Analysis of D 2 dopamine receptor occupancy with quantitative SPET using the high-affinity ligand [ 123I]epidepride: resolving conflicting findings

Abstract

Recent studies of limbic cortical dopamine D 2 receptor occupancy by clozapine using high-affinity PET and SPET radioligands have produced conflicting findings. It has been suggested that these divergent findings are due to between-study differences in the method used to estimate D 2 receptor-binding potential. We compared different methods for estimating striatal and temporal cortical D 2 receptor occupancy with high-affinity tracers. In vivo experimental SPET data, obtained with [ 123I]epidepride were analysed with reference tissue kinetic modeling and with the ratio method, applied to data corresponding to short (60 min) and long (240 min) acquisition times. Dopamine D 2 receptor occupancy by the atypical antipsychotic drug risperidone was evaluated. Simulation experiments were also performed, comparing occupancy values obtained for different receptor densities in relation to different data acquisition times. The simulation results revealed that previously published data regarding errors in occupancy estimation by analysis of time activity data acquired for 60 min cannot be extrapolated to studies performed over 240 min. The ratio method provided accurate temporal cortical D 2 receptor occupancy values when applied to data from a late time period, but underestimated the occupancy with earlier data. In striatum, both the late data ratio method and reference tissue kinetic modeling using all data underestimated D 2 receptor occupancy. However, more accurate analyses of striatal D 2 occupancy still showed selective limbic/cortical occupancy by risperidone. Our results substantiate the previous [ 123I]epidepride findings of high temporal cortical occupancy by other atypical antipsychotic drugs and suggest that a potential source of conflicting findings might be short scanning times imposed by [ 11C]FLB 457, leading to underestimation of temporal cortical D 2 receptor occupancy by this method.