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Biomedical subjects

L Farde

Publications and source records attributed to L Farde.

At least 73 records · Page 4Linked to original sources
PubMed1998

Plasma prolactin and central D2 receptor occupancy in antipsychotic drug-treated patients.

Previous studies of the relationship between plasma prolactin and clinical effects in patients treated with antipsychotic drugs have yielded inconsistent results. A possible explanation may be that most studies have not included subtherapeutic or low doses of antipsychotics. In this exploratory, double-blind study, the relationship between plasma prolactin concentration and central D2 receptor occupancy was examined in 13 schizophrenic patients treated with the experimental antipsychotic drug raclopride (2, 6, or 12 mg daily). D2 receptor occupancy was determined by positron emission tomography and was related to antipsychotic effect as measured by the Brief Psychiatric Rating Scale. Plasma prolactin concentration was increased in eight of nine patients with a D2 receptor occupancy greater than 50%, whereas it was normal among patients with a D2 receptor occupancy less than 50% (p < 0.01). Plasma prolactin concentration measured 4 hours after the morning dose of raclopride correlated significantly with plasma raclopride concentration (r = 0.92, p < 0.01), the degree of D2 receptor occupancy (r = 0.81,p < 0.01), and the antipsychotic effect (r = 0.79, p < 0.01). Further controlled studies that include low doses of antipsychotic drugs may warrant a reconciliation of plasma prolactin as a useful tool in clinical monitoring of antipsychotic drug treatment.

Adult↗
PubMed1998

Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain.

Selective 5-hydroxytryptamine-2A (5-HT2A) antagonism has been proposed as a mechanism of atypical antipsychotic drug action. MDL 100,907, a new selective 5-HT2A receptor antagonist, has high affinity in vitro for 5-HT2A receptors and is being developed as a potential antipsychotic drug. In this study, neocortical 5-HT2A receptor occupancy was measured in six healthy male volunteers after placebo and escalating single doses (1-72 mg) of MDL 100,907 using positron emission tomography and the nonspecific radioligand [11C]N-methylspiperone ([11C]NMSP). Receptor occupancy was calculated using a ratio-equilibrium analysis, assuming that maximal radioligand binding inhibition represents 100% 5-HT2A receptor occupancy. Plasma concentrations of MDL 100,907 were measured with high-pressure liquid chromatography. The pharmacokinetic parameters area under the curve and peak plasma concentration increased linearly with dose, with rapid absorption and a 6- to 9-hour elimination half-life. The neocortical binding of [11C]NMSP was inhibited dose-dependently. After administration of 6 mg of MDL 100,907 the inhibition was 70%, corresponding to a 5-HT2A receptor occupancy of 90%. The calculated maximal inhibition was 77%. These observations indicate that MDL 100,907 passes the blood-brain barrier and binds to 5-HT2A receptors in a saturable manner in the living human brain. Repeated doses of MDL 100,907, 10 mg/day or more, should induce a sustained 5-HT2A receptor occupancy in most patients. Thus, MDL 100,907 provides a suitable tool to evaluate the potential of selective 5-HT2A receptor antagonism in the treatment of schizophrenia.

Binding, Competitive↗
PubMed1998

Implications of brain imaging for the management of schizophrenia.

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

Antipsychotic Agents↗
PubMed1998

PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907.

UNLABELLED: Serotonergic 5-HT2A receptors are of central interest in the complex pathophysiology of schizophrenia. These receptors have also been proposed as putative targets for atypical antipsychotic drugs. Suitable radioligands for 5-HT2A receptors are required to evaluate this hypothesis in vivo with PET. MDL 100,907 is a highly selective 5-HT2A receptor antagonist that is currently being developed as a potential antipsychotic drug. We have previously reported on the preparation of [11C]MDL 100,907 and initial characterization of [11C]MDL 100,907 binding in the monkey brain. In this preliminary PET study, the regional distribution and binding kinetics of [11C]MDL 100,907 were examined in healthy men. METHODS: A PET examination was performed in each of three subjects after intravenous injection of [11C]MDL 100,907. The metabolite-corrected arterial input function was used in a kinetic analysis according to the standard three-compartment model. RESULTS: The highest radioactivity concentration was observed in the neocortex, whereas radioactivity was lower in the cerebellum, pons, thalamus, striatum and white matter. The binding potential (BP) in the neocortical regions was 4-6 times higher, whereas BP in the striatum was slightly higher than that in the cerebellum, demonstrating a regional distribution in good agreement with 5-HT2A receptor densities measured in vitro. The BP in the cerebellum was small but not negligible. CONCLUSION: This preliminary study suggests that [11C]MDL 100,907 is a suitable PET radioligand for studies on 5-HT2A receptors in man. The high selectivity of MDL 100,907 represents a major advantage as compared to presently available radioligands with poor selectivity. Thus, [11C]MDL 100,907 is recommended in the future for PET studies in healthy subjects and schizophrenic patients, including the determination of drug-induced 5-HT2A receptor occupancy.

