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- Kågedal, Matts, et al.
(författare)
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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
- 2013
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 82, s. 160-169
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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)
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Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions : extending the simplified reference tissue model
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 80:1, s. 116-127
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extended the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared to other brain regions, could be better explained by a difference in the extent of non-displaceable binding.METHODS: The analysis was based on a PET study in 6 healthy volunteers using the 5-HT1B receptor radioligand [(11) C]AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT1B receptor antagonist AZD3783. Nonlinear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies.RESULTS: The estimate (95% CI) of KiPL was 10.2 ng/ml (5.4-15) and 10.4 ng/ml (8.1-13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference respectively. The estimate (95% CI) of KiPL for caudate relative to other brain regions was 55% ( 48% -62%).CONCLUSIONS: The extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. The AZD3783 affinity appears to be higher in caudate compared with other brain regions.
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