PET examination of the monkey heart with high specific radioactivity [11C]norepinephrine and [11C]metaraminol.
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Adrenergic Uptake Inhibitors↗
Biomedical subjects
L Farde
Publications and source records attributed to L Farde.
Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidone-treated schizophrenic patients.
By the use of positron emission tomography (PET), high central dopamine D2 receptor occupancy (70 to 90%) has been demonstrated in patients treated with conventional neuroleptics. In patients treated with the atypical antipsychotic clozapine, the D2 occupancy was low (20 to 67%). The effects of clozapine may thus be mediated by a mechanism distinct from D2 occupancy. The observation that low doses of clozapine (125 to 175 mg daily) induced more than 80% (5-hydroxytryptamine) 5-HT2 occupancy supports the view that 5-HT2 antagonism may be related to the atypical effects of clozapine. Risperidone is a new antipsychotic drug with high affinity in vitro for both central 5-HT2 and D2 receptors. In this study, we determined the D2 and 5-HT2 occupancy induced by clinical treatment with risperidone. Four patients with acute exacerbation of schizophrenia were examined by PET after 4 weeks of treatment with risperidone, 6 mg daily. The D2 occupancy in the striatum was 75 to 80%. The 5-HT2 occupancy in the neocortex was 78 to 88%. This study confirms that, in patients with schizophrenia, treatment with risperidone induces a high D2 and 5-HT2 occupancy. Risperidone is, accordingly, a suitable drug for the examination of the clinical benefit of combined serotonin and dopamine antagonism.
Adult↗
Central D2 receptor occupancy and effects of zuclopenthixol acetate in humans.
Repeated positron emission tomography (PET) measurements of D2 receptor occupancy, plasma concentrations of zuclopenthixol and reaction time were performed in three healthy subjects after injection of 12.5 mg zuclopenthixol acetate (ZPTA) in an open study design. Five control subjects were examined for reaction time only. D2 receptor occupancy was 51%, 71% and 75% after 7 h and 75%, 83% and 87% after 31 h in the three subjects. The subjects reported sedation, but reaction time was not prolonged. After the low dose of 12.5 mg ZPTA, D2 receptor occupancy exceeded the 70% assumed to be required to induce antipsychotic effect. Extrapolation of data to a clinical dose interval indicates that 50-150 mg ZPTA should induce very high D2 receptor occupancy lasting several days after injection. Such high doses may be required to induce sedation and to avoid frequent intramuscular injections in acutely psychotic patients. However, the simultaneously induced very high D2 receptor occupancy calls for careful assessment of acute extrapyramidal symptoms.
Adult↗
D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients.
OBJECTIVE: Central D1, D2, and 5-HT2 receptor occupancy in schizophrenic patients treated with clozapine was determined and related to clozapine serum concentrations. METHOD: Seventeen patients treated with clozapine (125-600 mg/day) were examined with positron emission tomography (PET) and one to three of the following selective radioligands: [11C]SCH23390 (N = 11), [11C]raclopride (N = 16), and [11C]N-methylspiperone (N = 5). Clozapine concentration in serum was determined by gas chromatography/mass spectrometry. RESULTS: D2 receptor occupancy (20%-67%) was lower than that previously determined in patients treated with classical neuroleptics (70%-90%). D1 receptor occupancy (36%-59%) was higher than that induced by classical neuroleptics (0%-44%). 5-HT2 receptor occupancy was very high (84%-94%), even at low clozapine doses. Despite a 20-fold range in clozapine serum concentration (105-2121 ng/ml) at the time of PET examination, D2 receptor occupancy was low in all patients and was not described by the curvilinear relationship between serum drug concentration and receptor occupancy that has been demonstrated for classical antipsychotics. CONCLUSIONS: The results confirm in an extended series of patients that clozapine is atypical with regard to degree of D2 receptor occupancy, a finding that may explain the lack of extrapyramidal side effects. The combination of relatively high D1, low D2, and very high 5-HT2 receptor occupancy values is unique to clozapine. Clozapine serum concentrations have not been unequivocally shown to predict clinical effects. In this study, concentration did not predict degree of occupancy in brain. Thus, careful clinical titration cannot be replaced by monitoring of drug concentrations for optimization of clozapine treatment in individual patients.
Adult↗
D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate.
