PurposeHigh resolution and sensitivity brain SPECT is promising for the accurate diagnosis of Alzheimer's disease (AD) and Parkinson's disease (PD). Multi-pinhole (MPH) collimators with a good performance in imaging small field-of-view (FOV) could be better used for brain SPECT. In this study, we aim to evaluate the impact of varying the number of pinholes and the number of projections on the performance of MPH brain SPECT.MethodsThe system design was based on a commercial clinical dual-head SPECT/CT scanner, with target spatial resolutions of 12 mm and 8 mm for AD and PD SPECT, respectively. In total, 1–25 pinholes were modeled for 64, 32, 16, 8, 4, and 2 projections. The 3D NURBS-based HUman Brain (NHUB) phantom was used in the analytical simulation to model 99mTc-HMPAO and 99mTc-TRODAT distributions. The 2D Derenzo hot-rod phantom and star phantom were used in Monte Carlo simulations to evaluate the spatial resolution and angular sampling performance of MPH. The influence of different detector positions was also evaluated for 2, 4, and 6 angular views. The projections were reconstructed using the 3D MPH ML-EM method. Normalized mean square error, coefficient of variation, and image profiles were evaluated.ResultsAlong with the decrease in the number of projections, more pinholes are required to achieve the optimum performance. For 32 projections, 9- and 7-pinhole collimators provide the best normalized mean square error (NMSE) to the coefficient of variation (COV) trade-off for 99mTc-HMPAO and 99mTc-TRODAT, respectively. Detector positions substantially affect the image quality for MPH SPECT for 2 and 4 angular views. The smallest rod size for the Derenzo hot-rod phantom, which could be resolved, is 7.9 mm for the MPH general purpose collimator (MPGP) with more than 16 projections and 6.4 mm for MPH high-resolution collimator (MPHR) with more than 8 projections.ConclusionThe number of pinholes affects the performance of the MPH collimator, especially when the projection views become fewer. More pinholes are required for fewer projections to provide better angular sampling in MPH for complex activity distributions. Detector positions affect the image quality of MPH SPECT for 2 and 4 angular views, where L-mode acquisition is slightly superior to H-mode. MPH collimators exhibited improved spatial resolution and angular sampling compared with both LEHR and single pinhole collimators.