Biomedical subjects

B Långström

Publications and source records attributed to B Långström.

At least 19 recordsLinked to original sources

PubMed2006

Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine.

The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

Acetylcholinesterase↗

PubMed2006

Determination of metabolic stability of positron emission tomography tracers by LC-MS/MS: an example in WAY-100635 and two analogues.

A method is presented for determination of microsomal metabolic stability of potential positron emission tomography (PET) tracers by LC-MS/MS in the lower nm range. The PET tracers used for the study were the serotonin receptor antagonist WAY-100635 and two potential tracer analogues. The sensitivity permitted the substrates to be directly collected from PET radiolabelling batches, containing very low amounts of substance (0.3-7 microg), for subsequent metabolic stability incubations. Sample preparation was minimal, with addition of internal standard, acetonitrile and a fast centrifugation step, as a result of the low protein concentration of the microsome solutions. Linearity (R2 > or = 0.99), precision (inter-assay R.S.D. < 7%) and accuracy (bias < or = 8%) for the tested concentration range 0.5-5 nM proved to be well within accepted limits. No significant differences in metabolic rates were detected using substrates from cold (non-labelling) chemistry syntheses and PET labelling batches, indicating the validity of using substrates from the latter source. A para-methoxy-benzamide analogue (MeO-WAY) displayed a significantly lower rate of metabolism compared to WAY-100635, whereas a para-iodo-benzamide analogue was more susceptible to metabolic transformation. LC-MS/MS Analysis of formed metabolites from WAY-100635 and MeO-WAY suggested similar metabolic pathways, with hydroxylation, demethylation and dearylation reactions. The main metabolic route in humans, amide hydrolysis, was not observed with the rat liver microsome assay.

Animals↗

PubMed2005

Carbidopa pretreatment improves image interpretation and visualisation of carcinoid tumours with 11C-5-hydroxytryptophan positron emission tomography.

PURPOSE: Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) as tracer is a promising imaging instrument in the management of patients with neuroendocrine tumours (NETs). However, high radioactivity concentrations in the urinary collecting system sometimes produce image reconstruction artefacts that can make detection of small NETs difficult. As a means to decrease urinary excretion of radioactivity and thereby improve image quality, we examined the effect of pretreatment with carbidopa (CD), a peripheral inhibitor of aromatic amino acid decarboxylase (AADC), which converts 5-HTP to serotonin (5-hydroxytryptamine, 5-HT). METHODS: Six patients with midgut carcinoid metastases were examined with 11C-5-HTP PET before and 1 h after oral administration of 100 or 200 mg of CD. RESULTS: There was a fourfold significant reduction of tracer uptake in the urinary collecting system after CD administration (p=0.0277, n=6), with a mean standard uptake value (SUV) of 155+/-195 before CD and 39+/-14 after CD. In tumour lesions there was a significant increase in SUV after CD administration (p<0. 0001, n=18), with a mean SUV of 11+/-3 before CD and 14+/-3 after CD. There was no difference between the doses (100 and 200 mg) of CD in this respect. In all patients, image interpretation and tumour detection were markedly improved after CD administration. CONCLUSION: We conclude that CD premedication improves 11C-5-HTP PET image quality and facilitates detection of NET lesions. Because of the similarity of metabolic pathways, this method could probably be applied to improve PET imaging using other tracers like 18F-DOPA and 11C-DOPA.

5-Hydroxytryptophan↗

PubMed2005

Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer's disease.

In this study 11 patients with mild Alzheimer's disease (AD) were treated with the cholinesterase inhibitor rivastigmine (mean dose 8.6 +/- 1.3'mg) for 12 months and underwent positron emission tomography (PET) studies of cerebral glucose metabolism (CMRglc) and neuropsychological testing at baseline and after 12 months. An untreated group of 10 AD patients served as control group. While the untreated AD patients showed a significant decline of CMRglc in the temporo-parietal and frontal cortical regions after 12 months follow-up the rivastigmine-treated patients showed no decline in CMRglc in corresponding cortical brain regions. Furthermore, a significant dose-related increase in CMRglc was recorded in the right frontal association region after 12 months rivastigmine treatment. A positive correlation was observed between changes in CMRglc and several cognitive tests in patients receiving higher doses (10.5-12'mg) of rivastigmine. These results suggest a stabilization effect of rivastigmine on CMRglc in mild AD patients receiving long-term rivastigmine treatment.