Adult↗
PubMed1998

Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man.

UNLABELLED: The serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor subtype is of central interest in research on the pathophysiology and treatment of psychiatric disorders. Carbonyl-11 C-WAY-100635 is a new radioligand that, in PET experiments, provides high-contrast delineation of brain regions that are rich in 5-HT1A receptors. The aim of this PET study was to examine the prospects for quantitation of carbonyl-11C-WAY-100635 binding to 5-HT1A receptors in the human brain. METHODS: A PET examination was performed in each of six healthy male subjects after intravenous injection of carbonyl-11C-WAY-100635. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. The metabolite-corrected arterial input function was used in a kinetic three-compartment analysis, and the cerebellum was used as reference region in linear graphical and transient equilibrium analyses. RESULTS: The highest radioactivity concentration was observed in the neocortex and the raphe nuclei, whereas radioactivity was low in the cerebellum. The time-activity curves were well-described by a three-compartment model for all regions. Uptake in the cerebellum could not be described by a two-compartment model. The transient equilibrium and linear graphical analyses, which are both dependent on the cerebellum as the reference region, gave lower binding potential values than did the kinetic analysis. The metabolism was rapid, and the fraction of unchanged carbonyl-11C-WAY-100635 was <10% 10 min after injection in all human subjects. The major radioactive metabolites were unidentified polar components. One metabolite comigrated with reference cyclohexanecarboxylic acid, and another comigrated with reference desmethyl-WAY-100635. CONCLUSION: The suitability of carbonyl-11C-WAY-100635 for research on central 5-HT1A receptors in neuropsychiatric disorders was supported by the observation that the high signals in the neocortex and raphe nuclei can be described using a kinetic analysis with a metabolite-corrected arterial input function. It cannot be excluded that kinetically distinguishable nonspecific binding or the formation of a metabolite that passes the blood-brain barrier may represent measurable components of the low radioactivity in the cerebellum. Simplified quantitative methods, using the relatively low radioactivity in the cerebellum as reference, should accordingly be applied with some caution until the biochemical nature of the radioactivity is better understood and the reliability of these approaches has been confirmed in larger samples.

Adult↗
PubMed1998

Carbon-11-NNC 112: a radioligand for PET examination of striatal and neocortical D1-dopamine receptors.

UNLABELLED: The aim of this work was to explore the potential of a selective D1-dopamine receptor antagonist as a new radioligand for PET examination of striatal and neocortical D1-dopamine receptors. METHODS: The active (+)- and inactive (-)-enantiomers of [11C]NNC 112 were radiolabeled using the N-methylation approach and were examined by PET in cynomolgus monkeys and healthy men. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). RESULTS: N-methylation of the corresponding desmethyl precursors with [11C]methyl triflate gave high total radiochemical yield (50%-60%) and specific radioactivity (110 GBq/micromol). (+)-[11C]NNC 112 binding in cynomolgus monkeys was 5.77+/-0.31 and 2.36+/-0.14 times higher in the striatum and neocortex, respectively, than in the cerebellum at a transient equilibrium that appeared 40-50 min after injection. The binding of (+)-[11C]NNC 112 is stereoselective, because the brain distribution of the inactive (-)-enantiomer was on an equally low level for all brain regions. Displacement and pretreatment experiments using unlabeled SCH 23390 and ketanserin confirms that (+)-[11C]NNC 112 binds specifically and reversibly to D1-dopamine receptors. The radioactivity ratios of the striatum, frontal cortex and nucleus accumbens to the cerebellum were 3.8-4.0, 1.7-2.0 and 2.8-3.1, respectively, at a transient equilibrium that appeared 40-50 min after injection in four healthy human subjects. Linear graphical analysis gave distribution volume ratios of 3.9 and 1.5 in the putamen and frontal cortex, respectively. The fraction of the total radioactivity in human plasma representing unchanged (+)-[11C]NNC 112 was 85% at 5 min and 25% at 75 min after injection. CONCLUSION: (+)-[11C]NNC 112 should be a useful PET radioligand for quantitative examination of not only striatal but neocortical D1-dopamine receptors in man.

