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Rationale: Unlike other antipsychotics, our previous positron emission tomography (PET) study demonstrated that a single dose of blonanserin occupied dopamine D 3 as well as dopamine D 2 receptors in healthy subjects. However, there has been no study concerning the continued use of blonanserin., Objectives: We examined D 2 and D 3 receptor occupancies in patients with schizophrenia who had been treated with blonanserin., Methods: Thirteen patients with schizophrenia participated. PET examinations were performed on patients treated with clinical dosage of blonanserin or olanzapine alone. A crossover design was used in which seven patients switched drugs after the first scan, and PET examinations were conducted again. D 2 and D 3 receptor occupancies were evaluated by [ 11 C]-(+)-PHNO. We used nondisplaceable binding potential (BP ND ) of 6 healthy subjects which we previously reported as baseline. To consider the effect of upregulation of D 3 receptor by continued use of antipsychotics, D 3 receptor occupancy by blonanserin in seven subjects who completed 2 PET scans were re-analyzed by using BP ND of olanzapine condition as baseline., Results: Average occupancy by olanzapine (10.8 ± 6.0 mg/day) was as follows: caudate 32.8 ± 18.3%, putamen 26.3 ± 18.2%, globus pallidus - 33.7 ± 34.9%, substantia nigra - 112.8 ± 90.7%. Average occupancy by blonanserin (12.8 ± 5.6 mg/day) was as follows: caudate 61.0 ± 8.3%, putamen 55.5 ± 9.5%, globus pallidus 48.9 ± 12.4%, substantia nigra 34.0 ± 20.6%. EC 50 was 0.30 ng/mL for D 2 receptor for caudate and putamen (df = 19, p < 0.0001) and 0.70 ng/mL for D 3 receptor for globus pallidus and substantia nigra (df = 19, p < 0.0001). EC 50 for D 3 receptor of blonanserin changed to 0.22 ng/mL (df = 13, p = 0.0041) when we used BP ND of olanzapine condition as baseline., Conclusions: Our study confirmed that blonanserin occupied both D 2 and D 3 receptors in patients with schizophrenia.

Background: Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application., Methods: This open-label, phase II study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale score <120 at screening) treated with blonanserin 8-mg or 16-mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [11C]raclopride positron emission tomography scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in Positive and Negative Syndrome Scale and Clinical Global Impressions-Severity of Illness-Severity scores, patient attitudes towards adherence, and patch adhesiveness., Results: Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns., Conclusions: Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia., Trial Registry: JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914)., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Background: Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8-24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects., Methods: Six healthy males (mean 35.7±7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12 mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [11C]-(+)-PHNO., Results: Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%-81.5%; mean±SD, 74.3±5.6%), putamen (range 60.4%-84.3%; mean±SD, 73.3%±8.2%), ventral striatum (range 40.1%-88.2%; mean±SD, 60.8%±17.1%), globus pallidus (range 65.8%-87.6%; mean±SD, 75.7%±8.6%), and substantia nigra (range 56.0%-88.7%; mean±SD, 72.4%±11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D2-rich (caudate and putamen) and D3-rich (globus pallidus and substantia nigra) regions showed that EC50 for D2-rich region was 0.39 ng/mL (r=0.43) and EC50 for D3-rich region was 0.40 ng/mL (r=0.79)., Conclusions: A single dose of 12 mg blonanserin occupied D3 receptor to the same degree as D2 receptor in vivo. Our results were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D3 receptor antagonism.

Methods: Seven healthy volunteers underwent PET scans with [18F]altanserin and [11C]FLB 457 for 5-HT2A and D2 receptors, respectively. As a measure of receptor density, a binding potential (BP) was calculated from PET data for 76 cerebral cortical regions. A correlation matrix was calculated between the binding potentials of [18F]altanserin and [11C]FLB 457 for those regions. The regional relationships were investigated using a bicluster analysis of the correlation matrix with an iterative signature algorithm., Results: We identified two clusters of regions. The first cluster identified a distinct profile of correlation coefficients between 5-HT2A and D2 receptors, with the former in regions related to sensorimotor integration (supplementary motor area, superior parietal gyrus, and paracentral lobule) and the latter in most cortical regions. The second cluster identified another distinct profile of correlation coefficients between 5-HT2A receptors in the bilateral hippocampi and D2 receptors in most cortical regions., Conclusions: The observation of two distinct clusters in the correlation matrix suggests regional interactions between 5-HT2A and D2 receptors in sensorimotor integration and hippocampal function. A bicluster analysis of the correlation matrix of these neuroreceptors may be beneficial in understanding molecular networks in the human brain.