Adult↗

PubMed2005

Developments in PET for the detection of endocrine tumours.

Positron emission tomography (PET) supplies a range of labelled compounds to be used for the characterization of tumour biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow-up, and clinical research. (18)F-fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology, reflecting increased expression of glucose transporters in cancerous tissue. This tracer, however, does not show sufficient uptake in well-differentiated tumours such as neuroendocrine tumours. Endocrine tumours have the unique characteristics of taking up and decarboxylating amine precursors. These so-called APUD characteristics offer highly specific targets for PET tracers. Using this approach, radiopharmaceuticals such as [(11)C]-5-hydroxytryptophan and [(11)C]-L-dihydroxyphenylalanine for localization of carcinoid and endocrine pancreatic tumours, 6-[(18)F]-fluorodopamine and [(11)C]-hydroxyephedrine for phaeochromocytomas, and [(11)C]-metomidate for adrenal cortical tumours have been developed. Functional imaging with PET using these compounds is now being employed to complement rather than replace other imaging modalities. Development of new PET radiopharmaceuticals may in the future allow in vivo detection of tumour biological properties, such as malignant potential and responsiveness to treatment.

Carbon Radioisotopes↗

PubMed2005

Neuroanatomical correlates of voluntary inhibition of accommodation/vergence under monocular open-loop viewing conditions.

The purpose of this work is to identify human neural circuits involved in inhibition of accommodation/vergence by contrasting the cortical functions subservient to negative voluntary accommodation/vergence (NVA) with those evoked by active fixation in darkness (FIX). Five subjects with normal corrected acuity were studied using positron emission tomography and the HO bolus technique. The dominant right eye viewed a laser speckle pattern (633 nm) whose direction and velocity of motion were determined by the refractive state of the eye. The speckle pattern was presented at a distance of 1.8 m (0.55 D). The non-dominant eye was patched. Subjects performed two tasks counterbalanced for order effects: (i) attempted fixation on the remembered target in darkness with the dominant eye open and 'fixating'; and (ii) voluntary reduction of the laser speckle flow during each alternate 20-s epoch when a convex +2.0 D lens was placed in front of the right eye causing the speckle pattern to move downwards at 3 degrees /s. Comparison of the condition of NVA with the condition of FIX indicated widespread occipital activation. Decreases in absolute regional cerebral blood flow occurred in the superior parietal cortex (BA 5), frontal cortex (BA 8 and 10) and within the postcentral/precentral gyrus (BA 1/2/3/4) bilaterally where deactivation clusters eclipsed the presumed neck and shoulder areas. Negative accommodation/vergence appears to be driven by a reduction of parasympathetic tone, and has the effect of shutting down brain regions known to be involved in regulating visual search as well as a centrally controlled eye-head-neck-shoulder motor programme responsible for posturing gaze.

Accommodation, Ocular↗

PubMed2005

Distribution of intranasal C-zolmitriptan assessed by positron emission tomography.

Nine healthy volunteers aged 18-28 years were recruited into this open, single-centre, two-phase trial. In phase 1, two volunteers received a single dose of 11C-zolmitriptan 2.5 mg administered as a nasal spray and then underwent positron emission tomography (PET) scanning to determine the most appropriate times for scanning in phase 2. In phase 2, six volunteers received two doses and an additional volunteer one dose of 11C-zolmitriptan 2.5 mg intranasally. Volunteers underwent PET scanning over sectors covering one of the nasopharynx, lungs or abdomen, for up to 1.5 h postdose. The brain was also scanned and plasma zolmitriptan levels were measured. Almost 100% of the administered dose was detected in the nasopharynx immediately after dosing. This declined thereafter to about 50% at 20 min and to 35% at 80 min after dosing. Radioactivity appeared slowly in the upper abdomen, with 25% of given radioactivity detected at 20 min and persisting until 80 min after dosing. Minimal radioactivity was detected in the lungs. Radioactivity was detectable within brain tissue suggesting central penetration of zolmitriptan. Zolmitriptan in plasma had approached its maximum concentration by 15 min postdose. The data indicate initial absorption across the nasal mucosa contributing to an early systemic availability. 11C-Zolmitriptan administered intranasally was well tolerated.

