of the study was to evaluate with autoradiographic technique whether or not [11C]vin-pocetine, a compound widely used in the prevention and treatment of cerebrovascular diseases (Cavinton®, Gedeon Richter Ltd., Budapest), binds to specific sites in the human brain in post mortem human brain sections. Binding was assessed under four conditions: the incubation was performed using Tris-HCl buffer with or without the addition of salts (0.1% (weight/vol) ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2and 1 mM MgCl2), with or without the addition of excess (10 µM) unlabelled vinpocetine. Measurements on digitized autoradiograms indicated that [11C]vinpocetine labelled all grey matter areas in the human brain to a similar extent and no significantly heterogeneous binding could be demonstrated among cortical or subcortical regions. The addition of excess unlabelled vinpocetine lowered the binding slightly in all regions. Although these results indicate that [11C]vinpocetine does not bind to human brain transmitter receptors or transporters with a high affinity (Ki < 10 nM), it cannot be ruled out that the compound binds to receptors and/or transporters with lower affinity.

Extrastriatal D2dopamine receptors represent an important target of research into the pathophysiology and pharmacotherapy of psychiatric disorders. The high affinity radioligand 11CFLB 457 makes possible the measurement of low concentrations of D2receptors in extrastriatal regions using positron emission tomography (PET). The aim of this study was to assess the testretest variability and reliability of 11CFLB 457 binding using a reference tissue model. Eight healthy male subjects (aged 20-33 years) underwent two 11CFLB 457 PET examinations. Radioactivity in the cerebellum was used as the reference. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calculated using the reference tissue model. The BP was also calculated for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The testretest reproducibility for 11CFLB 457 binding was good, with a mean variability ranging from 4.5 for the thalamus to 15.5 for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using 11CFLB 457 for the quantitative evaluation of extrastriatal D2receptors and for protocols requiring repeated measurements in the same individual.

To investigate whether dopamine D2 and D3 receptor subtypes (D2/3Rs) outside the caudate-putamen are affected in PD.

SCH 39166 is the first selective D1 dopamine receptor antagonist developed for the treatment of schizophrenic patients. To examine potential antipsychotic effect, tolerability and safety, SCH 39166 was given orally to 17 acutely ill drug free schizophrenic patients (DSMIIIR) in an open 4-week study. Doses were escalated from 10 to 100 mg b.i.d. according to a fixed schedule over 17 days and remained at 100 mg b.i.d. for another 11 days. The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166. In the nine patients participating for more than 2 weeks, none had an apparent reduction of BPRS or CGI scores. Side effects were agitation, akathisia and emesis in single patients. After withdrawal of SCH 39166 of the patients improved when treated with classical neuroleptics or clozapine. The result of the study does not support the prediction that selective D1 dopamine receptor antagonism will produce antipsychotic effects in schizophrenia

SCH 39166 is the first selective D1-dopamine receptor antagonist developed for clinical trials in schizophrenia. SCH 39166 was evaluated as a radioligand for PET, labeled with11C, and as a D1-dopamine receptor antagonist after single oral doses in healthy men. After intravenous injection of [11C]SCH 39166 distribution of radioactivity in brain grossly reflected D1-dopamine receptor density. The putamen to cerebellum ratio at equilibrium was low (1.54±0.18 SD), which makes [11C]SCH 39166 less suitable as a radioligand for applied PET studies. Saturability of specific binding was demonstrated after IV injection of [11C]SCH 39166 with low specific radioactivity. Stereospecificity of binding was examined using the stereoisomer [11C]SCH 39165. D1-Receptor occupancy was demonstrated with [11C]SCH 39166 2 h after administration of single oral doses of unlabeled SCH 39166 to each of three healthy subjects (25, 100 and 400 mg). There was a substantial reduction of specific [11C]SCH 39166 uptake in the putamen after all doses. Single oral doses of 100 mg induced approximately 70% D1-dopamine receptor occupancy in the basal ganglia, which should be sufficient to investigate the antipsychotic potential of D1-dopamine receptor antagonism in clinical studies.

