Collimator penetration, down-scatter related to 123I high energy photons, and scatter within detectors can significantly degrade the imaging performance of any system. Precise selection of pinhole and collimator parameters using simulation studies has the potential to considerably reduce these effects. This type of investigation, thus represents an essential step in system development. An innovative multi-pinhole system, AdaptiSPECT-C, dedicated to clinical brain SPECT imaging, is currently under development at the universities of Massachusetts and Arizona. The aim of this work was to determine the system parameters which considerably improve AdaptiSPECT- C imaging performance for the criteria of sensitivity and relative amounts of scatter and penetration. A 20 mm thick, tungsten alloy collimator leads to the best trade-off between performance and price in case of 123I imaging. Tungsten alloy provided performance relatively close to that of gold in terms of stopping power as compared to lead alloy. A pinhole center distance of 0.5 cm to the aperture entry port led to the best compromise for locating the aperture within the aperture plate in terms of sensitivity and relative amounts of scatter and penetration.