GABA receptor occupancy by subtype selective GABA modulators: PET studies in humans.

Rationale: Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABA receptor positive modulators with limited sedative effects.

Objectives: The current study aimed to confirm target engagement at GABA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABA receptor occupancy, and tolerability.

["Active health management" can provide support for vulnerable patients. New model for the prevention of unplanned healthcare].

A small group of frequent emergency department visitors account for a disproportionally large fraction of health care consumption, including unplanned hospitalizations and overall healthcare costs. In response, case and disease management programs aimed at reducing health care consumption in this group have been tested, however results vary widely. In this study, we aimed to investigate if a telephone-based, nurse led case management intervention can reduce health care consumption for frequent emergency department visitors in a large-scale set-up.

A case management intervention targeted to reduce healthcare consumption for frequent Emergency Department visitors: results from an adaptive randomized trial.

Background: A small group of frequent visitors to Emergency Departments accounts for a disproportionally large fraction of healthcare consumption including unplanned hospitalizations and overall healthcare costs. In response, several case and disease management programs aimed at reducing healthcare consumption in this group have been tested; however, results vary widely.

Objectives: To investigate whether a telephone-based, nurse-led case management intervention can reduce healthcare consumption for frequent Emergency Department visitors in a large-scale setup.

Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR.

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET).

A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 - estimating occupancy in the absence of a reference region.

AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [(11)C]-ABP688.

Pharmacokinetic profile of the extended-release formulation of quetiapine fumarate (quetiapine XR): clinical implications.

Objectives: A series of studies were conducted to guide the development and characterise the pharmacokinetics of extended-release quetiapine fumarate (quetiapine XR), a once-daily formulation to control the release of the drug.

Methods: Data from these studies are described and discussed herein.

Results: Once-daily quetiapine XR produced a similar area under the plasma concentration-time curve (AUC), minimum plasma concentration (Cmin) and a slightly lower maximum plasma concentration (Cmax) than the equivalent dose of immediate-release quetiapine (quetiapine IR) given twice daily.

AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects.

The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO.

Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine.

Quetiapine alleviates both positive and negative symptoms as well as certain cognitive impairments in schizophrenia despite a low D2 receptor occupancy and may also be used as monotherapy in bipolar and major depressive disorder. The mechanisms underlying the broad clinical utility of quetiapine remain to be clarified, but may be related to the potent inhibition of the norepinephrine transporter (NET) by norquetiapine, the major metabolite of quetiapine in humans. Since norquetiapine is not formed in rodents we here investigated in rats whether NET-inhibition may, in principle, contribute to the clinical effectiveness of quetiapine and allow for its low D2 receptor occupancy, by combining quetiapine with the selective NET-inhibitor reboxetine.

Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers.

The aim of this work was to develop a model simultaneously estimating (11)C-AZD9272 radioligand kinetics and the relationship between plasma concentration of AZD9272 and receptor occupancy in the human brain. AZD9272 is a new chemical entity pharmacologically characterised as a noncompetitive antagonist at the metabotropic glutamate receptor subtype 5 (mGluR5). Positron emission tomography (PET) was used to measure the time course of ((11)C-AZD9272) in the brain.

Comparison of D₂ dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects.

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation.

Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369.

Rationale: The serotonin 5-HT(1B) receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT(1B) receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT(1B) receptor antagonist with potential antidepressant properties.

Radiosynthesis of the candidate beta-amyloid radioligand [(11)C]AZD2184: Positron emission tomography examination and metabolite analysis in cynomolgus monkeys.

Beta-amyloid accumulation is associated with the pathogenesis of Alzheimer's disease (AD). AZD2184, a new radioligand for high-contrast positron emission tomography (PET) imaging of Abeta-deposits, has recently been developed and characterized in vitro and in rodents ex vivo. The objective of this study was to label AZD2184 with carbon-11, to perform in vivo characterization of [(11)C]AZD2184 ([(11)C]5) in the cynomolgus monkey brain as well as whole-body dosimetry, and to examine the metabolism of the labeled radioligand.

Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain.

A novel radioligand for positron emission tomography (PET) imaging of serotonin 5-HT(1B) receptors, [(11)C]AZ10419369, has been recently described. In this study, the potential for quantitative analysis of [(11)C]AZ10419369 binding to central 5-HT(1B) receptors was evaluated in human subjects. PET measurements were performed after injection of [(11)C]AZ10419369 in 10 subjects.

Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184.

Purpose: Current positron emission tomography (PET) radioligands for detection of Abeta amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [(11)C]AZD2184 and report here the first clinical evaluation.

Methods: Eight AD patients and four younger control subjects underwent 93-min PET measurements with [(11)C]AZD2184.

[11C]AZ10419369: a selective 5-HT1B receptor radioligand suitable for positron emission tomography (PET). Characterization in the primate brain.

The 5-HT1B receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. Here we report the synthesis of a novel PET radioligand, [11C]AZ10419369 (5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide), for in vivo visualization of 5-HT1B receptors in the brains of macaques and humans subjects. [11C]AZ10419369 was prepared by N-methylation of (8-(1-piperazinyl)-5-methylchrom-2-en-4-one-2-(4-morpholinophenyl) carboxamide, using carbon-11 methyl triflate.

Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia.

Thirteen patients with schizophrenia received injections of 25, 50, or 75 mg of long-acting risperidone every 2 wk. Brain D2 receptor occupancy was assessed with [11C]raclopride 2 wk after the last (fifth) injection (day 71) in seven subjects and 2 wk after the third injection (day 44) in one subject. Stable plasma concentrations were reached after the third injection and steady-state concentrations of the active moiety (risperidone + 9-hydroxyrisperidone) after the fourth injection.

Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole.

Rationale: Sertindole is a new atypical antipsychotic drug. Preclinical pharmacology suggests that sertindole has a preferential effect on the activity of limbic and cortical dopaminergic neurons. Clinical trials have shown antipsychotic efficacy and very few extrapyramidal symptoms (EPS) with sertindole at 20 mg/day.

Saturation of striatal D(2) dopamine receptors by clozapine.

Positron emission tomography (PET) studies have demonstrated low striatal D2 dopamine receptor occupancy in clozapine-treated schizophrenic patients. The aim of this pilot study was to explore if this low receptor occupancy indeed represents partial saturability of striatal D2 dopamine receptors by clozapine. Three anaesthetized Cynomolgus monkeys were examined during one day with PET and [11C]raclopride at baseline and after intravenous injections of clozapine 1.

D(2)- and 5-HT(2) receptor occupancy in high-dose neuroleptic-treated patients.

Individual schizophrenic patients are sometimes reported to benefit from unusually high doses of neuroleptics. Such patients may have poor drug penetration into the brain or ultra-rapid metabolism. Alternately, very high doses may be required to induce occupancy of 5-HT(2) receptors, which have been suggested as mediators of atypical effects.