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Biomedical subjects

L Farde

Publications and source records attributed to L Farde.

At least 181 records · Page 10Linked to original sources
PubMed1990

Recent advances in psychiatric brain imaging.

The characterization of neuroreceptor functions in the living human brain has hitherto been hampered by the lack of techniques useful for the measurement of physiologic events within the human brain in vivo. Recent developments in positron emission tomography (PET) has allowed the quantitative tracing of intravenously administered molecules within tissue compartments of the brain. Using ligands binding with high affinity to cerebral neuroreceptors it has been possible to examine not only the distribution but also some quantitative aspects of brain neuroreceptors in living human subjects by the PET technique. By the selection of highly selective ligands for different receptor systems and by labeling them with positron emitting isotopes as 11C or 18F, methods have been developed for the characterization of receptor subtypes for the endogenous ligands dopamine, serotonin, opiates, acetylcholine, glutamate and GABA. The present communication describes the use of 11C-SCH 23390 and 11C-raclopride for the analysis of D1 and D2 dopamine receptors, the benzodiazepine (BZ) antagonist 11C-Ro 15-1788 for benzodiazepine receptors and 11C-nicotine for nicotine receptors. Specificity of binding was verified by using active and inactive stereoenantiomers of the ligands. After the intravenous administration of the ligands quantitative aspects of the receptor binding was calculated using models according to equilibrium or dynamic approaches. Bmax and Kd values for D2 dopamine and BZ receptors could be determined in the brain of healthy human subjects and patients with neuropsychiatric disorders. No alteration of D2 dopamine receptors in the major basal ganglia were found in drug naive schizophrenic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzazepines↗
PubMed1990

Syntheses of [123I]-, [125I]- and unlabelled (S)-3-iodo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]salicylamide (NCQ 298), selective ligands for the study of dopamine D-2 receptors.

The salicylamide NCQ 298, (S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylami de (4), binds with a high affinity and selectivity to central dopamine D-2 receptors. In the present paper the synthesis of NCQ 298 and the efficient labelling both with 123I and 125I are described. The unlabelled NCQ 298 was synthesized by iodination of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,5,6-trimethoxybenzamide followed by demethylation with boron tribromide, which produced 4 and the regioisomer 5 in a ratio of 82:18. The two isomeric salicylamides were separated by radial chromatography and tested for their abilities to inhibit the binding of [3H]raclopride to rat striatal membranes in vitro in relation to some representative salicylamides. The 5,6-dimethoxysalicylamide 4 (NCQ 298) was found to be considerably more active than the corresponding 6-methoxysalicylamide 10 (FLA 961 or IBZM). The radioligands [123I]NCQ 298 and [125I]NCQ 298 were prepared in a carrier-free form from the corresponding desiodo compound by the chloramine-T protocol and isolated by semipreparative HPLC. The total radiochemical yields of [123I]NCQ 298 and [125I]NCQ 298 (based on [123I]- and [125I]iodide and decay-corrected) were 88% and 93%, respectively, with a radiochemical purity of greater than 99%. [125I]NCQ 298 will be studied to evaluate its potential as a radioligand in studies requiring a high specific activity, selectivity and high potency to label dopamine D-2 receptors. [123I]NCQ 298 has potential as a radioligand for the in vivo examination of central dopamine D-2 receptors in human brain by Single Photon Emission Computed Tomography (SPECT).

Animals↗
PubMed1989

D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics.

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

Antipsychotic Agents↗
PubMed1989

Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET--a comparison to the equilibrium analysis.

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

Adult↗
PubMed1989

The new selective D2-dopamine receptor antagonist raclopride--pharmacokinetics, safety and tolerability in healthy males.

Raclopride, a new potential antipsychotic drug, with high selectivity and affinity for central D2-dopamine receptors, was in this first human study administered to 8 healthy male volunteers in single oral doses from 0.1 to 16 mg. Two subjects, known to be slow metabolizers of debrisoquine, were also included. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. The maximum plasma concentrations of raclopride (Cmax) and the area under the raclopride curve vs time (AUC) increased proportionally with dose. No deviant kinetic parameters were seen in the slow debrisoquine metabolizers. Only minor deviations in biochemical and physiological safety parameters were found. Raclopride was well tolerated by all subjects at doses up to 8 mg but not at 16 mg because of akathisia. No other extrapyramidal side-effects were recorded. The drug induced a rapid and transient increase of plasma prolactin concentrations.

Administration, Oral↗
PubMed1989

Clinical melperone treatment blocks D2-dopamine receptors in the human brain as determined by PET.

Positron emission tomography and 11-C-labelled raclopride was used to determine central D2-dopamine receptor occupancy in three melperone treated patients. Treatment with melperone in daily doses of 250 and 300 mg for 3 to 6 weeks, resulted in a receptor occupancy above 70%. Thus, clinical doses of melperone as we previously demonstrated for several classical neuroleptics cause a substantial D2-dopamine receptor blockade in the human brain in vivo.

Adult↗
PubMed1988

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs.

Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.

Adult↗
PubMed1988

PET scanning--a new tool in clinical psychopharmacology.

