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Träfflista för sökning "WFRF:(Stenkrona Per) ;pers:(Hooker Andrew C.)"

Sökning: WFRF:(Stenkrona Per) > Hooker Andrew C.

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1.
  • Kågedal, Matts, et al. (författare)
  • A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
  • 2013
  • Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 82, s. 160-169
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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2.
  • Kågedal, Matts, et al. (författare)
  • Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers
  • 2012
  • Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 61:4, s. 849-856
  • Tidskriftsartikel (refereegranskat)abstract
    • 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. The study included PET measurements in six healthy volunteers where the radioligand was given as a tracer dose alone as well as post oral treatment with different doses of unlabelled AZD9272. Estimation of radioligand kinetics, including saturation of receptor binding was performed by use of non-linear mixed effects modelling. Data from the regions with the highest (ventral striatum) and lowest (cerebellum) radioligand concentrations were included in the analysis. It was assumed that the extent of non-displaceable brain uptake was the same in both regions while the rate of CNS uptake and the receptor density differed.The results of the analysis showed that AZD9272 binding at the receptor is saturable with an estimated plasma concentration corresponding to 50% occupancy of approximately 200nM. The density of the receptor binding sites was estimated to 800nM and 200nM in ventral striatum and cerebellum respectively. By simultaneously analysing data from several PET measurements and different brain regions in a non-linear mixed effects framework it was possible to estimate parameters of interest that would otherwise be difficult to quantify.
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