pyrimidinones and setoperone

Aripiprazole has a unique pharmacological profile that includes partial agonism at D(2) receptors, antagonism at 5-HT(2) receptors, and partial agonism at 5-HT(1A) receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder.. Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [(11)C]raclopride, [(18)F]setoperone, and [(11)C]WAY100635.. Very high occupancy was observed at striatal D(2) receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT(2) receptors (54%-60%), and even lower occupancy at 5-HT(1A) receptors (16%). D(2) occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D(2) occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%.. Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Basal Ganglia; Basal Ganglia Diseases; Carbon Radioisotopes; Caudate Nucleus; Cerebral Cortex; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Piperazines; Positron-Emission Tomography; Psychotic Disorders; Putamen; Pyridines; Pyrimidinones; Quinolones; Raclopride; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

Topics: Adult; Antipsychotic Agents; Benzamides; Benzodiazepines; Brain Chemistry; Corpus Striatum; Dopamine Antagonists; Female; Haloperidol; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Olanzapine; Positron-Emission Tomography; Pyrimidinones; Pyrrolidines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D3; Schizophrenia; Serotonin Antagonists

While serotonin 5HT2-receptors have been implicated in the etiology and pharmacological treatment of a number of neuropsychiatric conditions, there are few potent and specific agents available for use in human clinical studies. EMD 281014 is a highly specific 5HT2-receptor antagonist that is currently under development. To find optimal doses for early clinical studies, we conducted a PET study using [18F]setoperone in nine healthy subjects scanned at baseline and following the administration of 1, 3, and 7 mg EMD 281014. The study drug was well tolerated by all study participants, and all doses resulted in > or =70% occupancy at frontal 5HT2-receptors 3 h after drug administration. The data suggest that daily dosing of > or =3 mg EMD 281014 should be sufficient to provide sustained high levels of 5HT2-receptor occupancy in future clinical trials.

Topics: Adult; Dose-Response Relationship, Drug; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Indoles; Male; Middle Aged; Piperazines; Positron-Emission Tomography; Pyrimidinones; Radiopharmaceuticals; Receptors, Serotonin, 5-HT2; Serotonin 5-HT2 Receptor Antagonists

Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2) receptors compared with dopamine D(2) receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study.. The authors conducted a PET study to evaluate D(2) occupancy (using [(11)C]raclopride) and 5-HT(2) occupancy (using [(18)F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose.. The mean 5-HT(2) receptor occupancy was significantly higher than the mean D(2) receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT(2) receptor occupancy was almost four times lower than that for D(2) receptor occupancy.. These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2) than D(2) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D(2) receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.

Topics: Adult; Antipsychotic Agents; Brain; Corpus Striatum; Drug Administration Schedule; Female; Humans; Male; Piperazines; Psychotic Disorders; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia; Thiazoles; Tomography, Emission-Computed

Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. In healthy subjects, increasing serotonin (5-HT) agonism with a single dose of d-fenfluramine lowered dysfunctional attitudes. To investigate whether the converse, a low level of 5-HT agonism, could account for the higher levels of dysfunctional attitudes observed in patients with major depression or with self-injurious behavior, cortex 5-HT(2) receptor binding potential and dysfunctional attitudes were measured in patients with major depressive disorder, patients with a history of self-injurious behavior, and healthy comparison subjects (5-HT(2) receptor density increases during 5-HT depletion).. Twenty-nine healthy subjects were recruited to evaluate the effect of d-fenfluramine or of clonidine (control condition) on dysfunctional attitudes. Dysfunctional attitudes were assessed with the Dysfunctional Attitude Scale 1 hour before and 1 hour after drug administration. In a second experiment, dysfunctional attitudes and 5-HT(2) binding potential were measured in 22 patients with a major depressive episode secondary to major depressive disorder, 18 patients with a history of self-injurious behavior occurring outside of a depressive episode, and another 29 age-matched healthy subjects. Cortex 5-HT(2) binding potential was measured with [(18)F]setoperone positron emission tomography.. In the first experiment, dysfunctional attitudes decreased after administration of d-fenfluramine. In the second experiment, in the depressed group, dysfunctional attitudes were positively associated with cortex 5-HT(2) binding potential, especially in Brodmann's area 9 (after adjustment for age). Depressed subjects with extremely dysfunctional attitudes had higher 5-HT(2) binding potential, compared to healthy subjects, particularly in Brodmann's area 9.. Low levels of 5-HT agonism in the brain cortex may explain the severely pessimistic, dysfunctional attitudes associated with major depression.

Topics: Adolescent; Adult; Attitude; Brain Mapping; Cerebral Cortex; Clonidine; Depressive Disorder, Major; Female; Fenfluramine; Humans; Male; Personality Inventory; Pyrimidinones; Receptors, Serotonin; Reference Values; Self-Injurious Behavior; Tomography, Emission-Computed

Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients.. Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls.. There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions.. These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.

Topics: Adult; Aged; Antidepressive Agents; Binding Sites; Brain; Clomipramine; Depressive Disorder; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin; Tomography, Emission-Computed

5-HT2A receptors on platelet membranes are often measured as indirect markers of the central 5-HT2A receptors. However, the 5-HT2A receptors on the platelets and those in the brain have never been assessed simultaneously in humans. The purpose of this study was to evaluate the relationship between platelet membrane and neocortical 5-HT2A receptors measured simultaneously in normal healthy volunteers. Twelve healthy volunteers had the 5-HT2A receptors on their platelet membranes assessed in vitro using [3H]lysergic acid diethylamide ([3H]LSD) and their central 5-HT2A receptors measured in vivo using [18F]setoperone and positron emission tomography (PET) imaging. We find no significant correlation between the binding potential (Bmax/Kd) of 5-HT2A receptors on platelets and in brain in the same individual (F1,10 = 0.7, P = 0.42). The study was limited by a small sample and the fact the two different ligands were used (i.e. LSD for platelets and setoperone for brain); nonetheless, the findings suggest that changes in platelet 5-HT2A receptors may not indicate similar changes in central 5-HT2A receptors.

Topics: Adult; Blood Platelets; Central Nervous System; Female; Humans; Kinetics; Lysergic Acid Diethylamide; Male; Neocortex; Peripheral Nerves; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses.. Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained.. Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%.. Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Olanzapine; Pirenzepine; Prolactin; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Salicylamides; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

Topics: Brain; Butyrophenones; Humans; Isoxazoles; Piperidines; Pyrimidinones; Randomized Controlled Trials as Topic; Receptors, Serotonin; Risperidone; Ritanserin; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists

MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial.. To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin(2A) receptor levels.. Cross-sectional case-control study comparing serotonin(2A) receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin(2A) receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin(2A) receptor levels in the cerebral cortex were determined using serotonin(2A)-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer.. Academic medical center research laboratory.. A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness.. Cortical serotonin(2A) receptor nondisplaceable binding potential (serotonin(2A)BP(ND)).. MDMA users had increased serotonin(2A)BP(ND) in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal-parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin(2A)BP(ND) in frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin(2A)BP(ND).. The recreational use of MDMA is associated with long-lasting increases in serotonin(2A) receptor density. Serotonin(2A) receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

Topics: Adolescent; Adult; Amphetamine-Related Disorders; Cerebral Cortex; Female; Fluorine Radioisotopes; Functional Neuroimaging; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Positron-Emission Tomography; Pyrimidinones; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Substance-Related Disorders; Time Factors

The serotonergic system is implicated in disordered emotional behavior. Autism is characterized by impaired processing of emotional information. The serotonergic (5-HT) system is also critically involved in brain development, and abnormal brain synthesis of serotonin is observed in autism. Furthermore, whole blood and platelet serotonin have been reported to be elevated in autism. The authors examined the CNS serotonin system in autism in vivo. 5-HT2 receptors were visualized by PET imaging of [18F]setoperone-binding in this pilot study of 6 high-functioning autistic adults and 10 matched-control participants. Autism subjects had less thalamic [18F]setoperone binding than controls, when covaried for age, but no difference reached significance in other areas. A negative relationship between thalamic binding and history of language impairment was also observed. Further studies will be needed to gain a clearer picture of the role of the 5-HT system in autism.