OBJECTIVE: The aim of this study was to examine the relationships among clinical effects, central D2 dopamine receptor occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate. METHOD: During a 4-week interval of haloperidol decanoate dosage (dose range = 30-50 mg), the patients' D2 receptor occupancy was determined with positron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method. RESULTS: One week after injection of haloperidol decanoate, the mean D2 receptor occupancy was 73% (range = 60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range = 2.9-9.7). After 4 weeks, the mean D2 receptor occupancy had decreased to 52% (range = 20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range = 1.0-4.4). CONCLUSIONS: The D2 receptor occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D2 receptor occupancy during the latter part of the treatment interval. These observations indicate that continuously high D2 receptor occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies.
Adult↗
Utilization of radioligands in schizophrenia research.
Interest in the role of monoaminergic mechanisms in schizophrenia has stimulated the development of specific radioligands that allow PET analysis of quantitative aspects of monoamine receptor subtypes in the living human brain. Clinical studies with such ligands have not consistently demonstrated specific alterations of the total populations of D1 and D2 dopamine receptors in the caudate putamen complex of drug-naive schizophrenic patients. However, recent studies using [11C]SCH 23390, a specific D1 dopamine receptor ligand, disclosed a highly significant reduction of ligand binding in pixel elements of the basal ganglia that normally contain high activity. This finding may be related to reduced D1 dopamine regulated transmission in subsets of neuronal pathways within the basal ganglia. D3, D4, and D5 receptor subtypes constitute minor fractions of the total number of dopamine receptors in the human brain. However, efforts to find selective ligands for D3 and D4 subtypes also show promise. Radioligands for monoamine receptors have also been used to follow drug effects on receptor subtypes in schizophrenic patients treated with different types of antipsychotic drugs. Such studies have allowed the analysis of relationships between occupancy of dopamine receptor subtypes and some clinical manifestations of drug treatment. Such studies with the selective D2 antagonist raclopride indicated quantitative relationships between the degree of D2 dopamine receptor occupancy in the basal ganglia and the extrapyramidal manifestations, as well as the antipsychotic action. Some of the currently available antipsychotic drugs also induced significant occupancy of D1 dopamine receptors. However, the selective D1 antagonist SCH 39166 in doses inducing a more than 70% occupancy of D1 dopamine receptors in the caudate putamen failed to induce an antipsychotic action. This indicates that, in contrast to D2 blockade, selective antagonism of D1-regulated pathways does not mediate antipsychotic action in schizophrenia. Some but not all antipsychotic drugs also induced high occupancy of neocortical 5HT2A receptors. Because selective 5HT2A antagonism does not appear to be an efficient treatment for schizophrenia, it seems most likely that 5HT2A receptors and, perhaps, D1 receptors act in concert to modify aspects of the mandatory D2 blockade to induce antipsychotic actions. Computer graphic methods for image analysis add new dimensions to brain imaging research, allowing three-dimensional visualization of receptor populations computed from molecular PET data. This will make possible further exploration of the detailed molecular compartmentalization of the human brain using radioligand binding.
Brain↗
Recent developments in PET scan imaging of neuroreceptors in schizophrenia.
Among the brain imaging techniques developed during the past two decades, positron emission tomography (PET) has the highest sensitivity allowing the analysis of specific neurotransmitter mechanisms in the living human brain. By using a combination of selective ligands labeled with positron emitting isotopes D1- and D2 dopamine, serotonin 5HT2, and benzodiazepine receptors were examined in schizophrenic patients (DSM-III-R) and healthy control subjects. With this technique receptor populations could be excellently visualized and quantified with regard to number and binding characteristics in several brain regions. The characteristics of the total D1 and D2 dopamine receptor populations in the caudate and putamen did not differ in young drug-naive schizophrenic patients and age-matched control subjects. Also for 5HT2 and benzodiazepine receptors no major alteration of receptor characteristics was observed in several neocortical and limbic brain regions. However, in schizophrenic patients treated with chemically different types of antipsychotic drugs major reductions of ligand binding was observed indicating specific induction of neuroreceptor occupancy. Thus, all chemically different types of antipsychotic drugs examined induced a substantial occupancy of D2 dopamine receptors. Clozapine in high doses induced a significantly lower degree of D2 dopamine receptor occupancy than the conventional drugs. Some but not all antipsychotics also induced a significant D1 dopamine receptor occupancy. In spite of the fact that the selective D1 antagonist SCH 39166 induced a substantial D1 occupancy, this drug did not exhibit an antipsychotic effect in schizophrenic patients. A very high degree of 5HT2 occupancy in neocortical regions was observed after clinical treatment with antipsychotic drugs as clozapine, risperidone and thioridazine.(ABSTRACT TRUNCATED AT 250 WORDS)
Antipsychotic Agents↗
Carbon-11-FLB 457: a radioligand for extrastriatal D2 dopamine receptors.