Background: Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo., Methods: Eleven patients with schizophrenia, including 10 antipsychotic-naive and 1 antipsychotic-free individuals, and 17 healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale, and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total dopamine D2 receptor and D2High, respectively, in the striatum by measuring their binding potentials. Binding potential values of [11C]raclopride and [11C]MNPA and the binding potential ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the 2 diagnostic groups using multivariate analysis of covariance controlling for age, gender, and smoking. Correlations between binding potential and Positive and Negative Syndrome Scale scores were also examined., Results: Multivariate analysis of covariance demonstrated a significant effect of diagnosis (schizophrenia and control) on the binding potential ratio (P=.018), although the effects of diagnosis on binding potential values obtained with either [11C]raclopride or [11C]MNPA were nonsignificant. Posthoc test showed that the binding potential ratio was significantly higher in the putamen of patients (P=.017). The Positive and Negative Syndrome Scale "depressed" factor in patients was positively correlated with binding potential values of both ligands in the caudate., Conclusions: The present study indicates the possibilities of: (1) a higher proportion of D2High in the putamen despite unaltered amounts of total dopamine D2 receptors; and (2) associations between depressive symptoms and amounts of caudate dopamine D2 receptors in patients with schizophrenia., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Blonanserin is a novel antipsychotic with high affinities for dopamine D(2) and 5-HT(2A) receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D(2) receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [(11)C]raclopride for the striatum and 1 with [(11)C]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D(2) receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D(2) receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D(2) receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D(2) receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

Misestimating risk could lead to disadvantaged choices such as initiation of drug use (or gambling) and transition to regular drug use (or gambling). Although the normative theory in decision-making under risks assumes that people typically take the probability-weighted expectation over possible utilities, experimental studies of choices among risks suggest that outcome probabilities are transformed nonlinearly into subjective decision weights by a nonlinear weighting function that overweights low probabilities and underweights high probabilities. Recent studies have revealed the neurocognitive mechanism of decision-making under risk. However, the role of modulatory neurotransmission in this process remains unclear. Using positron emission tomography, we directly investigated whether dopamine D₁ and D₂ receptors in the brain are associated with transformation of probabilities into decision weights in healthy volunteers. The binding of striatal D₁ receptors is negatively correlated with the degree of nonlinearity of weighting function. Individuals with lower striatal D₁ receptor density showed more pronounced overestimation of low probabilities and underestimation of high probabilities. This finding should contribute to a better understanding of the molecular mechanism of risky choice, and extreme or impaired decision-making observed in drug and gambling addiction.

Objective: Hyperprolactinemia is a common side effect of antipsychotic drugs used in the treatment of schizophrenia. However, the magnitude of hyperprolactinemia differs among antipsychotics, and there is no reliable mechanism-related marker for the risk of hyperprolactinemia that would allow us to characterize antipsychotics., Method: In this study, 11 healthy male subjects taking different doses of sulpiride and 24 male patients with DSM-IV-diagnosed schizophrenia taking different antipsychotic drugs (risperidone, olanzapine, haloperidol, and sulpiride) participated. Positron emission tomography scanning using [¹¹C]FLB 457 was performed on all subjects. The dopamine D₂receptor occupancy of antipsychotics in the pituitary and temporal cortex was calculated. Correlations between plasma concentration of prolactin and dopamine D₂receptor occupancies were evaluated. The ratio of drug concentration of cerebral receptor site to that of pituitary receptor site (brain/plasma concentration ratio; B/P ratio) was calculated from the receptor occupancies in the 2 regions. Data were collected between November 2001 and September 2007., Results: Significant positive correlation was observed between the plasma concentration of prolactin and dopamine D₂receptor occupancy in the pituitary by all 4 antipsychotics (P = .001). Dopamine D₂receptor occupancies of sulpiride were markedly different between the pituitary and temporal cortex, and the B/P ratio for sulpiride (0.34) was significantly lower than for olanzapine (P = .007) and risperidone (P = .015). Olanzapine had a relatively high B/P ratio (2.70), followed by haloperidol (2.40) and risperidone (1.61)., Conclusions: Dopamine D₂receptor occupancy in the pituitary is a good indicator of hyperprolactinemia. B/P ratio, indicating the penetrating capability across the blood-brain barrier, seems to be a good characteristic biomarker of each antipsychotic drug for the risk of hyperprolactinemia at therapeutic dose., (© Copyright 2010 Physicians Postgraduate Press, Inc.)