Topics: Adult; Autistic Disorder; Brain; Case-Control Studies; Female; Fluorine Radioisotopes; Functional Neuroimaging; Humans; Language Disorders; Male; Pilot Projects; Positron-Emission Tomography; Pyrimidinones; Radioligand Assay; Radiopharmaceuticals; Receptors, Serotonin, 5-HT2; Thalamus

We explored whether prior findings of reduction in serotonin 2A receptor (5-HT(2A) R) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly.. We derived 5-HT(2A) R nondisplaceable binding potentials (BP(ND) ) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis.. The 5-HT(2A) R BP(ND) s decreased with age, a relationship best described by an exponential-decay regression. The BP(ND) s were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88.. These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects.

Topics: Adult; Aged; Aging; Brain; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Positron-Emission Tomography; Pyrimidinones; Radioisotopes; Receptor, Serotonin, 5-HT2A; Young Adult

Social behavior and desire for social relationships have been independently linked to the serotonergic system, the prefrontal cortex, especially the orbitofrontal cortex (OFC), and the anterior cingulate cortex (ACC). The goal of this study was to explore the role of serotonin 5HT(2A) receptors in these brain regions in forming and maintaining close interpersonal relationships. Twenty-four healthy subjects completed the Temperament and Character Inventory (TCI) prior to undergoing [(18)F]setoperone brain positron emission tomography (PET) to measure serotonin 5HT(2A) receptor availability within the OFC (BA 11 and 47) and ACC (BA 32). We explored the relationship between desire for social relationships, as measured by the TCI reward dependence (RD) scale, and 5HT(2A) receptor non-displaceable binding potential (BP(nd)) in these regions. Scores of RD were negatively correlated with 5HT(2A) BP(nd) in the ACC (BA 32, r = -.528, p = .012) and OFC (BA 11, r = -.489, p = .021; BA 47, r = -.501, p = .017). These correlations were corroborated by a voxel-wise analysis. These results suggest that the serotonergic system may have a regulatory effect on the OFC and ACC for establishing and maintaining social relationships.

Topics: Adolescent; Adult; Brain Mapping; Contrast Media; Female; Humans; Male; Middle Aged; Personality Tests; Positron-Emission Tomography; Prefrontal Cortex; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Social Behavior; Young Adult

Complex visual hallucinations (VHs) occur in several pathologic conditions; however, the neural mechanisms underlying these symptoms remain unclear. Although dopamine may have a role, indirect evidence indicates that serotonin may also contribute to the pathogenesis of complex VHs, probably via involvement of the serotonin 2 receptor.. To examine for the first time in vivo changes in serotonin 2A receptor neurotransmission among patients having Parkinson disease (PD) with VHs.. Case-control study.. Academic research.. Seven patients having PD with VHs and 7 age-matched patients having PD without VHs were recruited.. We used the selective serotonin 2A receptor ligand setoperone F 18 during positron emission tomography among nondemented patients having PD with VHs.. Patients having PD with VHs demonstrate increased serotonin 2A receptor binding in the ventral visual pathway (including the bilateral inferooccipital gyrus, right fusiform gyrus, and inferotemporal cortex) as well as the bilateral dorsolateral prefrontal cortex, medial orbitofrontal cortex, and insula.. This pilot study provides the first in vivo evidence suggesting a role for serotonin 2A receptors in mediating VHs via the ventral visual pathway in PD. Treatment studies should be performed using selective serotonin 2A receptor antagonists, which have important implications for the clinical management of VHs and psychosis in PD.

Topics: Aged; Brain; Brain Mapping; Case-Control Studies; Female; Hallucinations; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects; Positron-Emission Tomography; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin Antagonists; Temporal Lobe; Visual Cortex; Visual Pathways

Brain serotonin(2) (5-hydroxytryptamine(2); 5-HT(2)) receptors were considered potential targets for therapeutic efficacy of electroconvulsive therapy (ECT), but pre-clinical studies showed that electroconvulsive shock up-regulates 5-HT(2) receptors in contrast to antidepressant medications, which down-regulate brain 5-HT(2) receptors. Positron emission tomography (PET) studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT(2) receptors, but the effects of ECT on these receptors in individuals with depression are unknown.. To determine if a course of ECT alters brain 5-HT(2) receptors in individuals with depression and whether such changes correlate with improvement in symptoms.. Fifteen people with major depression, refractory to antidepressant therapy and referred for a course of ECT, had an [18F]setoperone scan during baseline drug-free washout period and another after a course of ECT. We assessed changes in brain 5-HT(2) receptors with ECT and their relationship to therapeutic outcome.. Widespread reduction in brain 5-HT(2) receptors was observed in all cortical areas with changes slightly more prominent in the right hemisphere. There was a trend for correlation between reduction in brain 5-HT(2) receptors in right parahippocampal gyrus, right lingual gyrus and right medial frontal gyrus, and improvement in depressive symptoms.. Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT(2) receptors in individuals with depression. The ability of ECT to further down-regulate brain 5-HT(2) receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression.

Topics: Adolescent; Adult; Aged; Brain Mapping; Contrast Media; Depressive Disorder, Major; Down-Regulation; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin, 5-HT2; Treatment Outcome; Young Adult

Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [(18)F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [(18)F]setoperone intensity in regions of interest (ROI) to cerebellar intensity. Cortical 5-HT2 BPs were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD. Further research should examine the relationship of reduced 5-HT2 receptor expression to underlying causation and to clinical and neurochemical correlates of autistic behavior.

Topics: Adult; Autistic Disorder; Cerebral Cortex; Child; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Phenotype; Pyrimidinones; Radionuclide Imaging; Receptors, Serotonin, 5-HT2; Reference Values; Serotonin Antagonists

Position emission tomography (PET) imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR) binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT2AR availability in subjects greater than 60 years old.. Six healthy subjects (age range = 65-78 years) completed two [18F]-setoperone PET scans on two separate occasions 5-16 weeks apart.. The average difference in the binding potential (BPND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions.. We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples.

Topics: Aged; Brain; Female; Humans; Image Enhancement; Male; Positron-Emission Tomography; Pyrimidinones; Radiopharmaceuticals; Receptors, Serotonin; Reference Values; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution

Dysfunction within the serotonin (5-HT) system plays a major role in the etiology of human depression, and treatment with antidepressant drugs downregulates 5-HT(2) receptors in rodents and humans. The consequences of another effective antidepressant treatment, electroconvulsive therapy (ECT), on 5-HT(2) receptors are less established.. We studied the effects of a course of electroconvulsive shock (ECS) on 5-HT(2) receptor binding in nonhuman primates in vivo using positron emission tomography (PET) and the radiotracer [(18)F]setoperone. Seven adult male rhesus monkeys received two bilateral ECS treatments per week for 3 weeks; PET scans were performed before treatment, and 24 hours, 1 week, and 4-6 weeks after completion of the course of ECS. Regions of interest were placed throughout the cortex, and the data analyzed as the ratio of specific:nonspecific radioactivity accumulation, with the cerebellum used as a measure of nonspecific binding.. Serotonin 5-HT(2) binding was significantly decreased at 24 hours and 1 week post-ECS, but returned to baseline 4-6 weeks posttreatment.. These results show for the first time in a primate species that chronic ECS decreases binding to 5-HT(2) receptors and indicate that 5-HT(2) receptor downregulation may be a common effect of both pharmacologic and nonpharmacologic antidepressant treatments.