NNC 756 is a new benzazepine with high affinity and selectivity for D1-dopamine receptors. In a double-blind, placebo controlled, cross-over study, positron emission tomography and the radioligand [11C]SCH 23390 were used to determine central D1-do-pamine receptor occupancy after a single oral dose of 80 mg NNC 756 in three healthy men. NNC 756 induced 75, 66 and 47% occupancy of D1-dopamine receptors in the putamen of at 1.5 h after drug administration and 46, 36 and 24% after 7.5 h. There was a hyperbolic relationship between the occupancy values and the serum concentrations. The Ki value for the hyperbola was 6.4 ng/ml (±SD 1.4). The occupancy at 1.5 h is on the same level as that shown to induce effects in animal models for prediction of antipsychotic effect. Restlessness (akathisia) appeared in two subjects and nausea in one subject at time of peak drug concentration in serum. The oral dose level of 80 mg should be appropriate to investigate the potential antipsychotic effect of NNC 756.

Twelve healthy male volunteers took part in a double-blind randomised cross-over study composed of three treatment sessions: remoxipride 100 mg; remoxipride 100 mg plus biperiden 4 mg; and biperiden 4 mg. Plasma and urine concentrations of remoxipride and biperiden, plasma prolactin levels, salivary flow and adverse events were recorded to assess pharmacodynamic interactions. Remoxipride and biperiden had no effect on each other's plasma concentrations. Biperiden did not affect the urinary recovery or renal clearance of remoxipride. Prolactin levels were unaffected by biperiden but increased following remoxipride administration. Differences in prolactin Cmax and tmax following remoxipride versus concomitant (remoxipride + biperiden) treatment were not statistically significant. However, a slight but statistically significant (P=0.04) increase in prolactin AUC was observed after concomitant treatment. No significant differences could be observed between the recorded salivary flow in all the treatment sessions. Single doses of remoxipride and biperiden showed no pharmacokinetic or pharmacodynamic interaction.

Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.

NCQ 298 ((S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylamide) has an iodine substituent. We have labelled NCQ 298 with123I and125I, and used the radioligands as tracers in receptor studies in vitro, in vivo in autoradiography and in SPECT studies on Cynomolgus monkeys.

Tracer doses of 11C-SCH 23390 and 11C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with 11C-SCH 23390, but not 11C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of 11C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis(Z)-flupentixol decanoate. 11C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis(Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis(Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.

Two substituted benzamides, FLB 524 and raclopride, were labeled with 11C and examined for their possible use as ligands for positron emission tomography (PET)-scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. [11C]Raclopride showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of [11C]raclopride in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. This and previous in vitro data indicate that [11C]raclopride binds selectively to striatal D-2 dopamine receptors. In healthy human subjects, [11C]raclopride binding in the caudate nucleus/putamen was 4- to 5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, [11C]raclopride appears to be advantageous with regard to (i) specificity of binding to D-2 receptors, (ii) the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and (iii) rapid association and reversibility of specific binding. [11C]Raclopride should be a valuable tool for characterizing D-2 receptors in the brains of patients with neuropsychiatric disorders.

Positron emission tomography (PET) and the selective radioligand 11Craclopride were used to measure D2receptor occupancy in several studies in schizophrenic patients and healthy subjects. Clinical effects of the treatment were recorded, and drug plasma concentrations measured. The hypothesized curvilinear relationship between receptor occupancy and drug plasma concentrations was supported experimentally. We suggest that there may be a distinct threshold for antipsychotic effect at about 70 D2receptor occupancy, and another threshold for extrapyramidal side effects above 80 D2receptor occupancy. Receptor occupancy was high even at low plasma drug concentrations. Our data indicate a need to establish dose-response curves for the conventional neuroleptics. Such a dose-response relationship might be expected for a much lower dose interval than those previously examined.

Using a new,125I-labeled, selective high affinity dopamine transporter ligand,N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)nortropane (PE2I), the distribution of the dopamine transporter was characterized in the normal postmortem human brain using whole hemisphere autoradiography. PE2I was radioiodinated to high specific radioactivity (2200 Ci/mmol, 81 GBq/μmol). PE2I binds to the dopamine transporter with high potency and, in contrast to β-CIT, it has very low affinities for the serotonin and noradrenaline transporters. The autoradiograms showed very intense binding in basal ganglia (putamen, nucleus caudatus, nucleus accumbens) and lower binding in substantia nigra. Very low or no binding was found in other brain structures, including the neocortex or cerebellum. The labeling of human dopamine transporters with [125I]PE2I was inhibited by the dopamine transporter inhibitors GBR 12909 and β-CIT, but not by citalopram (serotonin transporter inhibitor) or maprotiline (noradrenaline transporter inhibitor). Possibly due to the relatively high lipophilicity of the compound (theoretical logp=4.68), it accumulated slightly in white matter. Thus,in vitroautoradiography using [125I]PE2I provided detailed qualitative and quantitative evidence that the dopamine transporter is almost exclusively localized in the basal ganglia of the human brain. Moreover, the autoradiograms indicate that [11C]PE2I and [123I]PE2I should be suitable for thein vivovisualization of the human dopamine transporter with PET or SPECT, respectively.