Quantitative methods were developed for the determination of dopamine and benzodiazepine receptor characteristics in the living human brain by positron emission tomography (PET). As ligands, the 11C-labelled analogues of the selective antagonists of dopamine receptor subtypes, SCH 23390 and raclopride, and the benzodiazepine antagonist, Ro 15-1788, were used. Tracer amounts of the ligands were injected intravenously into healthy volunteers and schizophrenic patients. The distribution of ligand indicated high densities of D1 as well as D2 dopamine receptors in the basal ganglia. Binding of [11C]-SCH 23390 was also significant in the neocortex where it was shown to represent binding to D1 as well as to 5-HT2 serotonin receptors. High densities of specific benzodiazepine receptor binding were obtained in most neocortical brain areas and in the cerebellum. Using saturation procedures, Bmax and Kd values could be obtained for D2 and benzodiazepine receptors. A comparison of D2 receptor densities in drug-naive schizophrenic patients and healthy volunteers demonstrated similar receptor characteristics in the major basal ganglia in these groups of subjects. Different chemical classes of conventional and unconventional antipsychotic drugs produced a 65%-85% occupancy of D2 receptors when given in clinical doses to schizophrenic patients. High does of diazepam produced a marked occupancy of benzodiazepine receptors during the first hours after oral administration to healthy volunteers. These in vivo methods should be valuable tools for the further analysis of the effects of drug on neuroreceptors in the living brain of neuropsychiatric patients.

Animals↗
PubMed1988

Remoxipride--a new potential antipsychotic drug. Pharmacological effects and pharmacokinetics following repeated oral administration in male volunteers.

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

Administration, Oral↗
PubMed1988

Stereoselective binding of 11C-raclopride in living human brain--a search for extrastriatal central D2-dopamine receptors by PET.

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

Adult↗
PubMed1988

An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET.

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

Acute Disease↗
PubMed1988

Human dopamine receptor subtypes--in vitro binding analysis using 3H-SCH 23390 and 3H-raclopride.

Affinities and regional densities of the D1- and D2-dopamine receptor subtypes were studied in the human post-mortem brain in vitro using the two selective radioligands 3H-SCH 23390 and 3H-raclopride. 3H-Raclopride binding was confined to the caudate nucleus, the putamen and the substantia nigra, while 3H-SCH 23390 bound to cortical regions as well. The binding of 3H-SCH 23390 was reduced by a low concentration of ketanserin, indicating binding to 5-HT2 receptors in addition to the D1-dopamine receptors. The endogenous neurotransmitter dopamine interacted potently both with the D1-dopamine receptor and the D2-dopamine receptor, displaying two affinity states for each subtype. The distribution of the dopamine receptor subtypes obtained in the present in vitro investigation is in agreement with data obtained with 11C-SCH 23390 and 11C-raclopride in positron emission tomographic studies in human volunteers.

Adult↗
PubMed1988

Raclopride, a new selective ligand for the dopamine-D2 receptors.

1. The use of raclopride, a new compound of the salicylamide series, as a ligand for the labelling of dopamine-D2 receptors in vitro and in vivo is described. 2. 3H-Raclopride has a high affinity for the dopamine-D2 receptors (Kd = 1 nM in rat striatum) with much less affinity for any other receptor. 3. 3H-Raclopride enters the brain easily and has therefore also been used in in vivo binding and autoradiography. The nonspecific binding is very low both in vitro and in vivo. 4. Raclopride has been labelled with 11C, and is used as a marker for dopamine-D2 receptors in the living human brain using positron emission tomography.

Animals↗
PubMed1988

Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum.

Recently, two research groups published numbers for D2 receptor sites in the neostriatum of drug-naive schizophrenic patients, obtained in vivo by positron emission tomography (PET). One study appeared to confirm the increase of D2 receptor numbers, while the other study did not. A workshop was convened in Montreal to examine the reasons for the discrepancy between the results obtained by the two groups. The workshop considered patient populations, PET instrumentation and scanning methods, pharmacology, and modeling. The workshop identified differences between the approaches of the two groups that could contribute to the divergent results, including age and chronicity of the patient samples, brain region selected for study, metabolism of the different radioligands in blood and brain, reversibility of binding, PET instrumentation, and complexity of data analysis. The workshop concluded that these initial efforts had made considerable progress in establishing the role of PET in the understanding of the biochemical processes underlying mental illness. In particular, the unique ability to quantify regional neuroreceptor density at different stages in the evolution of the disease has been implemented. At the same time, the work so far and this conference served to identify the main sources contributing to the different findings from the two centers. This information will be important in designing the next phase of the research which will build upon and reconcile these apparent discrepancies.

Adult↗
PubMed1987

Transplantation in Parkinson's disease: two cases of adrenal medullary grafts to the putamen.

Autologous adrenal medullary tissue was transplanted unilaterally to the putamen in two patients with severe Parkinson's disease. The first patient exhibited a transient, two-day improvement of motor performance in the limbs contralateral to the implantation site. He also had significantly longer episodes of normal function for about two months. The second patient reported a minor improvement of balance and gait, again lasting for two months. Electrophysiological studies of the motor readiness and auditory evoked potentials were consistent with increased catecholaminergic activity in the basal ganglia after transplantation in both patients. Positron emission tomography showed no postoperative alteration of receptor density in the putamen. No significant adverse effects of the transplantation were observed in the patients' performance on neurological and psychological tests or in their quantitative electroencephalogram and cerebral blood flow recordings. Immediately after the grafting, one patient showed transient signs of sympathetic hyperactivity, probably caused by release of catecholamines from the implanted tissue into the peripheral circulation. We conclude that catecholamine-rich cellular implants in the basal ganglia have transient beneficial effects in patients with severe Parkinson's disease.

Adrenal Medulla↗