Topics: Analysis of Variance; Animals; Brain; Dose-Response Relationship, Radiation; Electroshock; Fluorine Radioisotopes; Macaca mulatta; Male; Positron-Emission Tomography; Protein Binding; Pyrimidinones; Receptors, Serotonin, 5-HT2; Seizures; Serotonin Antagonists; Time Factors; Tomography, Emission-Computed

To examine the effects of treatment with valproate on brain 5-HT2A receptors in acute manic patients using positron emission tomography (PET) and [18F]-setoperone.. Patients with DSM-IV bipolar I disorder-manic episode were recruited. Patients were drug free or drug naïve at the time of baseline PET scan. All patients were treated with valproate and one patient received lithium in addition to valproate for 3-5 weeks following which they had a post-treatment PET scan. The effect of treatment on brain 5-HT2A receptor binding was determined using statistical parametric mapping (SPM) and region of interest (ROI) analyses. Of the 12 manic patients recruited, seven patients had both baseline and post-treatment PET scans.. All seven patients improved with treatment and were in remission at the time of the second PET scan. Both SPM and ROI analyses showed that treatment with mood stabilizers had no significant effect on brain 5-HT2A receptor binding in manic patients.. This study suggests that changes in brain 5-HT2A receptors are not involved in the antimanic effects of mood stabilizers however, we cannot exclude the possibility of 5-HT2A receptor involvement in down-stream signaling pathways.

Topics: Acute Disease; Adult; Antimanic Agents; Bipolar Disorder; Brain; Contrast Media; Female; Humans; Lithium; Male; Middle Aged; Positron-Emission Tomography; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Valproic Acid

In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients.. After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects.. 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found.. 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

Topics: Adolescent; Adult; Age Factors; Cerebral Cortex; Depressive Disorder; Down-Regulation; Female; Fluorine Radioisotopes; Humans; Male; Paroxetine; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Tomography, Emission-Computed; Treatment Outcome

The mechanism by which rapid tryptophan depletion (RTD) paradigm induces depressive relapse in recently remitted patients with depression is unknown.. To determine the effects of RTD on brain 5-HT(2) receptors using positron emission tomography (PET) and (18)F-labelled setoperone.. Ten healthy women under went two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days.. The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT(2) receptor binding in various cortical regions following the RTD session.. When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT(2) receptors, these findings suggest that a decrease in 5-HT(2) binding following RTD might be an adaptive response that provides protection against depressive symptoms.

Topics: Adult; Affect; Brain; Female; Fluorine Radioisotopes; Humans; Middle Aged; Pyrimidinones; Receptors, Serotonin; Serotonin Antagonists; Tomography, Emission-Computed; Tryptophan

The authors compared serotonin receptor binding in patients with schizophrenia and healthy comparison subjects.. They used positron emission tomography with [(18)F]setoperone to examine six patients with schizophrenia who had never been given neuroleptics and seven age-matched subjects who did not have schizophrenia.. A nondirected voxel-based analysis of the subjects' entire search volume found that serotonin 2A binding potential in the frontal cortex index was significantly smaller (by 16.3%) in patients with schizophrenia than in healthy subjects.. The authors conclude that the decrease in serotonin receptor densities previously reported in postmortem studies of subjects with schizophrenia are present at the onset of the illness, before exposure to neuroleptics.

Topics: Adolescent; Adult; Antipsychotic Agents; Brain; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Male; Pyrimidinones; Radionuclide Imaging; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia

Postmortem and brain imaging studies that measured brain serotinin(2) (5-HT(2)) receptors in major depression reported an increase, decrease, and no change compared with controls. In this study, we assessed brain 5-HT(2) receptors in 20 depressed patients (mean +/- SD age, 40.1 +/- 9.5 years; range, 22-60 years) and 20 healthy controls similar in age (37.2 +/- 12.6 years; range, 19-59 years) using positron emission tomography and setoperone labeled with fluorine 18 ([(18)F]setoperone).. Patients with DSM-IV major depression and healthy controls underwent scanning with [(18)F]setoperone. All study subjects were drug free for at least 2 weeks. The 5-HT(2) binding images were created using region-to-cerebellum ratios. The differences in 5-HT(2) receptor binding potential between the two groups were determined with statistical parametric mapping software and region of interest analysis.. There was a significant negative correlation between 5-HT(2) receptor binding potential and age in both patients and controls, and the magnitude of this correlation was similar in both groups. Both statistical parametric mapping and region of interest analyses showed that, compared with healthy controls, depressed patients had significantly lower 5-HT(2) receptor binding potential in frontal, temporal, parietal, and occipital cortical regions. Statistical parametric mapping analysis showed that the mean decrease in 5-HT(2) receptor binding potential for the entire cluster in these regions was 22%, and it ranged from 22% to 27% for local maxima within the clusters of significant voxels.. This study suggests that brain 5-HT(2) receptors are decreased in patients with major depression.

Topics: Adult; Age Factors; Brain; Cerebellum; Depressive Disorder; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Male; Middle Aged; Occipital Lobe; Parietal Lobe; Pyrimidinones; Receptors, Serotonin; Sex Factors; Temporal Lobe; Tomography, Emission-Computed

Platelets share many properties with brain serotonergic neurons such as active 5-hydroxytryptamine (5-HT) transport, 5-HT2 receptors, and mitochondrial monoamine oxidase.. We measured brain 5-HT2 receptors and platelet 5-HT2 receptors in healthy volunteers to determine if there was any correlation between the two measures.. Ten healthy volunteers with no lifetime history of psychiatric illness or family history in first-degree relatives were recruited. 5-HT2 receptor binding was determined for each subject with positron emission tomography and [18F]setoperone scan in the brain and with 3H-LSD binding in platelets.. We found no significant correlation between 5-HT2 binding potential (BP) in platelets (Bmax/Kd) and a semiquantitative estimate of 5-HT2 BP in frontal, parietal, and temporal cortical regions. SPM voxel based analysis also showed no significant correlation between the 5-HT2 BP in platelets and in the brains of the study subjects.. Brain 5-HT2 receptor binding was not significantly correlated to platelet 3H-LSD binding in healthy subjects. This raises questions about the validity of generalizing findings from platelet studies to 5-HT neurons in the brain.

Topics: Adult; Blood Platelets; Brain Chemistry; Female; Humans; Lysergic Acid Diethylamide; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin; Tomography, Emission-Computed

Several postmortem studies have reported regionally localized decreases in serotonin(2A) receptors (5-HT(2A)R) in schizophrenia. This was not confirmed by two recent [18F]setoperone positron emission tomography (PET) studies. In these two studies relatively large regions of interest (ROIs) were used; hence, 5-HT(2A)R changes may have been missed in some brain areas. Therefore, data from one study were analyzed on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM). We also used this method to examine the relationship between 5-HT(2A)R binding potential (BP) and five PANSS-derived factors: negative, positive, activation, dysphoric and autistic preoccupation. Thirteen schizophrenic patients (10 antipsychotic-naïve, 3 antipsychotic-free; 11 M, 2 F; age 31+/-7 years) and 35 age-matched control subjects (15 M, 20 F; age 30+/-7 years) were scanned. The 5-HT(2A)R BP was determined for each voxel using the pseudoequilibrium ratio method on PET data obtained between 65 and 90 min after [18F]setoperone bolus injection. The resulting parametric 5-HT(2A)R BP images were spatially normalized using a ligand specific template. Analyses of covariance were done using SPM99 with age as covariate. In tests for the effect of schizophrenia and for partial correlations between 5-HT(2A)R BP and the five factors, corrected P values <0.05 at cluster or voxel level were considered significant. No significant differences were detected between patients and control subjects, and no significant correlations were observed between 5-HT(2A)R BP and any of the five factors. Thus, in agreement with the previous ROI studies, voxel-by-voxel analysis confirmed the lack of substantial 5-HT(2A)R BP differences between schizophrenic patients and control subjects.

