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A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2013 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 82, 160-169 p.Article in journal (Refereed) Published
Abstract [en]

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 [C-11]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived fro m each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.

Place, publisher, year, edition, pages
2013. Vol. 82, 160-169 p.
Keyword [en]
Nonlinear mixed effects modelling, Positron emission tomography, Receptor occupancy, [C-11]-ABP688, mGluR5 receptor
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-209453DOI: 10.1016/j.neuroimage.2013.05.006ISI: 000324568400018OAI: oai:DiVA.org:uu-209453DiVA: diva2:659134
Available from: 2013-10-24 Created: 2013-10-21 Last updated: 2015-02-12
In thesis
1. Nonlinear Mixed Effects Methods for Improved Estimation of Receptor Occupancy in PET Studies
Open this publication in new window or tab >>Nonlinear Mixed Effects Methods for Improved Estimation of Receptor Occupancy in PET Studies
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Receptor occupancy assessed by Positron Emission Tomography (PET) can provide important translational information to help bridge information from one drug to another or from animal to man. The aim of this thesis was to develop nonlinear mixed effects methods for estimation of the relationship between drug exposure and receptor occupancy for the two mGluR5 antagonists AZD9272 and AZD2066 and for the 5HT1B receptor antagonist AZD3783. Also the optimal design for improved estimation of the relationship between drug exposure and receptor occupancy as well as for improved dose finding in neuropathic pain treatment, was investigated.

Different modeling approaches were applied. For AZD9272, the radioligand kinetics and receptor occupancy was simultaneously estimated using arterial concentrations as input function and including two brain regions of interest. For AZD2066, a model was developed where brain/plasma partition coefficients from ten different brain regions were included simultaneously as observations. For AZD3783, the simplified reference tissue model was extended to allow different non-specific binding in the reference region and brain regions of interest and the possibility of using white matter as reference was also evaluated. The optimal dose-selection for improved precision of receptor occupancy as well as for improved precision of the minimum effective dose of a neuropathic pain treatment was assessed, using the D-optimal as well as the Ds-optimal criteria.

Simultaneous modelling of radioligand and occupancy provided a means to avoid simplifications or approximations and provided the possibility to tests or to relax assumptions. Inclusion of several brain regions of different receptor density simultaneously in the analysis, markedly improved the precision of the affinity parameter. Higher precision was achieved in relevant parameters with designs based on the Ds compared to the D-optimal criterion. The optimal design for improved precision of the relationship between dose and receptor occupancy depended on the number of brain regions and the receptor density of these regions.

In conclusion, this thesis presents novel non-linear mixed effects models estimating the relationship between drug exposure and receptor occupancy, providing useful translational information, allowing for a better informed drug-development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 57 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 188
PET, positron emission tomography, receptor occupancy, nonlinear mixed effects, NONMEM, optimal design, dose finding
National Category
Medical and Health Sciences Bioinformatics (Computational Biology)
Research subject
Pharmacokinetics and Drug Therapy
urn:nbn:se:uu:diva-222498 (URN)978-91-554-8942-7 (ISBN)
Public defence
2014-06-05, B41, Uppsala Biomedicinska Centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Available from: 2014-05-14 Created: 2014-04-11 Last updated: 2014-06-30

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Kågedal, MattsHooker, Andrew C.Karlsson, Mats O.
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