Adult↗
PubMed1997

Brain imaging of schizophrenia--the dopamine hypothesis.

The dopamine hypothesis of schizophrenia was formulated 30 years ago and postulates that the symptoms of schizophrenia are related to an increased central dopaminergic neurotransmission. The two fundamental assumptions that underlay the dopamine hypothesis of schizophrenia have received support from brain imaging studies on the dopamine system. There is a high occupancy of central D2-dopamine receptors in patients that are treated with clinically effective doses of classical antipsychotic drugs and recent studies indicate an abnormal function of the presynaptic dopaminergic neuron. Early reports of elevated postsynaptic D2-dopamine receptors in schizophrenic brains post mortem have, however, not been consistently confirmed by brain imaging studies of young neuroleptic-naïve patients with schizophrenia. Suitable methods are now being developed for brain imaging of the dopamine system in the limbic and neocortical regions that are of central interest in schizophrenia research.

Amphetamines↗
PubMed1997

Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635.

The distribution of 5-HT1A receptors was examined in the post-mortem human brain using whole hemisphere autoradiography and the selective 5-HT1A receptor antagonist [3H]WAY-100635 ([O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride). The autoradiograms showed very dense binding to hippocampus, raphe nuclei and neocortex. The labeling in neocortex was slightly lower than in the hippocampus and was mainly at superficial layers, although a faintly labeled band could be seen in deeper neocortical layers. Other regions, such as the amygdala, septum and claustrum, showed low densities caudatus and putamen, in cerebellum or in structures of the brain stem except in the raphe nuclei. The labeling of human 5-HT1A receptors with [3H]WAY-100635 was antagonised by the addition of 5-HT1A receptor ligands, 5-HT, buspirone, pindolol or 8-OH-DPAT (10 microM), leaving a very low background of non-specific binding. Saturation analysis of semiquantitative data from several human regions indicated that [3H]WAY-100635 has a Kd of approximately 2.5 nM. The selective labeling of 5-HT1A receptors with [3H]WAY-100635 clearly show that this compound is useful for further studies of the human 5-HT1a receptor subtype in vitro [11C]WAY-100635 is used for the characterization of 5-HT1A receptors with positron emission tomography (PET). WAY-100635 was also radiolabeled with the short-lived positron-emitting radionuclide carbon-11 (t1/2 = 20 min) and used for in vitro autoradiography on human whole hemisphere cryosections. [11C]WAY-100635 gave images qualitatively similar to those of [3H]WAY-100635, although with a lower resolution. Thus, the hippocampal formation was densely labeled, with lower density in the neocortex. Buspirone, pindolol or 8-OH-DPAT (10 microM), blocked all binding of [11C]WAY-100635. The in vitro autoradiography of the distribution of 5-HT1A receptors obtained with radiolabeled WAY-100635 provide detailed qualitative and quantitative information on the distribution of 5-HT1A-receptors in the human brain. Moreover, the studies give reference information for the interpretation of previous initial results at much lower resolution in humans with PET and [11C]Way-100635. These data provide a strong basis for expecting [11C]WAY-100635 to behave as a highly selective radioligand in vivo.

Autoradiography↗
PubMed1997

Delayed normalization of central D2 dopamine receptor availability after discontinuation of haloperidol decanoate. Preliminary findings.