Topics: Adult; Age Factors; Analysis of Variance; Brain; Case-Control Studies; Contrast Media; Female; Fluorine Radioisotopes; Humans; Male; Psychiatric Status Rating Scales; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Tomography, Emission-Computed

Several postmortem studies have reported a decreased density of serotonin 5-HT2 receptors in the prefrontal cortex in schizophrenia. The purpose of this study was to investigate this in patients with schizophrenia by means of [18F]setoperone and positron emission tomography (PET) imaging.. Thirteen neuroleptic-free patients with schizophrenia, 10 of whom were also neuroleptic-naive, were compared with a group of 26 normal subjects in the same age range. The density of 5-HT2 receptors was assessed with the use of [18F]setoperone and PET in standardized cortical regions of interest.. Increasing age was associated with similar declines in 5-HT2 receptors in all cortical regions in the patient group and in the normal comparison group. After control for the effect of age, there was no statistically significant difference between the patients and the comparison subjects in 5-HT2 receptor density in any of the cortical regions.. This study failed to find the decrease in 5-HT2 receptors reported in postmortem studies of schizophrenia. The study had the power to detect a decrease of 25% or more in 5-HT2 receptors, which was anticipated on the basis of the previous postmortem studies. Thus, a primary serotonergic abnormality in schizophrenia, if one exists, is either small or unlikely to be at the level of the 5-HT2 receptors. This finding does not rule out a therapeutic role for 5-HT2 antagonists in schizophrenia, but it does suggest that the therapeutic contribution is likely to be an indirect one.

Topics: Antipsychotic Agents; Brain Chemistry; Cerebral Cortex; Contrast Media; Fluorine Radioisotopes; Humans; Prefrontal Cortex; Pyrimidinones; Receptors, Serotonin; Schizophrenia; Tomography, Emission-Computed

Because of 5HT2A receptor's (5HT2AR) putative role in several neuropsychiatric diseases, studying it in vivo is an important goal. 18F-setoperone is a well-validated and widely used PET radioligand for the study of neocortical 5HT2AR. We have previously developed and validated in baboons a method to generate parametric maps of the binding potential (i.e., the k3-to-k4 ratio) on a pixel-by-pixel basis, based on a single-dose tracer amount dynamic 18F-setoperone PET paradigm, and with the receptor-poor cerebellum as reference structure. However, previous semiquantitative PET human studies suggested that nonspecific (NS) binding in the neocortex might not be identical to that in the cerebellum.. As a first step in the development of k3:k4 parametric mapping in humans, we therefore estimated directly the NS binding of 18F-setoperone in the neocortex of four young healthy volunteers who were studied with PET both before and after 2 wk of daily therapeutic oral doses of sertindole, an atypical neuroleptic possessing strong 5HT2AR antagonistic activity.. Visual analysis of the dynamic PET data obtained over 120 min confirmed that virtually full receptor saturation had indeed been achieved; however, the late neocortical time-activity curves (TACs) progressively fell to lower uptake values than corresponding cerebellar TACs and could not be fitted according to a four-compartment (four-Cpt) nonlinear model, indicating lack of specific binding. The cerebellum TACs for both the control and the challenge conditions, as well as the challenge neocortical TACs, were fitted according to three-Cpt modeling, providing the k/k6 ratio and in turn the f2 fraction for both structures. Despite the small sample of only four subjects, the f2 fraction for the neocortex was significantly larger (i.e., NS binding was smaller) than that estimated for the cerebellum. This allowed us to determine the k3-to-k4 ratio for the control neocortex using the challenge neocortex as reference structure, that is, without using the cerebellum at all. This "assumption-free" approach was also successfully used to generate k3:k4 maps for these four subjects, which showed highest values for the temporal cortex.. This study shows that, for every new PET or SPECT radioligand and when estimation of specific binding is based on a reference structure, it is important to determine the uniformity of nonspecific binding before proceeding with human investigations.

Topics: Adult; Cerebellum; Fluorine Radioisotopes; Humans; Imidazoles; Indoles; Male; Neocortex; Pyrimidinones; Radiopharmaceuticals; Receptors, Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens.. Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging.. Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine.. Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Clozapine; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts.. With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate.. Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant.. The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.

Topics: Adolescent; Adult; Age Factors; Depressive Disorder; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Prefrontal Cortex; Pyrimidinones; Receptors, Serotonin; Research Design; Suicide, Attempted; Tomography, Emission-Computed

Alterations in 5-HT2A receptor binding are implicated in suicidality and depression. 5-HT2A receptors may also be involved in the therapeutic effects of antidepressants.. The purpose of this study was to assess the effect of paroxetine and nefazodone on 5-HT2A receptors after a single dose.. Seven subjects received a single dose of nefazodone 200 mg and five subjects received a single dose of paroxetine 20 mg. Before and after the dose, 5-HT2A binding potentials (Bmax/Kd) were determined in each subject using [18F]-setoperone PET.. Nefazodone induced a significant change in 5-HT2A binding potential (-39+/-17%,, P = 0.003) while paroxetine showed no significant alteration of 5-HT2A binding potential (+3+/-13%, P = 0.73).. The change in 5-HT2A binding potential seen with nefazodone represents blockade of 5-HT2A receptors by the drug. We do not find evidence for acute downregulation of 5-HT2A receptors with paroxetine within 9 h.

Topics: Adult; Analysis of Variance; Antidepressive Agents; Binding, Competitive; Female; Fluorine Radioisotopes; Humans; Male; Paroxetine; Piperazines; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Tomography, Emission-Computed; Triazoles

The neuroreceptor changes involved in therapeutic efficacy of various antidepressants remain unclear. Preclinical studies have shown that long-term administration of various antidepressants causes down-regulation of brain serotonin 2 (5-HT2) receptors in rodents, but it is unknown if similar changes occur following antidepressant treatment in depressed patients. Our purpose, therefore, was to assess the effects of treatment with desipramine hydrochloride on brain 5-HT2 receptors in depressed patients using positron emission tomography (PET) and fluorine-18 (18F)-labeled setoperone.. Eleven patients who met DSM-IV criteria for major depression as determined by a structured clinical interview for DSM-III-R diagnosis and suitable for treatment with desipramine were recruited. Ten patients underwent a PET scan before and another after 3 to 4 weeks of treatment with desipramine.. Eight of the 10 patients responded to desipramine treatment as indicated by more than 50% decrease in Hamilton Depression Rating Scale scores. Depressed patients showed a significant decrease in 5-HT2 receptor binding as measured by setoperone binding in frontal, temporal, parietal, and occipital cortical regions following desipramine treatment. The decrease in 5-HT2 receptor binding was observed bilaterally and was particularly prominent in frontal cortex.. Depressed patients showed a significant reduction in available 5-HT2 receptors in the brain following desipramine treatment, but it is unknown if this change in 5-HT2 receptors is due to clinical improvement or an effect of desipramine that is unrelated to clinical status.

Topics: Antidepressive Agents, Tricyclic; Brain; Depressive Disorder; Desipramine; Down-Regulation; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Frontal Lobe; Humans; Occipital Lobe; Pyrimidinones; Receptors, Serotonin; Tomography, Emission-Computed

This study examined the binding to cortical serotonin 5-HT2A receptors of conventional doses of the typical neuroleptic chlorpromazine in comparison with clozapine, the prototype atypical antipsychotic, and amisulpride, a specific dopamine D2-D3 blocker.. Seventeen schizophrenic patients treated with chlorpromazine (75-700 mg/day), four treated with clozapine (200-600 mg/day), and five treated with amisulpride (200-1200 mg/day) were studied. Cortical 5-HT2A binding was estimated by reference to the values for 14 antipsychotic-free schizophrenic subjects with the use of positron emission tomography and [18F]setoperone, a high-affinity radioligand for cortical 5-HT2A receptors.. A dose-dependent decrease in the number of available cortical binding sites for [18F] setoperone was demonstrated in the chlorpromazine group; for the highest dose, there was a virtual lack of sites available for binding. A very low percentage of available binding sites was also observed in the clozapine-treated patients at all doses. This suggests a high level of 5-HT2A blockade with both clozapine and high doses of chlorpromazine. No significant binding of amisulpride to 5-HT2A receptors was detected.. A high level of 5-HT2A receptor blockade does not appear specific to clozapine in comparison with high doses of chlorpromazine, suggesting that the distinct clinical profiles of both drugs are unrelated to 5-HT2A blockade itself.

