We present three novel multi-slit-slat (MSS) system designs which allow for the acquisition of data with variable multiplexing in order to optimize the use of a high intrinsic resolution detector for clinical brain SPECT. In this paper we first study the relationship between the geometric parameters of a MSS collimator system and the resulting resolution and sensitivity for an on-axis point at the centre of the field-of-view (FOV), assuming a continuous cylindrical detector model. The model predicts that for optimal system sensitivity and resolution, the ratio of the detector radius to slit collimator radius should be 1.3-1.5, as any further increase in this ratio results in significant deterioration in both system resolution and sensitivity. The analytical results were used to fix the geometric parameters for the three novel MSS system designs. Comparison of the three designs, asymmetric rotating collimator (ARC), asymmetric rotating detector (ARD) and symmetric rotating collimator (SRC) with variable slit spacing, suggests that the SRC system performs better in terms of the system sensitivity (5.1 × 10 -4) for the same average resolution (6.0 mm) in comparison to designs based on an ARC (3.7 × 10 -4) and ARD (4.2 × 10 -4).