Administration, Inhalation↗

PubMed2004

Determination of flumazenil in human plasma by liquid chromatography-electrospray ionisation tandem mass spectrometry.

A liquid chromatography-electrospray ionisation-tandem mass spectrometry (LC-ESI-MS/MS) method was developed to determine unlabelled flumazenil (Ro 15-1788) in human plasma in [11C]flumazenil positron emission tomography (PET) studies. N-Methyl tri-deuterated flumazenil was used as an internal standard. The analyte and internal standard were extracted from plasma samples using solid-phase extraction, with a recovery of 78%. This was determined through the convenience of radioactivity measurements of 11C-labelled flumazenil. The evaporated and reconstituted eluate was analysed by LC-ESI-MS/MS. The calibration curve was linear over the tested concentration range of 0.05-0.5 nM (15-150 pg/ml) with a correlation coefficient, R2, of 0.998+/-0.001. A high precision was achieved, with mean intra-assay and inter-assay relative standard deviations of at most 6 and 7%, respectively. The accuracy of the method ranged from 95 to 104%. As a proof of concept, the validated method was applied in the determination of flumazenil in plasma from two healthy volunteers participating in a PET study with three repeated investigations. A bolus-infusion protocol was used to achieve a constant concentration level of flumazenil. The average plasma concentrations ranged from 0.11 and 0.19 nM and all measurements were within the calibration standard range. The flumazenil concentrations were relatively constant within each scan and the average intra-scan precision was 15%.

Chromatography, Liquid↗

PubMed2004

Analysis of microsomal metabolic stability using high-flow-rate extraction coupled to capillary liquid chromatography-mass spectrometry.

A method is described for on-line high-speed extraction of microsomal samples and analysis by capillary liquid chromatography-mass spectrometry (LC-MS) for the determination of metabolic stability in connection with the development of positron emission tomography (PET) tracers. The method allowed direct injections of large sample volumes at a fast extraction rate, providing a gain in both sensitivity and sample preparation time. The calibration curve of the test compound flumazenil (Ro 15-1788) was linear in the concentration range of 1-150 nM, with a correlation coefficient exceeding 0.999. The accuracy of the method ranged from 98 to 101%. A high precision was obtained, with mean intra-assay and inter-assay relative standard deviations of at most 1.4 and 1.5%, respectively, for quality control (QC) samples. The extraction efficiency was determined to be 99.4%, the total recovery 96% and the carryover to <or=0.23%. Extractions were performed in a concentration interval of 30-3000 nM without any sign of column overload. The method was successfully used for determining the microsomal metabolic stability of flumazenil. As a result, the described analysis system is currently used for metabolic screening of PET tracer candidates in our laboratory.

Animals↗

PubMed2004

Haemodynamic and metabolic disturbances in the acute stage of subarachnoid haemorrhage demonstrated by PET.

OBJECTIVE: To investigate the occurrence of early haemodynamic and metabolic changes in the acute stage of subarachnoid haemorrhage (SAH). MATERIAL AND METHODS: Eleven SAH patients were studied. Regional cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction ratio (OER) were measured with positron emission tomography (PET) 22-53 h after haemorrhage, utilizing 15O-labelled water bolus and the 15O-inhalation technique. Ten volumes of interest (VOIs) representing vascular territories were outlined in each patient according to a standardized procedure. The occurrence of irreversible ischaemia, penumbra, oligaemia, hyperperfusion and normal haemodynamics according to PET criteria was investigated. These pathophysiological categories were related to final tissue outcome as determined by follow-up computed tomography (CT). RESULTS: All five tissue subtypes were represented in the vascular region VOIs; oligaemia was the predominant pathophysiological pattern. When global changes were analysed, blood flow was reduced in three, oxygen metabolism was reduced in four, and OER was increased in four of seven unsedated patients, respectively. The sedated patients all had markedly reduced CBF and CMRO2 and OER in the high or supranormal range. CONCLUSION: Haemodynamic and metabolic disturbances proved to be common after SAH. These abnormalities probably reflect the primary brain injury caused by the initial haemorrhage. The impact of secondary insults such as acute hydrocephalus, brain oedema, vasospasm, seizures, hypotension and hypoxaemia are likely to be dependent on the degree of primary injury, which can be assessed by PET.