Topics: Adolescent; Adult; Amisulpride; Animals; Antipsychotic Agents; Cerebral Cortex; Chlorpromazine; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Sulpiride; Tomography, Emission-Computed

To investigate putative abnormalities of cortical 5-HT2A receptor density in schizophrenia, we used positron emission tomography and [18F]setoperone, a high-affinity 5-HT2A receptor radioligand, in 14 neuroleptic-free or -naive schizophrenic patients and in 15 normal controls. No significant difference between the groups was observed in the whole or regional cortical binding potential of [18F]setoperone, indicating an absence of major 5-HT2A receptor cortical density abnormalities in schizophrenics.

Topics: Adult; Cell Count; Cerebral Cortex; Female; Functional Laterality; Humans; Male; Pyrimidinones; Receptors, Serotonin; Schizophrenia; Tomography, Emission-Computed

Topics: Adult; Cyproheptadine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Fluorine Radioisotopes; Humans; Male; Prefrontal Cortex; Pyrimidinones; Receptors, Dopamine D2; Receptors, Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

Position emission tomography (PET) imaging of 5-HT2 receptors can be potentially very useful in investigating neuropsychiatric disorders and their pharmacological treatments. [18F]-setoperone, a PET radio-ligand, has been shown to be useful for the delineation of 5-HT2 receptors in the cortex. However, there is no available data regarding the scan-rescan reliability of this technique. The purpose of this study was to assess the reliability of the [18F]-setoperone PET technique for assessing the binding potential (Bmax/ Kd) for 5-HT2 receptors. Ten healthy subjects had two [18F]-setoperone PET scans on two separate occasions 6-21 days apart. The average difference in the 5-HT2 binding potential (BP) as measured on the two occasions in the prefrontal, temporal, parietal and occipital region was between 5 and 7%. Thus 5-HT2 BP can be measured with a high reliability using a non-invasive technique that uses the cerebellum as a reference region. A power analysis based on the reliability data suggests that this technique can be used to detect within-subject differences of 10% or more, and between-group differences of 25% or more, with a reasonable number of subjects. It is concluded that [18F]-setoperone can be routinely produced and reliably used for the PET imaging of 5-HT2 receptors in clinical situations.

Topics: Adult; Brain; Cerebellum; Female; Fluorine Radioisotopes; Humans; Male; Pyrimidinones; Receptors, Serotonin; Reference Values; Reproducibility of Results; Serotonin Antagonists; Tomography, Emission-Computed

To investigate adaptative changes of 5-HT2A receptors induced by SSRIs, six patients chronically treated for a depressive episode (four with fluoxetine, two with fluvoxamine) were studied with PET and [18F]setoperone. They were compared to eight untreated depressive patients. The mean frontal to cerebellum radioactivity concentration ratio, an index of the [18F]setoperone specific binding to 5-HT2A receptors, was higher in treated than in untreated patients, when age was taken into account. This suggests that chronic treatment by SSRIs could induce an up-regulation of the 5-HT2A receptors, and that 5-HT2A receptor down-regulation is not a common mechanism for the therapeutic effects of all serotoninergic antidepressive drugs.

Topics: Adult; Antidepressive Agents; Depressive Disorder; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Male; Middle Aged; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Tomography, Emission-Computed

Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses.. Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively.. The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors.. Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.

Topics: Adult; Cerebellum; Corpus Striatum; Dopamine Antagonists; Female; Fluorine Radioisotopes; Humans; Loxapine; Male; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Because it satisfies most of the characteristics required to quantify in vivo neocortical serotonin-2 (5HT2) receptors, 18F-setoperone was selected for use in PET estimation of the neocortical 5HT2 binding parameters in baboons according to a single-dose paradigm.. The neocortical binding potential (i.e., Bmax/KD or the k3/k4 ratio) was assessed by three different methods, with the cerebellum taken as the reference structure in all instances. Method 1 was based on a Logan-Patlak graphical analysis of both cerebellar and neocortical data, which allows estimation of the neocortical k3'/k4 ratio; it required a separate estimation of k5 and k6 from classical nonlinear least-squares (NLSQ) three-compartment modeling of cerebellar data. Method 2 was an original combination of a four-compartment Logan-Patlak procedure for neocortical data and an NLSQ three-compartment procedure for cerebellar data, allowing the neocortical k3/k4 ratio to be obtained directly. In Method 3, an NLSQ three-compartment procedure was applied to cerebellar data and an NLSQ four-compartment procedure to neocortical data, allowing separate determinations of k3 and k4 for the neocortex and, in turn, the k3/k4 ratio.. In all three methods, the arterial plasma input function was corrected for the presence of 18F-metabolites, and the vascular fraction was either fitted or fixed. Statistical analysis showed no significant difference among the k3/k4 values obtained from the three methods. Method 3 was the least stable because of an occasional poor NLSQ four-compartment fit on neocortical data. Method 2 provided the least cumbersome estimate of the k3/k4 ratio and was found easy and accurate for generating parametric maps of the 5HT2 binding potential.. This method might be useful in clinical investigations to provide quantitative assessment of receptor binding potential. In semiquantitative investigations, the neocortical-to-cerebellum pseudoequilibrium ratio may be adequate, as suggested by the significant correlations with measured k3/k4 ratios found here.

Topics: Animals; Cerebellum; Cerebral Cortex; Computer Simulation; Feasibility Studies; Fluorine Radioisotopes; Papio; Pyrimidinones; Receptors, Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

Ziprasidone is a novel antipsychotic agent, with high affinity for dopamine D2 and serotonin (5-HT2) receptors in vitro and in animal models. The goal of this study was to determine the time course of 5-HT2 receptor occupancy (%RO) in healthy humans after a single p.o. dose. Positron emission tomography with the 5-HT2 ligand, [18F]setoperone, was performed in eight male volunteers, in the drug-naive, base-line (BL) state and 4 to 18 hr after ziprasidone (40 mg). Cerebral cortical binding potential [BP, maximum number of available receptors/KD or association rate for specific binding (k3)/dissociation rate for specific binding (k4)] was estimated using the cerebellum as reference. Transport rate from plasma to brain (K1), transport rate from brain to plasma (k2), association rate of nonspecific binding (k5) and dissociation rate of nonspecific binding (k6) were derived by fitting cerebellar time-activity curves to a three-compartment model. Fitting of cortical data to a 4-compartment model with K1/k2, k5 and k6, fixed at cerebellar values, was used to determine k3 and k4. %RO was calculated using the relation: %RO = [(BPBL-BPDRUG)/BPBL] x 100%. At BL, cortical parameter (mean +/- S.E.M) were: K1 = 0.121 +/- 0.0072 ml.min-1.g-1; k2 = 0.0581 +/- 0.004 min-1; k3 = 0.321 +/- 0.0026 min-1; k4 = 0.0957 +/- 0.0059 min-1; k5 = 0.0147 +/- 0.00066 min-1; and k6 = 0.0059 +/- 0.00042 min-1. Ziprasidone did not effect K1, k2, k5 or k6; however, k3 was reduced and k4 was elevated (P < .01). RO was nearly complete at 4 hr after dosing (98%) and remained elevated at 18 hr (46%). Plasma concentrations were well described by a biexponential function and decreased much more rapidly than RO. These results establish that ziprasidone has high potency for blocking 5-HT2 receptors in healthy humans; a potentially important characteristic of atypical antipsychotic agents.

