M. Kågedal(1), MO Karlsson(2) AC Hooker(2)
(1) AstraZeneca R&D Södertälje, Sweden (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: Analyses of receptor occupancy studies are often performed using the concentration in a reference region in the brain as input function. These analyses assume identical non-specific binding in the reference region and in the region of interest (ROI). In the present work it is investigated if an apparent difference in occupancy between regions could be explained by different non-specific uptake. In addition it is investigated whether the use of white matter as reference region is possible by estimation of non-specific uptake in the ROI relative to reference. The analysis is based on data from a study published previously (Varnäs et al 2011) [1].
Methods: Nonlinear mixed effects modelling of data from PET scans with the 5-HT1B radioligand [11C] AZ10419369 was applied. Data from all PET-scans and several brain regions of interest were included simultaneously in the analysis. The simplified reference tissue model with cerebellum as reference region was applied as described previously (Zamuner et al) [2] but modified to allow nonspecific uptake to differ between regions. The use of white matter as reference region was also explored. A simulation experiment was performed to assess the ability of the model to pick up a difference in non-specific uptake and the consequence of not accounting for this difference. The study included six healthy subjects with PET-scans at baseline and after different oral doses of the 5-HT1B antagonist AZD3783.
Results: Based on the likelihood ratio test, regional difference in occupancy was more likely than differences in non-specific uptake. Using white matter as reference region resulted in a similar affinity estimate as that obtained with cerebellum as reference region if the difference in non-specific uptake was accounted for. The simulation experiment, showed a bias in occupancy when differences in non-specific uptake were not accounted for.
Conclusions: In the present case, difference in occupancy rather than in non-specific uptake between regions was concluded. This evaluation was possible by a simultaneous analysis of several regions of interest and all PET-measurements. Estimation of occupancy by the use of white matter is possible by accounting for any difference in non-specific uptake. Results presented show that differences in non-specific binding between the reference region and the regions of interest can markedly bias the occupancy estimate if not accounted for.
References:
[1] 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. Varnas K. Nyberg S. Karlsson P. Pierson ME. Kagedal M. Cselenyi Z. McCarthy D. Xiao A. Zhang M. Halldin C. Farde L. Psychopharmacology. 213(2-3):533-45, 2011 Feb.
[2] Estimate the time varying brain receptor occupancy in PET imaging experiments using non-linear mixed effects modelling approach. Stefano Zamuner, Roberto Gomeni, Alan Bye. Nuclear Medicine and Biology 29 (2002) 115-123.
Reference: PAGE 22 (2013) Abstr 2832 [www.page-meeting.org/?abstract=2832]
Poster: CNS