Biomedical subjects

C Halldin

Publications and source records attributed to C Halldin.

At least 145 records · Page 8Linked to original sources

PubMed1995

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↗

PubMed1994

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↗

PubMed1994

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↗

PubMed1994

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↗

PubMed1994

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↗

PubMed1994

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↗

PubMed1994

PET studies of the uptake of (S)- and (R)-[11C]nicotine in the human brain: difficulties in visualizing specific receptor binding in vivo.

(S)- and (R)-[11C]nicotine were synthesized by methylation of (S)- and (R)-nornicotine using [11C]methyl iodide. Following their intravenous injection in tracer doses to smoking and nonsmoking healthy males the radioactivity in arterial blood showed a sharp peak at about 1 min followed by a plateau level for the remaining 50 min of recording. Uptake in the brain, as measured by positron emission tomography (PET), was rapid with a peak at 5 min followed by a steady decline towards the end of the measurement. The regional distribution of radioactivity followed essentially the distribution of gray matter with high uptake in the cortex, the thalamus and the basal ganglia and low uptake in the pons, cerebellum and white matter. Levels of the labelled natural enantiomer, (S)-[11C]nicotine, were higher than those of the synthetic enantiomer, (R)-[11C]nicotine, particularly in the smokers. The time-activity curves of (S)-[11C]nicotine uptake were not changed by co-administration of 1.0 mg of unlabelled nicotine with the labelled nicotine. Similarly administration of unlabelled nicotine at the peak of radioactivity, 6 min following (S)-[11C]nicotine, had no effect on the time-activity curves. Thus essential criteria for visualizing receptor binding with the PET technique could not be fulfilled. Calculation of kinetic constants using a two-compartment model gave values indicating that the brain uptake of [11C]nicotine is mainly determined by the cerebral blood flow, extraction of the tracer over the blood-brain barrier and unspecific binding. Thus 11C-labelled nicotine does not seem to be a suitable tracer for PET studies of nicotinic cholinergic receptors in the human brain.

Adult↗

PubMed1994

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↗

PubMed1994

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↗

PubMed1994

Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain.

Densities and distribution of D1-dopamine and D2-dopamine receptors were investigated in vitro using [3H]SCH 23390 and [3H]raclopride in receptor binding assays and autoradiography on human post mortem whole hemisphere slices to serve as anatomical correlates to PET studies using [11C]SCH 23390 and [11C]raclopride. In addition, the levels of dopamine and its metabolites were determined by HPLC in various brain regions. Both dopamine receptor subtypes, as well as dopamine, HVA and DOPAC, were primarily found in the basal ganglia. Very high densities of D1-dopamine receptors were found particularly in the medial caudate nucleus, whereas D2-dopamine receptors were evenly distributed throughout the caudate. The densities of D1- and D2-dopamine receptors were similar in the caudate nucleus and the putamen, whereas there were 4 to 7 times higher densities of the D1- than of the D2-dopamine receptors in several limbic and neocortical regions. The receptor distribution in the autoradiographic study was consistent with that demonstrated in the living human brain using [11C]SCH 23390 and [11C]raclopride.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Regional cerebral oxidative and total glucose consumption during rest and activation studied with positron emission tomography.

The relationship between regional oxidative and total rCMRglc in five healthy volunteers in activated and non-activated areas of the brain has been investigated with positron emission tomography (PET). The tracers [1-11C]-D-glucose and [2-18F]2-fluoro-2-deoxy-D-glucose were used. A previous study has shown that the former may be used to measure the rate of glucose oxidation while the latter tracer is used to measure the total rate of glucose consumption. Regional activation was performed (voluntary finger movements). Use of a computerized brain atlas enabled comparison between the regional oxidative and total rCMRglc in each volume element of the brain for the group of subjects. The values of total and oxidative rCMRglc, when calculated for each volume element of the brain and displayed in a scatter plot, were found to be symmetrically grouped around a straight line which passes close to the origin. The slope of this line varied between the subjects. This indicates that, on the average, the fraction of non-oxidative glucose utilization is constant within each subject, regardless of the value of rCMRglc and, further, that the fraction of non-oxidative glucose utilization varies between subjects. The total and oxidative CMRglc in the activated left hand area were 23.4 +/- 0.9% (mean +/- SEM) and 11.7 +/- 0.3%, respectively, higher than in the contralateral homologous non-activated area. Our interpretation of the difference is that regional activation increases the fraction of non-oxidative glucose consumption. This interpretation is supported by a previous PET study using [15O]O2, and by studies using MRS technique.

Adult↗

PubMed1994

D1-, D2-, and 5-HT2-receptor occupancy in clozapine-treated patients.

Positron emission tomography (PET) and selective radioligands were used to determine central D1- and D2-dopamine- and 5-HT2-receptor occupancy in clozapine-treated patients with schizophrenia. In 16 patients, the mean D2-receptor occupancy was 47% (range, 20%-67%), which is lower than that previously demonstrated in patients treated with classical neuroleptics (range, 70%-89%). In 11 patients, the mean D1-receptor occupancy was 44% (range, 33%-59%), which is high when compared with that for classical neuroleptics. In a group of 5 patients, including some treated with low doses of clozapine, the mean 5-HT2-receptor occupancy was a high 89% (range, 84%-94%). By comparison to classical neuroleptics, clozapine is atypical with regard to central binding characteristics in the brain of treated patients.

Adult↗

PubMed1993

Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients.