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D(2) receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D(2) receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [(11)C]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5-20 mg/day of olanzapine participated. Dopamine D(2) receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED(50) value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED(50) values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.

Objective: Electroconvulsive therapy (ECT) has been confirmed as one of the most effective treatments in drug-resistant major depression. However, the mechanism of ECT is still poorly understood. Although several lines of studies have focused on its effect on dopamine neurotransmission, the effects of ECT on dopamine D(2) receptors in a living human brain have not been investigated. Using positron emission tomography (PET) scans with the radioligand [(11)C]FLB 457, we aimed to evaluate the effect of ECT on extrastriatal D(2) receptor binding in medicated patients with major depressive disorder (MDD)., Method: Seven patients with a DSM-IV diagnosis of MDD underwent PET scans before and after a series of 6-7 treatments with bilateral ECT. Eleven healthy controls were scanned for comparison. All participants were scanned at the National Institute of Radiological Sciences, Chiba, Japan, between November 2000 and September 2005. The parametric images of [(11)C]FLB 457 binding were generated on the basis of a simplified reference tissue model. Voxel-based methods were used to assess the effect of ECT on D(2) receptor binding., Results: There were no significant differences in D(2) receptor binding between patients with MDD and controls. All 7 patients showed clinical improvements in response to ECT treatment (P < .001). Significant changes in D(2) receptor binding, a mean of 25.2% reduction, were found in the right rostral anterior cingulate (AC) following ECT (P < .001)., Conclusions: Electroconvulsive therapy decreased D(2) receptor binding in the rostral AC in MDD patients responding to ECT. Our finding suggests that one of the biologic mechanisms of ECT could be related to dopaminergic alteration in the rostral AC., (2010 Physicians Postgraduate Press, Inc.)

Rationale: Perospirone is a novel second-generation antipsychotic drug with high affinity to dopamine D(2) receptor and short half-life of plasma concentration. There has been no investigation of dopamine D(2) receptor occupancy in patients with schizophrenia and the time course of occupancy by antipsychotics with perospirone-like properties., Objective: We investigated dopamine D(2) receptor occupancy by perospirone in patients with schizophrenia and the time course of occupancy in healthy subjects., Materials and Methods: Six patients with schizophrenia taking 16-48 mg/day of perospirone participated. Positron emission tomography (PET) scans using [(11)C]FLB457 were performed on each subject, and dopamine D(2) receptor occupancies were calculated. Moreover, baseline and three serial PET using [(11)C]raclopride were performed at 1.5, 8, and 25.5 h after administration of a single dose of 16 mg of perospirone on four healthy male subjects, and occupancy was calculated for each scan., Results: Dopamine D(2) receptor occupancy in the temporal cortex of patients ranged from 39.6% to 83.8%. Especially, occupancy in two patients who took 16 mg of perospirone 2.5 h before PET was over 70%. Mean occupancy in the striatum of healthy subjects was 74.8% at 1.5 h, 60.1% at 8 h, and 31.9% at 25.5 h after administration., Conclusion: Sixteen milligrams of perospirone caused over 70% dopamine D(2) receptor occupancy near its peak level, and then occupancy dropped to about half after 22 h. The time courses of receptor occupancy and plasma concentration were quite different. This single dosage may be sufficient for the treatment of schizophrenia and might be useful as a new dosing schedule choice.