Abstract: The use of benzhydryl substituted piperazine derivatives and 3-substituted cocaine analogues as radioligands are compared for in vivo visualization of dopamine transporter by PET.

Summary Affinities and regional densities of the D1- and D2-dopamine receptor subtypes were studied in the human post-mortem brain in vitro using the two selective radioligands3H-SCH23390 and3H-raclopride.3H-Raclopride binding was confined to the caudate nucleus, the putamen and the substantia nigra, while3H-SCH23390 bound to cortical regions as well. The binding of3H-SCH 23390 was reduced by a low concentration of ketanserin, indicating binding to 5-HT2 receptors in addition to the D1dopamine receptors. The endogenous neurotransmitter dopamine interacted potently both with the D1-dopamine receptor and the D2-dopamine receptor, displaying two affinity states for each subtype. The distribution of the dopamine receptor subtypes obtained in the present in vitro investigation is in agreement with data obtained with11C-SCH 23390 and11C-raclopride in positron emission tomographic studies in human volunteers.

Anatomic localization in functional (such as PET) imaging often requires a structural (such as CT or NMRI) study of the brain in the same plane. Some neuropsychiatric conditions make it difficult for a patient to hold his/her head immobile even when a rigid head holder is used. We studied the effect of tilt of the anatomic reference image, in this instance CT, relative to the functional image, here PET, on the quantification of receptor ligand concentration in anatomically defined regions of the brain.

Repeated positron emission tomography (PET) measurements of D2receptor occupancy, plasma concentrations of zuclopenthixol and reaction time were performed in three healthy subjects after injection of 12.5 mg zuclopenthixol acetate (ZPTA) in an open study design. Five control subjects were examined for reaction time only. D2receptor occupancy was 51, 71 and 75 after 7 h and 75, 83 and 87 after 31 h in the three subjects. The subjects reported sedation, but reaction time was not prolonged. After the low dose of 12.5 mg ZPTA, D2receptor occupancy exceeded the 70 assumed to be required to induce antipsychotic effect. Extrapolation of data to a clinical dose interval indicates that 50–150 mg ZPTA should induce very high D2receptor occupancy lasting several days after injection. Such high doses may be required to induce sedation and to avoid frequent intramuscular injections in acutely psychotic patients. However, the simultaneously induced very high D2receptor occupancy calls for careful assessment of acute extrapyramidal symptoms.

The effect of the selective serotonin-2 antagonist ritanserin was investigated in an open study of patients with schizophrenia. The patients were in an acute psychotic state considered to require neuroleptic medication. No neuroleptic drug was allowed during the study or during the last month preceeding the study. Oxazepam or nitrazepam were allowed for sedation or sleep inducement. Safety, tolerability, potential antipsychotic effect, and drug effects on monoamine metabolites in serum and CSF and prolactin in serum were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography. Ten male patients (mean age 32.4) fulfilling DSM-III-R criteria for schizophrenia were included in the study. Nine of these patients completed 4 weeks' treatment with ritanserin 10 mg b.i.d. The clinical effect was evaluated by means of CPRS and SANS and significant improvement was seen after 4 weeks' treatment both in positive and negative symptoms. Ritanserin was well tolerated and no extrapyramidal symptoms or akathisia were seen. Concentrations of monoamine metabolites and prolactin did not change during treatment. Ritanserin did not occupy D2-dopamine receptors. Thus, no indications of any D2-dopamine-antagonistic activity were obtained. All patients had expected ritanserin levels in plasma during the whole study. This first study of a selective serotonin-2 antagonist in the treatment of acute schizophrenic patients demonstrated significant clinical effects. However, the open design of the study does not allow us to conclude with any certainty that the patients' improvement was due to a specific blockade of serotonin-2 receptors or unspecific factors, although a direct D2-dopamine blockade could be ruled out.