BACKGROUND: Antipsychotic drugs in depot formulations may prevent psychotic relapses, even after complete withdrawal. To examine the duration of drug remaining in the brain, central D2 dopamine receptor occupancy was measured with positron emission tomography for a year after discontinuation of depot neuroleptic treatment. METHODS: Four schizophrenic patients were withdrawn from low-dose treatment with haloperidol decanoate (30-50 mg every 4 weeks). They were examined repeatedly with positron emission tomography and the radioligand carbon 11-labeled raclopride during the following year. At end point, a Scatchard analysis was performed to determine the density and affinity of D2 dopamine receptors. RESULTS: Occupancy of D2 dopamine receptors was highest 1 week after depot injection (66%, 77%, 82%, and 78% in 4 patients) and then decreased slowly. Six months after discontinuation of treatment, D2 dopamine receptor occupancy was 24%, 32%, and 34% in 3 patients. After 1 year, D2 dopamine receptor density and affinity in 2 patients were within the ranges of control subjects, suggesting no remaining haloperidol. CONCLUSIONS: Our preliminary finding of persistence of D2 dopamine receptor occupancy indicates that commonly used doses of haloperidol decanoate (200 mg every 4 weeks) maintain antipsychotic levels of receptor occupancy even 16 weeks after discontinuation of treatment. This may explain the lower relapse rates in patients withdrawn from depot neuroleptic treatment compared with those withdrawn from oral treatment. In addition, the remaining occupancy may confound the clinical evaluation of subsequent treatments. For controlled clinical trials of new antipsychotic drugs, we suggest a minimum washout of 6 months after the last depot injection.

Adult↗
PubMed1997

Effect of reserpine-induced depletion of synaptic dopamine on [11C]raclopride binding to D2-dopamine receptors in the monkey brain.

Positron emission tomography was used to examine the in vivo binding of [11C]raclopride to D2-dopamine (DA) receptors in the striatum of two Cynomolgus monkeys after a single dose of reserpine (1 mg/kg, i.v.). A Scatchard procedure was repeated five times to follow D2 receptor density and apparent affinity for 7 weeks after reserpine. Reserpine-induced depletion of DA lead to a marked increase in [11C]raclopride binding, which was still detectable 20 days after treatment. Scatchard analyses indicated that the measured increase in [11C]raclopride binding reflected an increase in receptor affinity but no evident change in receptor density (Bmax). Thus, the increase in [11C]raclopride binding after reserpine should correspond to a reduced competition with endogenous DA for binding to D2 receptors. The results were used to estimate the DA-induced D2 occupancy to be about 40% at physiological conditions.

Animals↗
PubMed1997

In vitro and in vivo characterisation of nor-beta-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain.

Radiolabelled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) has been used in clinical studies for the imaging of dopamine and serotonin transporters with single-photon emission tomography (SPET). 2beta-Carbomethoxy-3beta-(4-iodophenyl)nortropane (nor-beta-CIT) is a des-methyl analogue of beta-CIT, which in vitro has tenfold higher affinity (IC50=0.36 nM) to the serotonin transporter than beta-CIT (IC50=4.2 nM). Nor-beta-CIT may thus be a useful radioligand for imaging of the serotonin transporter. In the present study iodine-125 and carbon-11 labelled nor-beta-CIT were prepared for in vitro autoradiographic studies on post-mortem human brain cryosections and for in vivo positron emission tomography (PET) studies in Cynomolgus monkeys. Whole hemisphere autoradiography with [125I]nor-beta-CIT demonstrated high binding in the striatum, the thalamus and cortical regions of the human brain. Addition of a high concentration (1 microM) of citalopram inhibited binding in the thalamus and the neocortex, but not in the striatum. In PET studies with [11C]nor-beta-CIT there was rapid uptake of radioactivity in the monkey brain (6% of injected dose at 15 min) and high accumulation of radioactivity in the striatum, thalamus and neocortex. Thalamus to cerebellum and cortex to cerebellum ratios were 2.5 and 1.8 at 60 min, respectively. The ratios obtained with [11C]nor-beta-CIT were 20%-40% higher than those previously obtained with [11C]beta-CIT. Radioactivity in the thalamus and the neocortex but not in the striatum was displaceable with citalopram (5 mg/kg). In conclusion, nor-beta-CIT binds to the serotonin transporter in the primate brain in vitro and in vivo and has potential for PET and SPET imaging of the serotonin transporter in human brain.

Animals↗
PubMed1997

Central 5-HT2A and D2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men.