Acute Disease↗

PubMed2004

Is positron emission tomography using 18F-fluorodeoxyglucose and 11C-acetate valuable in diagnosing indeterminate pancreatic masses?

BACKGROUND: It can be impossible to differentiate a mass forming chronic pancreatitis from adenocarcinoma of the pancreas using standard anatomical imaging. Positron emission tomography using 2-[18F] fluoro-2deoxy-D-glucose (18FDG-PET) and 1-[11C]-acetate (11C-acetate-PET) are methods taking advantage of the metabolic differences between benign and malignant tissues. AIMS: To determine the diagnostic accuracy of 18FDG-PET and 11C-acetate-PET in indeterminate pancreatic masses. METHODS: Twenty patients with an indeterminate mass of the head of the pancreas were prospectively studied. All patients underwent 18FDG-PET and eighteen of them 11C-acetate-PET. Scans were evaluated qualitatively and quantitatively; the later by using regional standardised uptake value (SUV). Final diagnosis was established using histopathologic evaluation of resected specimen or biopsy. RESULTS: Adenocarcinoma was diagnosed in twelve patients and chronic pancreatitis in eight. Qualitative evaluation of 18FDG-PET imaging revealed three false negative and one false-positive results. The sensitivity, specificity, and diagnostic accuracy were 75 %, 88 %, and 80 %, respectively. The cut-off SUV to differentiate malignant from benign disease was 3,5 demonstrating a sensitivity of 91.7 % and a specificity of 75 %. CONCLUSION: 18FDG-PET imaging could not confirm or exclude malignancy in indeterminate masses of the head of the pancreas with high sensitivity and diagnostic accuracy. 11C-acetate-PET provided no additional diagnostic benefits.

Adenocarcinoma↗

PubMed2003

Demonstration of high monoaminoxidase-A levels in neuroendocrine gastroenteropancreatic tumors in vitro and in vivo-tumor visualization using positron emission tomography with 11C-harmine.

BACKGROUND AND AIMS: A majority of neuroendocrine gastroenteropancreatic (GEP) tumors can be detected by conventional radiological methods and scintigraphic techniques. Still there are problems to visualize small tumor lesions and non-functioning tumors. The aim of this study was to investigate some of the monoamine processing pathways of neuroendocrine GEP-tumors and try to find a new tracer substance for in vivo characterization and visualization by Positron Emission Tomography (PET). SUBJECTS AND METHODS: Autoradiography of tumor sections from 8 midgut carcinoids (MGC) and 8 endocrine pancreatic tumors (EPT) was performed with (11)C-labeled tracers for serotonin and dopamine transporters, serotonin HT2A-, dopamine D1- and muscarinic receptors and for monoamine oxidase A (MAO-A). The in vitro results initiated PET studies with (11)C-Harmine in 4 patients with MGC and 7 patients with EPT (one insulinoma, two glucagonomas and four non-functioning EPT). RESULTS: The MAO-A-ligand Harmine expressed specific in vitro binding of 87 +/-21% for MGC and 125 +/- 50% for EPT, compared to reference tissue (rat brain, 100%). All other substances showed relatively low specific binding. (11)C-harmine-PET could visualize tumors in all patients. The mean standardized uptake value (SUV) for MGC was 7.5 +/- 3.9 and for EPT 12.9 +/- 2.7, whereas the SUV of normal liver, intestine and pancreas were 3.1 +/- 0.5, 3.4 +/- 1.2 and 8.9 +/- 3.0 respectively. CONCLUSIONS: This study demonstrates in vitro and in vivo that neuroendocrine GEP-tumors are characterized by a high MAO-A-expression, thereby adding to the similarities of neuronal and neuroendocrine tissue. It also indicates a possible application for (11)C-harmine as a new PET-tracer for neuroendocrine GEP-tumors with the potential to visualize also non-functioning EPT's.

