Significant progress has been achieved in the design of pixelated CZT detectors dedicated to cardiac and breast SPECT imaging. However, their detector geometry and associated collimators' design have limited their clinical use. The aim of this work is to determine the best combination between a large pixelated CZT detector and parallel-hole collimator that can provide high spatial resolution at low injected activity with low-energy radiotracers. Our proposed combination resulted in the design of a novel four-hole matched pixel detector (4-HMPD) configuration. Our novel 4-HMPD design based on large pixelated CZT detector was firstly compared to the standard one-hole matched pixel detector (1-HMPD) configuration using Monte Carlo simulation. We have also predicted the influence of pixel size, interpixel gap and source-to-collimator distance on the basis of resulting spatial resolution, sensitivity and crosstalk events fraction for three collimator hole lengths for Tc-99m (140 keV) . Thereafter, we used the same detector and collimator settings of the 1-HMPD configuration as constructed with the D-SPECT camera module (Redlen Technologies, BC, Canada) for our 4-HMPD design to compare the performance of the two configurations. Our preliminary results showed that a large pixel size, a small interpixel gap and a small collimator hole length increased significantly the sensitivity at the detriment of spatial resolution. The performance comparison between the 4-HMPD and the 1-HMPD configurations demonstrated an improved reconstructed spatial resolution (by a factor two), higher contrast with the large sphere of the modified Jaszczak phantom (from 63.1% to 39.1%), clear appearance of cold spheres (>14 mm diameter) and the cold cylinders (> 11.1 mm diameter). The crosstalk events fraction varied from 8.5% to 12.8%. Our novel detector/collimator combination allows less electronic readout complexity, less crosstalk events between pixels and twofold increase in septal thickness resulting in low septal penetration compared to the classical 1-HMPD configuration. It also showed the highest enhancement in terms of spatial resolution even in cases of low sensitivity with less injected activity, and outperformed the performance of existing conventional NaI (TI) crystal-based systems.