UNLABELLED: D2 dopamine receptors in extrastriatal brain regions are of central interest for research in schizophrenia and antipsychotic drugs. This article reports the development of [11C]FLB 457 for PET examination of extrastriatal D2 dopamine receptors. METHODS: Carbon-11-FLB 457 was prepared by O-methylation of FLB 604 (2-hydroxy precursor) with [11C]methyl iodide. Total radiochemical yield was 25%-35% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was about 1300 Ci/mmole (48 GBq/mumole). RESULTS: FLB 457 bound with high affinity to D2 and D3 dopamine receptors, whereas binding to other putative central receptors was negligible. PET studies in Cynomolgus monkeys demonstrated 15 times higher accumulation of radioactivity in the striatum than in the cerebellum after 60 min. Uptake in the thalamus and neocortex, extrastriatal regions with a low density of D2 dopamine receptors, was, respectively, 4 and 2.5 times higher than in the cerebellum. Radioactivity was displaced by raclopride and haloperidol which confirms the selectivity and reversibility of [11C]FLB 457 binding to D2 dopamine receptors in vivo in the striatum, thalamus and neocortex. CONCLUSION: Carbon-11-FLB 457 should be a useful PET ligand for quantitative examination of D2 dopamine receptors in extrastriatal regions in the human brain.
Animals↗
Positron emission tomography studies on D2 dopamine receptor occupancy and plasma antipsychotic drug levels in man.
Positron emission tomography (PET) and the selective radioligand [11C]raclopride were used to measure D2 receptor occupancy in several studies in schizophrenic patients and healthy subjects. Clinical effects of the treatment were recorded, and drug plasma concentrations measured. The hypothesized curvilinear relationship between receptor occupancy and drug plasma concentrations was supported experimentally. We suggest that there may be a distinct threshold for antipsychotic effect at about 70% D2 receptor occupancy, and another threshold for extrapyramidal side effects above 80% D2 receptor occupancy. Receptor occupancy was high even at low plasma drug concentrations. Our data indicate a need to establish dose-response curves for the conventional neuroleptics. Such a dose-response relationship might be expected for a much lower dose interval than those previously examined.
Antipsychotic Agents↗
PET study of [11C]beta-CIT binding to monoamine transporters in the monkey and human brain.
The cocaine congener beta-CIT has been labeled with 11C for positron emission tomographic (PET) studies of the dopamine transporter. In the present autoradiographic study on human brain sections and PET study on monkey and human [11C]beta-CIT accumulated markedly in the striatum. [11C]beta-CIT binding in the striatum was selective to the dopamine transporter. The binding in the thalamus was on an intermediate level and was displaced by compounds having affinity for norepinephrine and serotonin transporters. The neocortical binding was on a low level and could be displaced only by citalopram, a serotonin uptake inhibitor. A high dose of cocaine intravenously (7 mg/kg) induced a 50% occupancy of specific [11C]beta-CIT binding to the dopamine transporter in the striatum. This dose is much higher than the doses of 0.25-0.5 mg/kg i.v. for cocaine arousal in human subjects. The finding indicates that cocaine arousal may be induced at a low dopamine transporter occupancy of a few percent. [11C]beta-CIT should be a useful radioligand to explore cocaine actions in humans and to follow the pathophysiological process in vivo by PET in neurodegenerative diseases of the striatum.
Adult↗
PET-determination of benzodiazepine receptor binding in studies on alcoholism.