Biomarkers, Tumor↗

PubMed2002

11C-harmine as a potential PET tracer for ductal pancreas cancer: in vitro studies.

Our objective was to find a tracer in diagnosing human pancreatic cancer using positron emission tomography (PET). For this purpose in vitro test of pancreatic tissues with autoradiography was used. Autoradiography was performed with (11)C-harmine (a MAO-A-inhibitor) with and without competitive inhibition. Tissue preparations were obtained from normal human pancreas and pancreatic cancer. The uptake was compared with rat brain or pig brain, tissues with high expression of MAO-A. Nine autoradiography studies on 16 samples from five different human pancreatic cancers gave a significant level of specific binding of (11)C-harmine in 13, and 3 samples did not give a significant level of specific binding of (11)C-harmine. All 16 samples were analysed with autoradiography. Compared with rat brain, the uptake in the human cancers varied between 9 and 43% except for one tissue preparation which had a too low value for measurement. This study shows expression of MAO-A in human pancreatic cancer. This is readily characterised in vitro. The potential use of (11)C-harmine in the diagnosis of pancreatic cancer using PET might be limited, but further PET studies are necessary.

Animals↗

PubMed2002

Long-term adaptation to prism-induced inversion of the retinal images.

For 1 week, healthy human participants ( n=7) were devoid of normal vision by exposure to prism lenses that optically rotated their perceived world around the line of sight by 180 degrees. Adaptation to such prisms involved sustained and vigorous practice of the ability to redirect the unadapted efferent motor command; because prior to all visually guided movements, the to-be-executed efferent command was based on incorrect (prismatically reversed) spatial information. The time course of this sort of adaptation was systematically explored in Cooper-Shepard mental rotation (MR) tests and in naturalistic motor-tasks for the purpose of investigating whether mental rotations of the direction of the intended movement share common aspects with the process of MR. A control group ( n=7) intermittently exposed to the distorted spatial organization of the central visual field was studied in parallel. The main results were as follows: (a) the MR reaction times (RTs) day 1 with prisms appeared to be very similar to the normal RTs (day 1, no-prisms) with the one exception that subjects now responded within a prism (rotated) frame of spatial reference rather than within the environmentally upright. The visuomotor performance became grossly irregular and dysmetric. (b) The majority of the visuomotor adaptation functions began to level off on the 3rd day. (c) The increases in natural motor proficiency were accompanied by a systematic and noticeable decrease in magnitude of the MR Y-intercept obtained from the linear regression line calculated between each subject's RT and the various stimulus angles. MR slopes were stable through days 1-7 for both the experimental and control group. An increased correlation between rotational stimulus angle and RT suggested that the MR function also became progressively more tightly coupled to the stimulus angles. (d) Postadaptation measures of performance indicated the occurrence of selective and minimal adaptation in the natural motor tasks only. It is suggested that these results reflect an improved attentional (strategic) ability to replace incorrect (error producing) control signals with correct (error reducing) control signals. As a result, perceptual-motor start-up processes directly related to spatial coding and to the planning, initiation and correction of the intended direction of motor-or-mental movement improved while the subprocess ("stage") concerned with transformations of such movements remained unchanged. Visuomotor adaptation to inverting prisms engages, and thereby stimulates, a cortical system also invoked in the preparatory process of MR.

Adaptation, Physiological↗

PubMed2001

Studies of signal suppression in liquid chromatography-electrospray ionization mass spectrometry using volatile ion-pairing reagents.

Volatile ion-pairing reagents are useful due to their compatibility with liquid chromatography-electrospray ionization (ESI) mass spectrometry. In this study trifluoroacetic acid, heptafluorobutanoic acid and perfluoroheptanoic acid were used as ion-pairing reagents. The signal intensities of eight amine analytes were measured in the presence of these fluorinated carboxylic acids and compared with the signal intensity when using an ion-pair free formic acid-ammonium formate buffer. It was shown that the ESI signal from most of the studied analytes decreased about 30-80% when the fluorinated carboxylic acids were added to the mobile phase at useful concentrations. The use of these acids in ion-pair chromatography was also compared to the more conventional sodium heptane sulphonate additive. It was found that the chromatographic performance was comparable. Finally, the long-term performance of the ESI interface and the chemical background caused by these fluorinated reagents were examined. No degradation of the ESI interface performance could be seen for over 24 h of continuous infusion.