The relationship between central D2-dopamine receptor occupancy and antipsychotic drug effects was examined in a double-blind study. Raclopride was the compound used to induce a selective occupancy of the D2-dopamine receptors. In addition, 11C-labeled raclopride was the radioligand used to measure occupancy by positron emission tomography (PET). Seventeen schizophrenic patients were randomly assigned to one of three parallel groups treated for 4 weeks with daily doses of 2, 6, or 12 mg of raclopride. D2-receptor occupancy was determined by PET at steady-state conditions in 13 patients who completed the study. A statistically significant relationship was demonstrated between antipsychotic effect and degree of D2-receptor occupancy (p < 0.05). Patients with extrapyramidal side effects had significantly higher D2-receptor occupancy than those without (p = 0.02). The finding of a relationship between selective occupancy of the D2-dopamine receptors and clinical effects in schizophrenic patients principally provides new support for the dopamine hypothesis of antipsychotic drug action.

Adult↗

PubMed1993

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor.

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D1-dopamine receptor antagonists. Both compounds have been labeled with 11C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D1-dopamine receptors. This striatal uptake was displaced by high doses of the selective D1-antagonist SCH 23390 (2 mg/kg) but not by the 5HT2-antagonist ketanserin (1.5 mg/kg) or the selective D2-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [11C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [11C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24-28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [11C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [11C]NNC 756 the ratio was about 5. This ratio of 5 for [11C]NNC 756 is the highest obtained so far for PET radioligands for the D1-dopamine receptor.

Adult↗

PubMed1993

5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone.

It has been suggested that a combined blockade of 5-HT2 and D2 dopamine receptors may be superior to D2 dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT2 and D2 dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT2 and D2 dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [11C]N-methylspiperone ([11C]NMSP) was used as a radioligand for determination of 5-HT2 receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT2 receptor occupancy about 60%. [11C]raclopride was used as a radioligand for determination of D2 dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT2 receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT2 receptor occupancy should be very high at the dose level of 4-10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT2 and D2 dopamine receptor blockade in the treatment of schizophrenia.

Adult↗

PubMed1993

High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET.

The clinical benefit of the atypical antipsychotic drug clozapine may be related to a combined effect on D2 and 5-HT2 receptors. To examine the basis for this hypothesis, positron emission tomography (PET) and the radioligand [11C]N-methylspiperone were used to determine cortical 5-HT2 receptor occupancy in three psychotic patients treated with 125 mg, 175mg and 200mg clozapine daily. The uptake of [11C]N-methylspiperone in the frontal cortex was very low compared to that in neuroleptic naive schizophrenic patients. 5-HT2 receptor occupancy calculated in the clozapine treated patients was 84%, 87% and 90%. The results show that clinical treatment with clozapine induces a high 5-HT2 receptor occupancy in psychotic patients at a low dose level.

Adult↗

PubMed1993

PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls.

Benzodiazepine (BZ) receptor binding in the brain was determined in five chronic alcohol-dependent men and in five healthy male control subjects using [11C]flumazenil (Ro 15-1788) and positron emission tomography (PET). Magnetic resonance imaging was used to evaluate brain anatomy and pathology, and to define regions of interest in the brain. [11C]Flumazenil binding was quantified by applying a saturation procedure with two PET experiments, the first with high (400-3400 Ci/mmol) and the second with low (approximately 1 Ci/mmol) specific radioactivity. Radioactivity in the pons was taken as an estimate of free and nonspecifically bound radioligand. Equilibrium was defined to prevail when the derivative of specific binding (dCb(t)/dt) was equal to zero. The values were used in a Scatchard analysis for determination of the maximum density of binding sites (Bmax) and the equilibrium binding constant (Kd). The mean values of Bmax and Kd were about the same in the two groups, but the Bmax variance for the alcoholics was significantly greater for all regions of interest as compared with the healthy volunteers. The results may indicate that chronic alcohol consumption has multiple effects on the BZ receptor complex.

Adult↗

PubMed1993

Preparation of [1-11C]dopamine, [1-11C]p-tyramine and [1-11C]m-tyramine. Autoradiography and PET examination of [1-11C]dopamine in primates.

A method for no-carrier-added 1-11C-labelling of 3-hydroxy-, 4-hydroxy- and 3,4-dihydroxy-substituted phenethylamines is described. [11C]Dopamine, [11C]p-tyramine and [11C]m-tyramine were prepared from on-line produced [11C]nitromethane. Condensation of [11C]nitromethane with various protected and unprotected benzaldehydes was investigated. A one-pot two-step reduction of the substituted 11C-labelled nitrostyrene intermediates, gave after hydrolysis and reversed-phase semi-preparative HPLC-purification the corresponding labelled amines in a total radiochemical yield of 8-20% (based on [11C]CO2 and decay-corrected). The total synthesis time was 45-50 min with a specific radioactivity of 400-1000 Ci/mmol (15-37 GBq/mumol). The radiochemical purity was higher than 98% [11C]Dopamine was used for in vitro autoradiography on human post-mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. Autoradiographic examination of [11C]dopamine binding on human brain section post-mortem demonstrated specific binding in the caudate putamen and the substantia nigra, regions with a dense dopaminergic innervation. Some binding was also seen in the globus pallidum, nucleus ventralis of the thalamus and in nucleus dentatus of the cerebellum, regions where the dopaminergic innervation is very low. In PET examinations of [11C]dopamine binding in Cynomolgus monkeys there was a high uptake of radioactivity in the pituitary, the kidneys and the heart. Any passage of [11C]dopamine across the blood-brain barrier could not be demonstrated. In human PET studies [11C]dopamine has potential as a radioligand for examination of the myocardium, pituitary and kidneys.

Animals↗