Voxel-based NK1 Receptor Occupancy Measurements with [18F]SPA-RQ and Positron Emission Tomography: A Procedure for Assessing Errors from Image Reconstruction and Physiological Modeling

Abstract

Receptor occupancy studies with positron emission tomography (PET) are widely used as aids in the drug development process. This study introduces a general procedure for assessing errors that arise from the applied image processing methods in PET receptor occupancy studies using the neurokinin-1 (NK1) receptor occupancy study as an example. The bias and variance among eight combinations of image reconstruction and model calculation methods for estimating voxel-level receptor occupancy results were examined. The tests were performed using a dynamic numerical phantom based on a previous PET drug occupancy study with the NK1 receptor antagonist tracer [(18)F]SPA-RQ. The simplified reference tissue model with basis functions (SRTM BF) was best at estimating receptor occupancy in terms of average bias. On the other hand, median root prior (MRP) image reconstruction produced the lowest variances in the occupancy estimates. These results suggest that SRTM BF and MRP is, in this case, the combination of choice in voxel-based receptor occupancy calculation. In the calculation of regional binding potential values, the commonly used sample mean is not applicable and, e.g., the median could be used instead. This study shows that even this kind of complicated receptor study can be statistically evaluated. The reconstruction methods had an effect on the variance in the voxel-based receptor occupancy calculation. The model calculation methods influenced the average bias. The test method was found useful in assessing the methodological sources of systematic and random error in receptor occupancy estimation with PET.