Dopamine D(1) receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D(1) receptors induces an inverted U-shaped response, such that too little or too much D(1) receptor stimulation impairs prefrontal functions. Less is known of the role of D(2) receptors in cognition, but previous studies showed that D(2) receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions. We measured both D(1) and D(2) receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D(1) and D(2) receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D(1) receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D(2) binding has no relation with any neuropsychological measures. Hippocampal D(2) receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D(1) receptor binding had no association with any memory and prefrontal functions. Hippocampal D(2) receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC-PFC pathway. Our findings suggest that orchestration of prefrontal D(1) receptors and hippocampal D(2) receptors might be necessary for human executive function including working memory.

Rationale: Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects., Objectives: In this study, we measured striatal and extrastriatal dopamine D2 receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose., Materials and Methods: Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [11C]raclopride and one with [11C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D2 receptor occupancy was calculated., Results: The dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride and the temporal cortex measured with [11C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED50 values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D2 receptor occupancy between the striatum and the temporal cortex., Conclusions: The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D2 receptor occupancy between 70-80% and that the magnitude of dopamine D2 receptor occupancy is similar between the striatum and temporal cortex.

Cerebral cortical regions are thought to be important for cognitive functions such as memory and executive function. Although the functional associations between dopamine D2 receptors and motor and cognitive functions have been extensively examined in the striatum using positron emission tomography (PET), the role of dopamine D2 receptors in extrastriatal regions has been unexplored. We aimed to investigate the relationship between dopamine D2 receptors in extrastriatal regions and the performance of a broad spectrum of cognitive functions including memory, language, attention, and executive function in healthy subjects. Extrastriatal dopamine D2 receptors were measured in 25 male subjects using PET with [(11)C]FLB457. After the PET scans, a battery of neuropsychological tests was administered to all subjects. We found that the binding potential (BP) of [(11)C]FLB457 in the hippocampus was positively correlated with memory function. Furthermore, BP of [(11)C]FLB457 in the hippocampus, but not in the prefrontal cortex, was associated with frontal lobe functions such as executive function and verbal fluency. Our findings suggest that dopamine D2 receptors in the hippocampus might affect the local hippocampal function, but also brain functions outside the hippocampus such as the prefrontal cortex.

The aim was to test the dopamine hypothesis of schizophrenia in a further analysis of D(2)-like dopamine binding using the radioligand [(11)C]raclopride and high resolution 3-dimensional (3D) PET. Eighteen drug-naive patients with schizophrenia and seventeen control subjects were examined. The D(2) binding potential (BP) in the putamen, the caudate and the thalamus was calculated using the simplified reference tissue model. The volume of regions of interest was controlled for by MRI. Symptoms were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). No significant group differences were found for D(2) BP in the putamen or in the caudate and there was no significant hemispheric difference for any region. In the right thalamus the D(2) BP was significantly lower in patients as compared to control subjects, whereas a numerical difference did not reach statistical significance for the left thalamus. There was no significant correlation between D(2) BP and total PANSS score in any region. There was a highly significant age effect in the caudate and in the putamen, but not in the thalamus. In this relatively large PET study of exclusively drug-naive schizophrenic patients, a lower D(2) BP in the right thalamus was found in the patient group. This finding is in agreement with two previous studies in Sweden and in Japan using the high-affinity radioligand [(11)C]FLB 457 and provide further support for a role of dopamine in the thalamus related to the pathophysiology of schizophrenia.

Conventional antipsychotics tend to elicit extrapyramidal symptoms at clinical doses, but dose optimization could reduce the risk of such side-effects. In-vivo receptor-binding studies have suggested that 70-80% of dopamine D2 receptor occupancy provides the desired antipsychotic effects without extrapyramidal symptoms. In terms of dose optimization based on the occupancy, there has not been enough supporting data regarding the clinical doses of the respective antipsychotics. In this study, we measured dopamine D2 receptor occupancy of two conventional benzamide antipsychotics, sulpiride and sultopride, using positron emission tomography, to investigate the rationale of their clinical dose. Although they are prescribed at similar doses (300-1200 mg), the doses required to obtain similar receptor occupancy (70-80%) were quite different: 1010-1730 mg for sulpiride but 20-35 mg for sultopride. In terms of dose, sultopride has about 50 times greater potency than sulpiride based on dopamine D2 receptor occupancy. Evidence for the optimal doses of conventional antipsychotics based on dopamine D2 receptor occupancy would be helpful for rational antipsychotic therapy.