It has been suggested that a combined blockade of 5-HT2A and D2-dopamine receptors improves efficacy and reduces the risk for extrapyramidal symptoms when treating schizophrenic patients with antipsychotic drugs. ORG 5222 is a new potential antipsychotic drug which has high affinity for 5-HT2A, D2-dopamine and alpha 1 adrenergic receptors in vitro. The objective of this study was to examine if ORG 5222 occupies 5-HT2A and D2-dopamine receptors in human subjects in vivo. Central receptor occupancy was measured by positron emission tomography (PET) in three healthy subjects after sublingual administration of 100 micrograms ORG 5222. [11C]N-methylspiperone ([11C] NMSP) was the radioligand used to measure 5-HT2A receptor binding in the neocortex and [11C]raclopride to measure D2-dopamine receptor binding in the striatum. The 5-HT2A occupancy was 15-30% and the D2-dopamine receptor occupancy was 12-23%. The study confirms that ORG 5222 binds to 5-HT2A and D2-dopamine receptors in human brain. Since receptor occupancy of ORG 5222 is rather low, doses higher than 100 micrograms are suggested in future clinical trials to evaluate the antipsychotic drug effect of ORG 5222.

Administration, Sublingual↗
PubMed1997

PET-characterization of [carbonyl-11C]WAY-100635 binding to 5-HT1A receptors in the primate brain.

[carbonyl-11C]WAY-100635 is a new radioligand which can be used with positron emission tomography (PET) to provide high contrast delineation of human brain regions that are rich in 5-HT1A receptors. In the present PET study, the binding of [carbonyl-11C]WAY-100635 was characterized in the cynomolgus monkey brain. Pretreatment with each of the two reference compounds, WAY-100635 and 8-OH-DPAT, as well as the drugs buspirone and pindolo, induced a marked inhibition of [carbonyl-11C]WAY-100635 binding in the neocortex and the raphe nuclei. A preliminary Scatchard analysis yielded 5-HT1A receptor density values of the same order as those that have been reported in vitro. The study shows that [carbonyl-11C]WAY-100635 binds specifically to 5-HT1A receptors in the primate brain and has potential for determination of 5-HT1A receptor occupancy and density in psychiatric patients.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

A PET-study of [11C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients.

We recently developed [11C]FLB 457 a substituted benzamide with the very high affinity of 20 pM for D2-dopamine receptors in vitro. The aim of the present exploratory study was to examine the anatomical distribution of [11C]FLB 457 binding in the human brain and to determine extrastriatal D2-receptor occupancy in antipsychotic drug-treated patients. [11C]raclopride was used to obtain reference values for D2-dopamine receptor occupancy in the putamen. After IV injection of [11C]FLB 457 there was a high concentration of radioactivity, not only in the caudate putamen but also in the thalamus and the temporal cortex. The concentration of radioactivity in the frontal cortex, the substantia nigra and the colliculi was slightly higher than in the cerebellum. Pretreatment with haloperidol and fluphenazine indicated that [11C]FLB 457 binding in extrastriatal regions to a high degree represent specific binding to D2-dopamine receptors. The D2-occupancy in antipsychotic drug-treated patients was on the same level in the thalamus and the temporal cortex as that determined with [11C]raclopride in the putamen. The study shows that [11C]FLB 457 has potential for quantitative PET-examination of D2-dopamine receptors in man.

Adult↗
PubMed1997

Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography.

NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared 76Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [11C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [76Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [76Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage.

Animals↗
PubMed1997

A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects.

Olanzapine is a new antipsychotic drug with affinity for 5-HT2, D2, D1, and muscarinic receptors. Positron emission tomography and the radioligands [11C]raclopride and [11C]NMSP were used to measure D2 and 5-HT2 receptor occupancy in three healthy subjects after 10 mg olanzapine orally. After seven hours D2 receptor occupancy was 63%, 62% and 59%, respectively. After 9.5 hours 5-HT2 receptor occupancy was 74%, 86% and 92%. D2 and 5-HT2 receptor occupancy was comparable to that found in patients continuously treated with clozapine. Clinical efficacy has been demonstrated for olanzapine in the dose range 5 to 15 mg per day. Extrapolation from our present observations after a 10 mg single-dose suggest, that at the lower end of the clinically examined dose range the D2 and 5-HT2 receptor occupancy should be similar to that induced by standard doses of clozapine. Detailed evaluation of the dose-response characteristics of olanzapine and direct clinical comparison to clozapine will thus provide valuable leads to the clarification of atypical antipsychotic action.

Adult↗