Topics: Adult; Antipsychotic Agents; Brain Chemistry; Cerebrovascular Circulation; Humans; Male; Piperazines; Pyrimidinones; Receptors, Serotonin; Serotonin Antagonists; Thiazoles; Tomography, Emission-Computed

Fluorine-18-setoperone PET imaging was used to investigate serotonergic 5-HT2-specific binding in unlesioned cerebral cortex in stroke patients.. Seventeen stroke patients (mean age 50 +/- 31 yr) with right (n = 9) or left (n = 8) chronic stroke (middle or anterior cerebral artery territory) underwent [18F]setoperone PET and MR imaging. The distribution volume of the 5-HT2-specific binding at equilibrium (DVSe) was determined in the unlesioned cortical regions. The results were compared with those obtained in 14 age-matched controls. In addition, we investigated the effect of the side of the stroke, lesion volume and its localization.. After removing the age effect by covariance analysis, we found a significant DVSe decrease in the temporal (p < 0.05) and frontal (p < 0.05) unlesioned cortices ipsilateral to the stroke. The changes were similar in patients with left and right stroke and did not correlate with the volume of the stroke. However, the localization of the stroke affected the topography of DVSe abnormalities. When the lesion did not extend more medially than the internal capsule, DVSe was significantly reduced in the temporal lobe (-30%, p < 0.05) but not in the frontal lobe (-21%, p = ns). Conversely, when the lesion extended subcortically in the anteromedial region, close to the midline, DVSe was reduced in both temporal (-40%, p < 0.05) and frontal (- 49%, p < 0.05) lobes.. This study confirms that stroke may alter 5-HT2 receptors in large unlesioned cortical areas and that the changes depend on the subcortical extent of the lesion.

Topics: Adult; Age Factors; Aged; Cerebral Cortex; Cerebrovascular Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin; Tomography, Emission-Computed

Since the brain 5HT2 receptors might be implicated in migraine pathogenesis, we have used positron emission tomography and 18F-fluorosetoperone, a 5HT2 specific radioligand, to investigate in vivo the cortical 5HT2 receptors in migraine subjects. Nine migraineurs who had either migraine with and without aura (n = 5) or only migraine without aura (n = 4) were studied between attacks. Twelve unmedicated healthy subjects of similar mean age were used as controls. Brain radioactivity was measured after 18F-setoperone IV injection for 90 min. A decrease of the regional specific distribution volumes (SDV) of the ligand was observed both in migraineurs and in controls. The age adjusted group means of SDV did not differ between patients and controls for the whole and for the right or left frontal, temporal, parietal and occipital cortex. These results suggest that cortical 5HT2 receptors may be unaltered between attacks in migraine sufferers.

Topics: Adult; Case-Control Studies; Cerebral Cortex; Fluorine Radioisotopes; Humans; Middle Aged; Migraine Disorders; Pyrimidinones; Radioligand Assay; Receptors, Serotonin; Statistics as Topic; Tomography, Emission-Computed

In vivo occupancy by typical or atypical antipsychotic drugs of dopamine D-1, D-2 and serotonin (5-HT)2 receptors in the membranes and slices of the rat brain was measured using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist at these receptor sites. In the membranes, the occupancy of D-1 receptors in the striatum by all tested drugs except cis-flupenthixol was minimal. Typical antipsychotic drugs such as chlorpromazine (10 mg/kg), haloperidol (1 mg/kg), cis-flupenthixol (1 mg/kg) and zotepine (5 mg/kg) occupied predominantly D-2 receptors in the striatum. Among atypical antipsychotic drugs, sulpiride (30 mg/kg) and amperozide (1 mg/kg) had no effect on the EEDQ-induced reduction in D-1, D-2 or 5-HT2 receptors, whereas clozapine (10 mg/kg), fluperlapine (10 mg/kg), risperidone (1 mg/kg), setoperone (0.25 mg/kg) and ORG 5222 (0.25 mg/kg) occupied mainly 5-HT2 receptors in the frontal cortex. In the slices, the occupancy by all tested drugs of D-1 receptors in the striatum, nucleus accumbens and substantia nigra was minimal with the exception of clozapine which showed about 30% occupancy in the substantia nigra. Typical antipsychotic drugs, chlorpomazine (10 mg/kg) and haloperidol (1 mg/kg) occupied predominantly D-2 receptors in the striatum and the nucleus accumbens. On the other hand, atypical antipsychotic drugs, clozapine (10 mg/kg) and risperidone (1 mg/kg), occupied mainly 5-HT2 receptors in the frontal cortex. These results suggest that there is a certain group of atypical antipsychotic drugs characterized by high occupancy of 5-HT2 receptors and low or minimum occupancy of D-2 receptors. These characteristics may be relevant to their weak potency in producing extrapyramidal side effects in man or catalepsy in rodents. Although we could find no clear regional differences in receptor occupancies by these antipsychotic drugs, further study are needed to elucidate this issue.

Topics: Animals; Antipsychotic Agents; Autoradiography; Brain; Chlorpromazine; Clozapine; Dibenzothiepins; Flupenthixol; Haloperidol; In Vitro Techniques; Isoxazoles; Male; Piperidines; Pyrimidinones; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Serotonin; Risperidone

Using [18F]setoperone and positron emission tomography (PET), alterations in serotonergic 5-HT2 receptor binding were studied in cerebral cortex of nine unmedicated patients with probable Alzheimer's disease and 37 healthy controls. The kinetics of unchanged radioligand in plasma and 18F-radioactivity in blood and brain were obtained for 90 min following tracer injection. The specific binding of [18F]setoperone to 5-HT2 receptors in the cerebral cortex was quantitated by subtraction using cerebellum as reference. In controls, a significant reduction in specific binding was associated with age and similar linear regression slopes were obtained in all the cortical regions studied. No significant difference was observed between patients with Alzheimer's disease and age-matched controls in the injected mass of setoperone, percentage of unmetabolized [18F]setoperone in plasma, 18F-radioactivity in blood fractions and cerebellar 18F-radioactivity concentration, indicating similar non-specific brain kinetics and metabolism of the radioligand. In contrast, there was a significant reduction in specific [18F]setoperone binding in the cerebral cortex in patients with Alzheimer's disease relative to control values (temporal, 69%; frontal, 69%; parietal, 55%; temporo-parietal, 54%; occipital cortex, 35%). The results demonstrate that the loss in 5-HT2 receptor binding in the cerebral cortex of patients with Alzheimer's disease, long documented by post-mortem studies, can now be assessed in vivo using PET.

Topics: Aged; Alzheimer Disease; Cerebral Cortex; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin; Tomography, Emission-Computed, Single-Photon

18F-Setoperone, a sensitive radioligand for brain serotonin 5-HT2 receptor positron emission tomography studies, is metabolized into 18F-labeled metabolites, which participate in blood 18F radioactivity. Its main metabolite, identified as reduced 18F-setoperone, was synthesized and studied in humans to determine if 18F-labeled metabolites of 18F-setoperone (a) enter into the brain, (b) bind to the 5-HT2 receptor, and (c) explain the increase of 18F radioactivity in the free fraction in blood measured following 18F-setoperone injection. After reduced 18F-setoperone injection, the brain-to-blood 18F radioactivity concentration ratio (a) was low, at the beginning, indicating that this metabolite did not cross the blood-brain barrier; (b) was increased thereafter, with a higher radioactivity level in the choroid plexus than in brain tissue, suggesting a blood-CSF barrier crossing due to radioligand hydrophilicity; and (c) showed similar kinetics for cerebellum and frontal cortex, indicating that radioactive metabolites of 18F-setoperone did not bind to the 5-HT2 receptor. Because hydrophilic 18F-labeled metabolites of 18F-setoperone increased 18F radioactivity in the free fraction in blood, we quantified the relation between 18F-setoperone metabolism and free fraction kinetics in blood. A significant negative correlation was found between metabolism and free fraction rate constants in blood, showing it was possible to predict the 18F-setoperone metabolism rate using free fraction kinetics in blood. This will allow us to avoid the use of radio-TLC, a reference method that is difficult to use when multiple samples must be analyzed. A hydrophilic positron-emitter radioligand could also be used to study the blood-CSF barrier.