We investigated feasibility of positron emission tomography (PET) with [11C]SA4503 for evaluating the sigma1 receptor occupancy rate by neuroleptics. Haloperidol, which is well known to bind dopamine D2-like receptor (D2R) as well as to be a representative non-selective antagonist for sigma1 receptor (sigma1R), was selected as a model drug. Three healthy male subjects underwent 60-min [11C]raclopride-PET and 90-min [11C]SA4503-PET scans successively at a 120-min interval twice in a day for baseline measurement and on another day for haloperidol-loading measurement 16 hours after peroral administration of 3 mg of haloperidol. Binding potential (BP) of [11C]raclopride and [11C]SA4503 was quantitatively evaluated and the sigma1R and D2R occupancy rates were determined. D2R occupancy rates by haloperidol were 64% and 62% in the caudate and putamen, respectively, 16 h after the administration, while sigma1R occupancy rates were approximately 80% in all seven regions investigated including the caudate, putamen and cerebellum 18 h after the administration, suggesting that the sigma1R receptor occupancy rate by haloperidol was slightly larger than the D2R receptor occupancy rate. We concluded that [11C]SA4503-PET can be used for evaluating the sigma1R occupancy rates by neuroleptics or other drugs.

Receptor binding has been examined region by region in both in vitro and in vivo studies, but less attention has been paid to the connectivity of regional receptor binding despite the fact that neurophysiological studies have indicated an extensive inter-regional connectivity. In this study, we investigated the connectivity of regional dopamine D2 receptor binding in positron emission tomography data from 10 drug-naive patients with schizophrenia and 19 healthy controls. We applied a structural equation method to regional receptor binding. The results indicated that the network models of the patients and normal subjects were significantly different. As to the individual path coefficients, (a) connectivity between cortical regions was different between groups; (b) connectivity from the prefrontal cortex, parietal cortex, and thalamus to the anterior cingulate differed from that in controls; and (c) connectivity from the prefrontal cortex to the anterior cingulate and thalamus via the hippocampus was observed in normal subjects but not in patients. These results suggest that a systems-level change reflected in the connectivity of D2 receptor binding is present in schizophrenia.

Objective: Several structural and functional brain imaging studies have pointed to a disturbance of thalamic subnuclei in patients with schizophrenia. The dopamine hypothesis of schizophrenia has, however, not been thoroughly examined in terms of this complex structure, which has connections with most brain regions of central interest in schizophrenia research. The aim of the present study was to examine dopamine D(2) receptor binding in subregions of the thalamus in patients with schizophrenia., Method: The authors used positron emission tomography and the radioligand [(11)C]FLB457 to examine dopamine D(2) receptor binding in thalamic subregions of 10 drug-naive patients with schizophrenia. Binding potential was calculated by the reference tissue method and used as an index for dopamine D(2) receptor binding. Comparisons were made with 19 healthy subjects. Subregions of interest were defined on individual magnetic resonance images using a percentage-based operational approach. Clinical symptoms were rated by using the Brief Psychiatric Rating Scale (BPRS)., Results: The [(11)C]FLB457 binding potential was lower in the central medial and posterior subregions of the thalamus in patients with schizophrenia. At a functional level, there was a significant negative correlation between binding potential and BPRS positive symptom scores., Conclusions: The subregions with low D(2) receptor binding comprise primarily the dorsomedial nucleus and pulvinar, two important components in circuitries previously suggested in the pathophysiology of schizophrenia. Aberrant dopaminergic neurotransmission in thalamic subregions might be a mechanism underlying positive symptoms in schizophrenia.

