In synthetic-collimator SPECT imaging, two detectors are placed at different distances behind a multi-pinhole aperture. This configuration allows for image detection at different magnifications and photon energies, resulting in higher overall sensitivity while maintaining high resolution. Image multiplexing the undesired overlapping between images due to photon origin uncertainty may occur in both detector planes and is often present in the second detector plane due to greater magnification. However, artifact-free image reconstruction is possible by combining data from both the front detector (little to no multiplexing) and the back detector (noticeable multiplexing). When the two detectors are used in tandem, spatial resolution is increased, allowing for a higher sensitivity-to-detector-area ratio. Due to variability in detector distances and pinhole spacings found in synthetic-collimator SPECT systems, a large parameter space must be examined to determine optimal imaging configurations. We chose to assess image quality based on the task of estimating activity in various regions of a mouse brain. Phantom objects were simulated using mouse brain data from the Magnetic Resonance Microimaging Neurological Atlas (MRM NeAt) and projected at different angles through models of a synthetic-collimator SPECT system, which was developed by collaborators at Vanderbilt University. Uptake in the different brain regions was modeled as being normally distributed about predetermined means and variances. We computed the performance of the Wiener estimator for the task of estimating activity in different regions of the mouse brain. Our results demonstrate the utility of the method for optimizing synthetic-collimator system design.