Topics: Adult; Blood-Brain Barrier; Brain; Cerebellum; Cerebral Cortex; Fluorine Radioisotopes; Humans; Pyrimidinones; Radioligand Assay; Receptors, Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

Following previous validation in baboons, we have studied the characteristics of [18F]setoperone as a radioligand for investigating serotonergic 5-hydroxytryptamine2 (5-HT2) receptors in the normal, unmedicated human brain with positron emission tomography (PET); subjects orally pretreated with therapeutic amounts of ketanserin, sulpiride, or prazosin were also studied to evaluate the specificity and sensitivity of [18F]setoperone brain specific binding. In controls (n = 10), the tracer showed a clear-cut retention in both frontal cortex and striatum (known to contain a high density of 5-HT2 receptors) relative to cerebellum (known to be devoid of 5-HT2 receptors). In the seven young controls (20-39 years old), the frontal cortex/cerebellum and striatum/cerebellum ratios increased during the first hour to reach similar values of 2.53 +/- 0.12 and 2.38 +/- 0.11 (mean +/- SEM), respectively, and were essentially stable during the second hour. Pretreatment with ketanserin (a 5-HT2 blocker) significantly reduced the frontal cortex/cerebellum ratio to 0.7-1.0 at 65 min, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. During sulpiride treatment (a D2 blocker), the frontal cortex/cerebellum ratio was not altered, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. With prazosin pretreatment (an alpha 1-adrenergic blocker), neither the frontal cortex/cerebellum nor the striatum/cerebellum ratio was modified. These data in humans with PET demonstrate that [18F]setoperone labels with high sensitivity and selectivity 5-HT2 receptors in the frontal cortex; in striata, however, binding is to both 5-HT2 and D2 receptors. The deproteinated-to-whole plasma radio-activity concentration ratio increased with time following injection. The mean percentage of intact [18F]setoperone, in deproteinated plasma, was 82, 74, 53, 45, 30, and 22% at 5, 10, 20, 30, 60, and 110 min following injection, respectively. These data indicate that [18F]setoperone (a) is significantly bound to plasma proteins and (b) is significantly metabolized into several labeled metabolites that are much more hydrophilic than setoperone and, hence, presumably do not cross the blood-brain barrier. These results suggest the suitability of [18F]setoperone data for modeling of 5-HT2 receptor binding in brain.

Topics: Adult; Aged; Brain; Cerebral Cortex; Fluorine Radioisotopes; Humans; Kinetics; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin; Sensitivity and Specificity; Serotonin Antagonists; Tissue Distribution; Tomography, Emission-Computed

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT2 receptor antagonists and 5-HT1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT2 antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT2 antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic-related dyskinesias in squirrel monkeys.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Apomorphine; Avoidance Learning; Buspirone; Dopamine; Haloperidol; Male; Movement Disorders; Pyrimidinones; Saimiri; Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes

The effect of acute treatment with seven atypical antipsychotic drugs and four typical antipsychotic drugs on serotonin2 (5-HT2) receptor binding sites in rat cerebral cortex was studied. Among the atypical antipsychotic drugs examined, clozapine, fluperlapine, RMI-81582 and setoperone decreased the density of 5-HT2 receptors, but ticspirone, amperozide and melperone did not. None of the drugs affected the Kd value. Among the typical antipsychotic drugs, loxapine decreased Bmax and increased the Kd of 5-HT2 receptor binding sites, whereas chlorpromazine and cis-flupenthixol had no effect. Clothiapine, a typical antipsychotic drug of the same chemical class as clozapine, decreased Bmax without increasing Kd. The downregulation of 5-HT2 receptor binding sites following a single injection of clozapine, 20 mg/kg, remained almost unchanged during the first 72 hrs and was still significantly decreased for up to 120 hrs. There was no relationship between the affinity for the downregulation of rat cortical 5-HT2 receptor binding site and 5-HT2 receptor density. Coadministration of the D1 dopamine agonist, SKF-38393, did not affect the clozapine-induced downregulation. It is suggested that rapid and prolonged downregulation of 5-HT2 receptor sites is characteristic of some but not all atypical antipsychotic drugs and is not specific to atypical antipsychotic drugs. Dibenzo-epines (clozapine, loxapine, amoxapine, chlothiapine) consistently downregulate 5-HT2 receptors in frontal cortex after acute treatment.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antipsychotic Agents; Butyrophenones; Cerebral Cortex; Chlorpromazine; Clozapine; Dibenzazepines; Dibenzothiazepines; Down-Regulation; Flupenthixol; Kinetics; Loxapine; Male; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Serotonin; Spiro Compounds; Time Factors

LY53857, spiperone, ketanserin, and setoperone were potent and competitive 5-HT2-receptor antagonists in the rat jugular vein with equivalent affinities at 5-HT2 receptors. In the rat jugular vein, ritanserin blocked 5-HT2-mediated contractile responses with a depression of the maximum response in concentrations greater than 3 X 10(-10) M. Ketanserin, spiperone, ritanserin, and setoperone were also alpha 1-adrenergic receptor antagonists, although affinity at alpha 1-adrenergic receptors was less for ritanserin and setoperone than for ketanserin or spiperone. Of the 5-HT2-receptor antagonists examined, LY53857 was the most selective with respect to alpha 1-adrenergic receptor affinity, showing 250,000-fold selectivity as an antagonist at 5-HT2 receptors. The possibility that the dual properties of 5-HT2- and alpha 1-receptor blockade confer greater antihypertensive efficacy than alpha 1-receptor blockade alone was also examined in vivo. However, acute administration of LY53857 at doses sufficient to abolish 5-HT2-receptor activation did not enhance blood pressure reduction produced by the alpha-adrenergic receptor antagonist phentolamine in normotensive or spontaneously hypertensive rats. These data argue against an important role for 5-HT2 receptors in blood pressure regulation even in combination with alpha-adrenergic receptor blockade.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Ergolines; Ketanserin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Phentolamine; Piperidines; Pyrimidinones; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Serotonin; Ritanserin; Serotonin Antagonists; Spiperone

The ability of atypical and typical antipsychotics to antagonize serotonin (5-HT) receptor-mediated temperature and neuroendocrine responses was tested in rats. Clozapine, melperone and setoperone, three atypical neuroleptics, blocked in a dose-dependent manner, the hyperthermic response to the 5-HT agonist, MK-212, whereas chlorpromazine and haloperidol were ineffective. The hypothermic response to the 5-HT1A agonist, 8-OH-DPAT, was unaltered by any of the atypical neuroleptics tested. Similarly, MK-212-induced corticosterone secretion was blocked in a dose-related manner by clozapine, melperone and setoperone but was relatively unaffected by either haloperidol or chlorpromazine. The increase in corticosterone secretion observed following 8-OH-DPAT administration was not attenuated by pretreatment with the atypical or typical antipsychotics tested. These data indicate that atypical neuroleptics are effective 5-HT2 but not 5-HT1A antagonists in vivo. Conversely, the typical neuroleptics, haloperidol and chlorpromazine do not block the 5-HT receptors involved in activation of the hypothalamic-pituitary-adrenal axis or thermoregulation.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Body Temperature; Butyrophenones; Chlorpromazine; Clozapine; Corticosterone; Haloperidol; Male; Neurosecretory Systems; Pyrazines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes

Setoperone, a piperidine derivative known for its potent serotonin and moderate dopamine receptor blocking properties was labelled with the positron emitter 18F using a nucleophilic substitution on the nitro derivative. The general pattern of the in-vivo and in-vitro rat brain distribution of this new radioligand was consistent with the mapping of serotonin (5HT2) and dopamine (D2) receptors. The cortical binding of 18F-setoperone was selectively inhibited by ketanserin and not by sulpiride. The affinity of the radiofluorinated ligand for the serotonin receptors was in the nanomolar range (Kd = 0.7 nM).