Although the kinetic profile of antipsychotics at dopamine D2 receptor sites has been suggested to be important for antipsychotic action and dosing schedule, the kinetic profiles of the respective antipsychotic drugs in the brain have not yet been clearly defined. We aimed to estimate the time-course of dopamine D2 receptor occupancy from plasma pharmacokinetics and the apparent in-vivo affinity parameter (ED50; concentration required to induce 50% occupancy). Dopamine D2 receptor occupancies and plasma concentrations of risperidone were measured in five patients with schizophrenia using positron emission tomography with [11C]FLB 457. Measured dopamine D2 occupancies were compared with those estimated from plasma kinetics and in-vivo ED50. The time-course of dopamine D2 receptor occupancy was simulated with altered plasma kinetics or apparent in-vivo affinity parameters of the drug. Mean half-life of dopamine D2 receptor occupancy of risperidone was 80.2 h while that of the plasma concentration was 17.8 h. Dopamine D2 receptor occupancy estimated from plasma pharmacokinetics and in-vivo ED50 was within 1 S.D. of the mean measured occupancy. When the ED50 value was changed to one-tenth and 10-fold, the simulated half-life of receptor occupancy changed to 117.6 h and 27.3 h respectively. Using plasma pharmacokinetics and in-vivo ED50, the time-course of receptor occupancy could be calculated. Simulation of drug kinetics at receptors would provide useful information for the evaluation of antipsychotics.

Background: The clinical efficacy of dopamine D2 receptor antagonism on the psychotic symptoms of schizophrenia has been widely demonstrated. However, most in vivo imaging studies have not been able to detect significant changes in striatal D2 receptors in schizophrenia. On the other hand, a number of studies have reported abnormalities in the cerebral cortex of schizophrenia. The aim of this study was to examine the extrastriatal D2 receptors of patients with schizophrenia., Methods: Eleven drug-naive male patients with schizophrenia were examined with positron emission tomography using carbon 11-labeled FLB 457. Symptoms were assessed using the Brief Psychiatric Rating Scale. Eighteen healthy controls were used for comparison. Region-of-interest analysis was performed using the reference tissue method, and binding potential (BP) was used for the index of dopamine D2 receptor binding., Results: The BP value was significantly lower, by about 12.5%, in the anterior cingulate cortex in drug-naive patients with schizophrenia than in healthy controls. A significant negative correlation was observed between BP in the anterior cingulate cortex and the positive symptom score on Brief Psychiatric Rating Scale., Conclusions: The lower BP values indicate fewer D2 receptors in the anterior cingulate cortex in patients with schizophrenia. Alterations in D2 receptor function in the extrastriatal region may underlie the positive symptoms of schizophrenia.

Although the aging effect of dopamine D2 receptor in the striatum is well-documented, the effect of age on the extrastriatal dopamine D2 receptor has not been fully examined. Since the density of extrastriatal dopamine D2 receptor is very low, suitable ligands are limited. In this study, we used [11C]FLB 457 to quantify the extrastriatal dopamine D2 receptor in the living human brain. Twenty-seven healthy male subjects aged from 21 to 82 years participated in the positron emission tomography study. Extrastriatal [11C]FLB 457 binding was quantified with a reference tissue model using cerebellum as a reference region. Binding potentials corresponding to Bmax/Kd were used to evaluate age-related change. We found age-related decreases of D2 receptor binding in all measured extrastriatal regions. The decrease of D2 receptor binding was 13.8% per decade in frontal cortex, 12.0% in temporal cortex, 13.4% in parietal cortex, 12.4% in occipital cortex, 12.2% in hippocampus, and 4.8% in thalamus. These findings suggest that the amounts of D2 receptor declines in all brain regions as part of the normal aging process.

Human personality has been considered to have a neurochemical background. We examined the relation between extrastriatal dopamine D2 receptor binding in living human brain and the personality trait of novelty seeking that has been proposed to be related to dopaminergic function in the brain. We measured extrastriatal dopamine D2 receptors of 24 healthy young male subjects using [(11)C]FLB 457 positron emission tomography. The personality trait of each subject was assessed by the Temperament and Character Inventory (TCI). Correlation of dopamine D2 receptor binding with novelty seeking was calculated using region-of-interest analysis and statistical parametric mapping based on the binding potential images generated using a reference tissue model. A significant negative correlation was observed between binding potential values and the novelty seeking scores on TCI in the right insular cortex. No significant correlation was observed in any other region. Our result indicates that there is a significant association between dopamine D2 receptor binding and the human novelty seeking trait in the right insular cortex., (Copyright 2001 Academic Press.)