Using positron emission tomography and the selective ligands 11C-SCH23390 and 11C-raclopride, central D1- and D2-dopamine receptor occupancy was determined in schizophrenic patients treated with clinical doses of classical and atypical neuroleptics. Treatment with ten chemically distinct classical neuroleptics resulted in a 65–89% occupancy of D2-dopamine receptors. This finding represents strong support for the hypothesis that the mechanism of action of antipsychotic drugs is indeed related to a substantial degree of D2-dopamine receptor occupancy. In two patients treated with teh atypical neuroleptic clozapine, 300 mg b.i.d. and 150 mg b.i.d., the D2-dopamine receptor occupancy was 65 and 40%, respectively. D1-dopamine receptor occupancy was determined in six antipsychotic drugtreated patients. No D1-dopamine receptor occupancy was found in patients treated with sulpiride and perphenazine, compounds known to be selective D2-dopamine receptor antagonists. The highest D1-dopamine receptor occupancy, 42%, was found in the patient treated with clozapine 150 mg b.i.d. The effects of the atypical neuroleptic clozapine may be related to a combined effect on both D1- and D2-dopamine receptors.

Remoxipride, a new potential antipsychotic drug, was administered over 4 days at two dose levels, 70 and 140 mg t.i.d., to eight healthy male volunteers. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. Remoxipride exhibited essentially linear pharmacokinetics. Only minor deviations in biochemical and physiological safety parameters were found. The drug was well tolerated by all subjects at the 70 mg dose level. At 140 mg akathisia appeared in seven subjects. The drug induced a rapid and transient increase in plasma prolactin concentrations at both dose levels after single doses. During steady state, a significant reduction in the prolactin response was observed as compared to after the first dose.

The selective D2-dopamine receptor antagonist raclopride and its pharmacologically inactive (R)-enantiomer FLB472 were labelled with 11C and used in a study with positron emission tomography to examine the stereoselectivity of 11C-raclopride binding to central D2-dopamine receptors in three healthy men. After the injection of 11C-raclopride, there was a high accumulation of radioactivity in the dopamine-rich basal ganglia, whereas after the injection of 11C-FLB472 there was no such accumulation of radioactivity. Thus, the binding of 11C-raclopride is stereoselective. Distribution ratios [radioactivity in a brain region/“free” (not protein-bound) radioactivity in plasma] were calculated for the two enantiomers to study regional differences in the accumulation of radioactivity. The distribution ratios in white matter were similar for the two enantiomers. In the putamen, a three to four-fold higher distribution ratio was found for 11C-raclopride than for 11C-FLB472, reflecting the presence of specific binding of 11C-raclopride binding to D2-dopamine receptors in the basal ganglia. In the temporal and frontal cortices the distribution ratios were, however, only a few per cent higher for 11C-raclopride than for 11C-FLB472, indicating that if D2-dopamine receptors are present in the human neocortex, then their density is indeed very low.

Raclopride, a highly selective D2-dopamine receptor antagonist, was administered in doses up to 4 mg b.i.d. to ten schizophrenic patients in an open label non-comparative study lasting 4 weeks. Safety, tolerability, potential antipsychotic effect, prolactin response and drug effect on plasma homovanillic acid were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography (PET). No major deviations were found in biochemical and physiological safety parameters. Raclopride was well tolerated. The mean BPRS score was reduced by 55% at endpoint. In the global evaluation seven patients were “very much” or “much” improved. Extrapyramidal side effects were recorded in four patients and disappeared after dose reduction or single doses of biperiden. An increase in plasma prolactin of short duration was observed in both sexes. A significant decrease of plasma HVA was obtained after 4 weeks of treatment. In two of the patients the central D2-dopamine receptors occupancy was measured using PET. The receptor occupancy was 68 and 72% which is the same as that found in patients treated with conventional neuroleptics.

[11C]Raclopride binding to central D2-dopamine receptors in humans has previously been examined by positron emission tomography (PET). Based on the rapid occurrence of binding equilibrium, a saturation analysis has been developed for the determination of receptor density (Bmax) and affinity (Kd). For analysis of PET measurements obtained with other ligands, a kinetic three-compartment model has been used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equilibrium analysis to data obtained from four PET experiments in each of three healthy subjects. First regional CBV was determined. In the second and third experiment, [11C]-raclopride with high and low specific activity was used. In a fourth experiment, the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concentration of free radioligand and nonspecific binding in brain. Radio-activity in arterial blood was measured using an automated blood sampling system. Bmaxand Kdvalues for [11C]raclopride binding could be determined also with the kinetic analysis. As expected theoretically, those values were similar to those obtained with the equilibrium analysis. In addition, the kinetic analysis allowed separate determination of the association and dissociation rate constants, konand koff, respectively. Examination of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.