Amines↗

PubMed2001

Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas.

BACKGROUND: Considerable numbers of patients with low-grade gliomas experience an early malignant course and may benefit from aggressive treatment. These patients are difficult to identify using established prognostic factors. A retrospective study was performed to determine whether the (11)C-methionine uptake in tumor is a survival factor in adult patients with supratentorial gliomas classified as World Health Organization Grade 2. METHODS: The authors identified 89 patients with histologically confirmed low-grade gliomas in whom an (11)C-methionine positron emission tomography (PET) scan had been performed as part of the diagnostic tumor investigation from 1983 to 1998. Clinical data were collected, and the PET scans were re-evaluated according to a fixed protocol. The (11)C-methionine uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analyses. RESULTS: At the end of the study, 49 patients (55.1%) had died. The median overall survival was 5.7 years. Low methionine uptake was significantly favorable in the multivariate survival analysis (P = 0.04) along with oligodendroglioma (P = 0.003). In the histologic subgroups, (11)C-methionine uptake was an important survival factor among patients with astrocytomas (P = 0.05) and oligodendrogliomas (P = 0.03). Tumor resection was a favorable prognostic factor in patients with high methionine uptake (P = 0.01) but not in patients with low uptake. CONCLUSIONS: Baseline (11)C-methionine PET is a prognostic indicator in patients with low-grade gliomas. The results imply that PET is a valuable tool in the clinical management of these patients and may assist in the selection of patients for therapy.

Adult↗

PubMed2001

Use of positron emission tomography in analysing receptor function in vivo.

The non-invasive radiotracer technique positron emission tomography (PET) may provide valuable information in the toxicokinetic-toxicodynamic evaluation of endogenous or toxic environmental compounds. Assessment of mechanism of action of toxins is often difficult to validate. In this respect, PET may offer advantages since it can quantify not only the distribution and kinetics of the radiolabelled toxin in the body, but also the altered rates of physiological or biochemical processes induced by the toxin. It is even possible to validate the body distribution and tissue accumulation of the toxic compound in primates, since linear kinetics can be assumed after administration of the radiolabelled compound in minute amounts without any toxic or physiological effects. Quantitative estimates can be derived with accuracy and high precision. Using a multi-tracer protocol, it is often possible to illuminate both the kinetics and the dynamics of a toxic compound. Long-term effects of different toxins on dopamine receptor function have been evaluated with PET as well as the influence of Parkinson disease medication on pre- and postsynaptic dopaminergic receptor function over the course of the disease. In conclusion, PET may provide very informative insight into complex receptor interactions of both toxic compounds and drugs under development.

Animals↗

PubMed2001

D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study.

OBJECTIVE: Quetiapine is a novel antipsychotic agent with many atypical features, including low D(2) and higher 5HT(2A) affinity in vitro, low propensity to induce extra-pyramidal side effects and minimal effects on prolactin levels. The purpose of this study was to investigate, using positron emission tomography (PET), the relationship between plasma concentrations of different doses of quetiapine and occupancy of D(2) and 5HT(2A) receptors in schizophrenic patients. METHODS: Five patients were treated with quetiapine (titrated to 750 or 450 mg/day) for 28 days, subsequently reduced weekly in a descending-dose schedule. Dopamine D(2) and 5HT(2A) occupancies were determined using [(11)C] raclopride and [(11)C] N-methylspiperone as ligands, respectively, and PET imaging. RESULTS: Mean D(2) receptor occupancies of 41 and 30% were observed at quetiapine doses of 750 and 450 mg/day. At lower dose levels no occupancy could be determined. Quetiapine induced a consistently higher degree of 5HT(2A) receptor occupancy, with mean occupancies of 74 and 57% at doses of 750 and 450 mg/day, respectively. No EPS emerged during the trial and most of the pre-trial EPS resolved during the study. CONCLUSIONS: In clinically effective doses, quetiapine induced low occupancy at D(2) receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine could not be calculated, although receptor occupancy increased with higher plasma concentrations for the 450 and 750 mg doses.

Adult↗