Positron Emission Tomography (PET) and the radioligand [11C]flumazenil were used to examine benzodiazepine (BZ) receptor binding in the human brain. In a first study of healthy males acute ingestion of alcohol did not alter total radioactivity uptake or specific [11C]flumazenil binding in the neocortex or cerebellum. In a second study [11C]flumazenil binding was determined in 5 healthy male controls and 5 chronic alcohol dependent men using a saturation procedure with two PET experiments. Mean values for BZ-receptor density and affinity were similar in the two groups but the Bmax variance for the alcohol dependents was significantly larger (p < 0.05) for all regions. The present studies do not support the view that alcohol affects central BZ receptor binding in man.
Adult↗
Preparation of a potential positron emission tomographic radioligand for the dopamine transporter.
NNC 12-0722 (1-[2-(bis(4-fluorophenyl)-methoxy)ethyl]-4-methyl piperazine) is a new selective inhibitor of the dopamine transporter. [11C]NNC 12-0722 was prepared by N-methylation of the desmethyl compound with [11C]methyl iodide. The total radiochemical yield of [11C]NNC 12-0722 was 40%-50% with an overall synthesis time of 30-35 min. The radiochemical purity was higher than 99% and the specific radioactivity about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 12-0722 binding on whole hemisphere cryosections from human brain post mortem demonstrated specific binding in the caudate nucleus and putamen. In a positron emission tomographic examination of [11C]NNC 12-0722 in a cynomolgus monkey there was a rapid uptake of radioactivity in the brain. In the striatum, a region with a high density of dopamine transporters, the radioactivity was two times higher than in the cerebellum. These results indicate that [11C]NNC 12-0722 may be a useful radioligand for labelling of the dopamine transporter in man.
Animals↗
Positron emission tomography shows high specific uptake of racemic carbon-11 labelled norepinephrine in the primate heart.
(-)-Norepinephrine is the predominant neurotransmitter of the sympathetic innervation of the heart. Racemic norepinephrine was labelled with carbon-11 and injected i.v. into Cynomolgus monkeys. Five minutes after injection there was a more than tenfold higher radioactivity in the heart than in adjacent tissue. Pretreatment with the norepinephrine reuptake inhibitor desipramine reduced the uptake by more than 80%. The high specific uptake of racemic [11C]norepinephrine indicates that enantiomerically pure (-)-[11C]norepinephrine has promising potential for detailed mapping of the sympathetic innervation of the human myocardium.
Animals↗
Dopamine D1 receptor number--a sensitive PET marker for early brain degeneration in Huntington's disease.
D1-dopamine receptor binding in the brain was determined by positron emission tomography (PET) in five patients with Huntington's disease, in one asymptomatic gene carrier and in five control subjects. [11C] SCH 23390 was used as the radioligand. Brain morphology was recorded by MRI. The patients who all had a mild to moderate functional impairment showed an almost 50% reduction of putamen volume as well as D1-dopamine receptor density as compared to the controls. The total D1-dopamine receptor number in the putamen was reduced by 75% in the patient group. A similar reduction was found for the caudate nucleus. The asymptomatic gene carrier had volume and density values in the lower range of the control subjects. In the frontal neocortex there also tended to be a reduced D1-dopamine receptor binding in the symptomatic patients. The results indicate that [11C] SCH 23390 binding in combination with MRI can be used as a sensitive marker for early brain degeneration in Huntington's disease. This marker may be useful to monitor the pathophysiological effect of the disease gene and also to follow therapeutic interventions aiming at preventing the degenerative process.
Adult↗
Influence of rate of administration of raclopride on akathisia and prolactin response.
The D2-dopamine receptor antagonist raclopride was administered to eight healthy male subjects, who had previously experienced akathisia following antipsychotic drugs. The influence of administration rate on onset, severity and duration of akathisia and on prolactin response was studied. Raclopride 3, 5 or 9 mg or placebo (P) was administered as single IV infusions during 10 min (R10 min/3 mg), 1 h (R1h/5 mg) or 4 h (R4h/9 mg) according to a randomized double-blind design. Despite a 24-fold difference in administration rate a similar peak raclopride concentration of about 350 nmol/l was obtained after all three infusions. Three of the eight subjects experienced akathisia following R10 min/3 mg and R1h/5 mg, respectively. After R4h/9 mg seven subjects experienced akathisia of longer duration but not more severe than after the short infusions. The incidence and duration of akathisia seem to be mainly related to the plasma raclopride concentrations over time, whereas the rate of administration might be more important for the severity. A maximal prolactin response was induced which was not markedly affected by the rate of administration.