Personality is a behavioral pattern, which differs among individuals. Kretschmer (Kretschmer, E., Physique and Character: an Investigation of the Nature of Constitution and the Theory of Temperament, New York, 1921) categorized personality variants according to the concept of fundamental body types. Recently, several lines of evidence suggest that the central dopamine system may underlie the regulation of weight and the personality trait. In this study, we examined the dopamine D2 receptor (D2R) binding using positron emission tomography with [11C]FLB 457 [(s)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-bromo-2,3-dimethyloxybenzamide] together with body mass index (BMI) and personality trait on the temperament and character inventory (TCI) in 16 normal subjects. Our data demonstrate that there was a significant relation among D2R binding in the amygdala, BMI and personality trait of harm avoidance. It can be assumed that variation of dopaminergic activity in the amygdala underlies the personality variants related to the concept of fundamental body type.

To estimate receptor binding of ligand by positron emission tomography (PET) without an arterial input function, several quantitative approaches based on the use of a reference region have been proposed. We compared three approaches for quantifying extrastriatal D(2) dopamine receptors using [(11)C]FLB 457. The PET measurements were performed on seven healthy men. Binding potential (BP) of [(11)C]FLB 457 was calculated by the reference tissue model method, transient equilibrium method, and late time method. The reference tissue model describes the time-activity curve in a brain region in terms of that in the reference region, assuming that the levels of nondisplaceable radioligand binding in both regions are the same. The transient equilibrium theoretically occurs when the derivative for specific binding is zero. With the late time method, BP is calculated by integrating a late part of the time-activity curve. BP values obtained by all methods were in good agreement with those obtained by the kinetic approach, and the highest coefficient of correlation was observed in the reference tissue model method. In the simulation study, the error of BP calculated by the reference tissue model method was smallest. Moreover, the effect of the difference in the influx rate constant K(1) between the brain and the reference regions on BP was nearly avoided as theoretically predicted. We concluded that the reference tissue model method is most suitable for calculating BP of extrastriatal D(2) dopamine receptors with [(11)C]FLB 457., (Copyright 2001 Academic Press.)

Rationale: It has been suggested that the antipsychotic effect of antipsychotics is mediated by the antagonism of the dopamine D2 receptor in the limbic-cortical regions. Risperidone has an atypical property, but its effect on limbic-cortical regions has not been evaluated., Objectives: In this study, we examined the relationship among doses of risperidone and limbic-cortical dopamine D2 receptor occupancy using positron emission tomography., Methods: Seven patients with schizophrenia were scanned during the steady state with risperidone. Their occupancies in limbic-cortical regions were determined using positron emission tomography with [11C]FLB 457., Results: The average occupancy ranged from 38% to 80% on doses of 1-6 mg/day. The saturation curve plotted against the drug level fit the data well., Conclusions: Our results demonstrate that the D2 receptor occupancy with risperidone in the limbic-cortical regions seems to be similar to that of previous reports regarding the striatum, and it would be comparable to that of typical antipsychotics.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies have demonstrated consistent findings of high dopamine D2 receptor occupancy (> 65-70%) in patients treated with antipsychotic drugs. Further, the risk of extrapyramidal side effects has been shown high in patients with occupancy above 80%. On the basis of these findings, an optimal interval for D2 receptor occupancy between 70% and 80% has been suggested. It has also been shown that several atypical antipsychotics induce marked occupancy of central 5-HT2 and D2 receptors in vivo. However, a low D2 occupancy has been observed in patients with clinical dose of clozapine or quetiapine. The antipsychotic effect of these atypical drugs with a low D2 receptor occupancy has been widely discussed with respect to actions on other receptor systems, limbic selectivity of antipsychotic action and episodic transient occupancy. The recent advances in PET/SPECT and developments of new radioligands have made it possible to evaluate antipsychotic drug actions directly in humans. The empirical data from occupancy measurements will enable us to open future directions of investigation of antipsychotic action and improvement of antipsychotic treatment.