Topics: Animals; Autoradiography; Brain; Brain Chemistry; Fluorine Radioisotopes; In Vitro Techniques; Isotope Labeling; Male; Pyrimidinones; Radionuclide Imaging; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists

The potential usefulness of 18F-labelled setoperone, a high-affinity antagonist of the serotonin-2 (S2) receptors, to study the S2 receptors in vivo with positron emission tomography (PET) was investigated in four baboons. In the control state, there was a rapid wash-out of intravenously injected tracer from the cerebellum, a structure essentially devoid of S2, receptors, and marked retention in both the cerebral cortex and the striatum (region/cerebellum ratios up to 3 and 3.5 after 60 min in cortex and striatum, respectively). The retention of radioligand in the cerebral cortex was abolished after pretreatment with spiperone or ketanserin at saturating doses. In striatum, however, radioligand retention was fully prevented by spiperone but only partly by ketanserin. These results demonstrate that [18F]setoperone was bound to the S2 receptors in the cerebral cortex, whereas the radioligand was bound to both the S2 and the dopamine D2 receptors in the striatum. The high cortex/cerebellum ratio achieved indicates that [18F]setoperone should be a useful radiotracer for PET studies of the S2 receptors.

Topics: Animals; Brain; Fluorine Radioisotopes; Injections, Intravenous; Ketanserin; Ligands; Male; Papio; Pyrimidinones; Receptors, Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

Topics: Animals; Brain; Corpus Striatum; Frontal Lobe; Male; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Serotonin; Ritanserin; Serotonin Antagonists

Rats were chronically treated with setoperone, a mixed serotonin and dopamine antagonist. Alterations in serotonin-S2 and dopamine-D2 receptors in the brain and changes in behavioural responses to tryptamine and apomorphine were studied along with duration of treatment and drug withdrawal. As with neuroleptics, behavioural supersensitivity to apomorphine and increase in the number of striatal dopamine-D2 receptor sites were apparent after 2 days setoperone treatment, both effects were maximal with 14 days treatment and were maintained over more than 20 days drug withdrawal. In contrast to the changes in the dopaminergic system, the rats showed a decreased response to tryptamine and serotonin-S2 receptor sites in the frontal cortex were significantly reduced in numbers. Both effects developed in parallel over 14 days treatment and extinguished over 10 days drug withdrawal. KD-values of radioligand binding to dopamine-D2 and serotonin-S2 receptor sites were unchanged by the setoperone treatment. The concomitant development and extinction of the in vivo and in vitro effects suggests a causal relationship between them. Chronic treatment with a selective histamine-H1 antagonist (levocabastine) or the tranquilizer diazepam did not affect dopamine-D2 or serotonin-S2 receptor sites. These observations demonstrate that in contrast to the receptor regulation theory, serotonin-S2 receptors are down regulated following persistent receptor blockade. Implications for the clinical use of serotonin antagonists and possible molecular mechanisms involved in the receptor regulation have been discussed.

Topics: Animals; Apomorphine; Behavior, Animal; Corpus Striatum; Diazepam; Dopamine Antagonists; Frontal Lobe; Gene Expression Regulation; Ketanserin; Male; Models, Biological; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Serotonin; Serotonin Antagonists; Tryptamines

Setoperone (R 52245), a serotonin S2 and dopamine D2 receptor blocker, was tested on eight healthy male volunteers, receiving 5 or 40 mg orally, in order to assess the modifications of plasma prolactin levels, as an index of receptor blocking activity. Both doses significantly increased plasma levels, confirming the dopamine blocking activity. In vitro and in vivo studies have shown serotonin S2 receptor blockade and lysergic acid diethylamide antagonist activity. Setoperone is proposed as a possible new neuroleptic drug.

Topics: Adolescent; Adult; Antipsychotic Agents; Dopamine Antagonists; Humans; Male; Prolactin; Pyrimidinones; Receptors, Serotonin

Ritanserin is a potent and selective serotonin-S2 antagonist which slowly dissociates from the receptor sites, while setoperone has potent serotonin and moderate dopamine antagonistic properties and dissociates rapidly from the receptor sites. Acute administration of ritanserin (1-10 mg/kg) produced a non-competitive inhibition of 3H-ketanserin binding, measured ex vivo in washed frontal cortex membranes, which lasted for 12 h. This is in accordance with the slow dissociation of the drug from the receptor sites. Setoperone (1-10 mg/kg orally) also produced a partially non-competitive inhibition of 3H-ketanserin binding in washed membranes, which is unlike its rapid dissociation. In contrast, there was no inhibition of dopamine receptor binding in washed striatal membranes. Chronic oral administration of 10 mg/kg X day of the drugs significantly reduced the Bmax values of 3H-ketanserin, without changing the KD value when drug-free periods were longer than 1 day. The maximum reduction following 25 days' treatment with 14 mg/kg ritanserin was 50% at 1 day drug-free; the Bmax values gradually returned to the control value in about 12 days. The receptor half-life was calculated to be 3.5 days and the receptor synthesis rate 4 fmoles/mg tissue X day. Ritanserin treatment did not alter radioligand binding to serotonin-S1, alpha 1-, alpha 2- and beta-adrenergic, dopamine-D2, benzodiazepine and substance P sites. Chronic treatment with setoperone at 10 mg/kg X day, orally, significantly reduced the Bmax value of 3H-ketanserin binding in frontal cortex but treatment with 1 mg/kg X day did not. In contrast, a dose-dependent increase in the number of striatal dopamine-D2 sites was observed, in accordance with the moderate dopamine-antagonistic properties of setoperone. Dopamine-D2 receptor up regulation up to 150% of control values, was maintained at the same level for 9 days, it started to decline 12 days after stopping drug treatment. Following chronic treatment and drug withdrawal for more than 1 day, ritanserin and setoperone levels in whole brain homogenates were below detection level (less than 1 ng/g). The similar reduction in the Bmax values of 3H-ketanserin binding following chronic treatment with the rapidly dissociating setoperone and the slowly dissociating ritanserin, the absence of effect on the KD value, the slow reappearance of the receptor sites and the opposite effect on serotonin-S2 and dopamine-D2 receptors with setoperone suggest that real seroto

Topics: Animals; Brain; Corpus Striatum; Frontal Lobe; Ketanserin; Male; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Neurotransmitter; Receptors, Serotonin; Ritanserin

The new antipsychotic drug setoperone is pharmacologically characterized by its potent serotonin and moderate dopamine receptor blocking properties. Forty chronic schizophrenic patients were included and 34 completed this pilot study. Following a drug-free period of 1 week the patients received setoperone 5 mg t.i.d. After 1 month of treatment, the psychotic symptoms, as measured by the BPRS, improved by approximately 50% (P less than 0.001) as compared with the condition under previous neuroleptic medication. Blockade of serotonin receptors may be related to improvement of autistic behaviour, dysphoria, and parkinson-like symptoms. In residual schizophrenic patients, the need for dopamine blockade, which is normally correlated with the therapeutic effect on positive symptoms, can be reduced substantially.

Topics: Adult; Aged; Basal Ganglia Diseases; Female; Humans; Male; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Pyrimidinones; Schizophrenia; Serotonin Antagonists