Adult↗
An open clinical and biochemical study of ritanserin in acute patients with schizophrenia.
The effect of the selective serotonin-2 antagonist ritanserin was investigated in an open study of patients with schizophrenia. The patients were in an acute psychotic state considered to require neuroleptic medication. No neuroleptic drug was allowed during the study or during the last month preceeding the study. Oxazepam or nitrazepam were allowed for sedation or sleep inducement. Safety, tolerability, potential antipsychotic effect, and drug effects on monoamine metabolites in serum and CSF and prolactin in serum were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography. Ten male patients (mean age 32.4) fulfilling DSM-III-R criteria for schizophrenia were included in the study. Nine of these patients completed 4 weeks' treatment with ritanserin 10 mg b.i.d. The clinical effect was evaluated by means of CPRS and SANS and significant improvement was seen after 4 weeks' treatment both in positive and negative symptoms. Ritanserin was well tolerated and no extrapyramidal symptoms or akathisia were seen. Concentrations of monoamine metabolites and prolactin did not change during treatment. Ritanserin did not occupy D2-dopamine receptors. Thus, no indications of any D2-dopamine-antagonistic activity were obtained. All patients had expected ritanserin levels in plasma during the whole study. This first study of a selective serotonin-2 antagonist in the treatment of acute schizophrenic patients demonstrated significant clinical effects. However, the open design of the study does not allow us to conclude with any certainty that the patients' improvement was due to a specific blockade of serotonin-2 receptors or unspecific factors, although a direct D2-dopamine blockade could be ruled out.
Acute Disease↗
Selective synthesis of racemic 1-11C-labelled norepinephrine, octopamine, norphenylephrine and phenylethanolamine using [11C]nitromethane.
A new and simple method for the selective condensation of no-carrier-added [11C]nitromethane (1) with various substituted (protected) benzaldehydes to [beta-11C]beta-nitrophenethyl alcohols was developed. This method which utilizes tetrabutylammonium fluoride in THF as a catalyst gave a condensation yield of 80-90% and a selectivity of 80-90% for [11C]nitroalcohol vs [11C]nitrostyrene formation within 2 min. Reduction of these [11C]nitroalcohols with Raney nickel in formic acid gave the corresponding [11C]aminoalcohols in a yield of 60-90%. Boron tribromide was used for the cleavage of 4-methoxy and 3,4-(methylenedioxy) phenol protecting groups. After HPLC-purification, racemic 1-11C-labelled norepinephrine (7), phenylethanolamine (4), norphenylephrine (5) and octopamine (6) were prepared in a 12-30% decay corrected total radiochemical yield (20-50% counted from 1) with an overall synthesis time of 40-70 min from end of bombardment (EOB). The radiochemical purity was > 98% and the specific radioactivity 700-1500 Ci/mmol (26-56 GBq/mumol).
2-Hydroxyphenethylamine↗
Fluorine-18-labelled NCQ 115, a selective dopamine D-2 receptor ligand. Preparation and positron emission tomography.
NCQ 115 ((+)-(R)-5-bromo-N-((1-(4-fluorobenzyl)-2-pyrrolidinyl)methyl)-2, 3-dimethoxybenzamide) is a selective dopamine D-2 receptor antagonist. NCQ 115 has a fluorine in a synthetically suitable position in the parent compound and was therefore suggested as a potential 18F-labelled radioligand for positron emission tomography (PET). [18F]4-Fluorobenzyl iodide was prepared in a 3-step synthesis from [18F]fluoride. N-4-Fluorobenzylation of the corresponding secondary pyrrolidine precursor was performed in DMF followed by purification with semi-preparative HPLC. The total radiochemical yield (EOB and decay-corrected) was 15-20% with a total synthesis time of 90 min and a radiochemical purity > 99%. The specific radioactivity at the end of synthesis (EOS) was about 1500 Ci/mmol (55.5 GBq/mumol). [18F]NCQ 115 was injected into a Cynomolgus monkey for PET examination of brain in vivo. There was a conspicuous uptake of radioactivity in the monkey striatum. A specific [18F]NCQ 115 binding reached a peak after about 60 min which indicates equilibrium.
Animals↗