The Computerized Brain Atlas (CBA) transforms PET images of individual subjects into a standard brain anatomy. We have previously applied this to PET images with [(11)C]raclopride and confirmed that the D2 dopamine receptors in the striatum can be evaluated accurately with a standard brain anatomy. There is growing evidence that extrastriatal D2 receptors, in spite of their low density, have pathophysiological significance for schizophrenia. We used the CBA to explore the extrastriatal distribution of D2 receptors in 13 healthy subjects using [11C]FLB 457, a substituted benzamide with very high affinity for D2 and D3 receptors. There was good agreement between the specific binding ratios from CBA quantification of standardized images and those from region-of-interest analyses of original images. The highest levels of binding were observed in the putamen and caudate nucleus, followed by the globus pallidus and nucleus accumbens. Besides the basal ganglia, the hypothalamus and nucleus ruber also showed high levels of binding. Intermediate levels were found in the substantia nigra, nucleus subthalami, amygdala, and thalamus. Interestingly, there was very heterogeneous binding among the thalamic nuclei. The anterior and mediodorsal nuclei showed relatively high binding. The cerebral cortices showed lower levels with significant regional differences. Binding was highest in the temporal cortex and hippocampus followed by the anterior cingulate gyrus, and the parietal and frontal cortices, but was lowest in the occipital cortex. The use of CBA for analysis of [11C]FLB 457 binding makes it possible to build a normal database for the extrastriatal D2 receptors in the living human brain. The heterogeneous distribution of D2 receptors provides an attractive opportunity for new research on the pathophysiology and drug treatment of schizophrenia., (Copyright 1999 Academic Press.)

D2 dopamine receptors are of interest in the pathophysiology of schizophrenia. For group comparisons of neuroreceptor distribution measured by PET on a pixel-by-pixel basis, an anatomic standardization technique is required. The aim of the present study is to build a database of normal D2 dopamine receptor distribution using [11C]raclopride and an anatomic standardization technique. In each subject, two PET measurements were performed with rapid bolus injection and with continuous infusion of [11C]raclopride. The radioactivity of the PET images were integrated in the time interval. Integrated images were normalized by the radioactivity of the cerebellum, providing a measure of the binding potential (BP) in each pixel. Each PET image was transformed into a standard brain anatomy using a Computerized Brain Atlas system. From the standardized PET images, the sample mean and the SD of the BP were calculated in each pixel. On the anatomically standardized average images for the both rapid bolus injection and continuous infusion, high BP was observed in the putamen and the caudate nucleus, whereas low BP was observed in the cerebral cortices. The BP for the thalamus and the substantia nigra were slightly higher than those for the cerebral cortices. This regional distribution is in good agreement with the distribution of D2 dopamine receptors known from in vitro studies. The anatomic standardization technique permits to build a database of the normal D2 dopamine receptor distribution in the living human brain. This technique can be applied for group comparisons on a pixel-by-pixel basis., (Copyright 1999 Academic Press.)

Positron emission tomography (PET) can be used to explore relationships between central neuroreceptor occupancy, psychotropic drug blood levels and clinical effects. Treatment with conventional neuroleptics induces high (70-90%) dopamine (D2)-receptor occupancy. The risk of extrapyramidal side effects increases at D2-receptor occupancies above 80%. Standard doses of clozapine induced a low (20-67%) D2-receptor occupancy, but very high (85-90%) 5-hydroxytryptamine (5-HT2A)-receptor occupancy. The novel antipsychotics risperidone and olanzapine induced high occupancy of both D2 and 5-HT2A receptors at suggested standard doses. The occurrence of extrapyramidal side effects in some patients in the higher dose ranges does not support the view that 5-HT2A-receptor occupancy completely prevents the development of extrapyramidal side effects. These results emphasize the need for further exploration of the low dose ranges of risperidone and olanzapine. A preliminary analysis of an ongoing PET study showed that a schizophrenic patient treated with sertindole at 20 mg/day had a D2-receptor occupancy of below 70%. Further studies are needed to show whether sertindole is the first new antipsychotic that induces low occupancy in the clinical dose range, suggesting a mechanism of action distinct from that of classical neuroleptics and analogous to that of clozapine.