Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions – extending the...

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 extend 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 with other brain regions, could be better explained by a difference in the extent of non-displaceable binding.

The analysis was based on a PET study in six 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. Non-linear 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.

The estimate (95% CI) of Ki(PL) was 10.2 ng ml(-1) (5.4, 15) and 10.4 ng ml(-1) (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 Ki(PL) for caudate relative to other brain regions was 55% (48, 62%).

The extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. AZD3783 affinity appears to be higher in the caudate compared with other brain regions.