Recent advances in preclinical SPECT instrumentation enable non-standard multi-isotope acquisitions at the edge of physical feasibility to improve efficiency of pharmaceutical research. Due to the variety of applications, optimization of imaging hardware, acquisition protocols and reconstruction algorithms is a central and recurring task. For this purpose, we developed a Monte Carlo simulation model of a preclinical state-of-the-art multi-pinhole SPECT system, the NanoSPECT/CTPLUS, with emphasis on high accuracy for multi-isotope experiments operating near the system range limits. The GATE/ GEANT4 model included an accurate description of multi-pinhole collimators and all substructures of the detector back compartment. The readout electronics was modeled with a variety of signal processors partially extended to incorporate non-simplified measured response functions. The final model was able to predict energy spectra, planar images and tomographic reconstructions with high accuracy for both standard and non-standard multi-isotope experiments. Complex activity distributions could be reproduced for a wide range of noise levels and different modes of angular undersampling. Using the example of a dual-isotope triple-tracer experiment, the model has proven to be a powerful tool for protocol optimization and quantitative image correction at the performance range limits of multi-isotope multi-pinhole SPECT.