Recent studies in the field of molecular imaging have demonstrated the need for PET probes capable of imaging very weak activity distributions. Over this range of applications the sensitivity and the energy resolution of a PET system can be critical, as it can possibly affect the minimum amount of activity which can be reliably detected. Clinical PET systems, as opposed to small animal systems, are less sensitive and, therefore, imaging of very low activity sources could be challenging. Moreover the presence of LSO crystal detectors can further raise the minimum detection threshold due to the intrinsic radioactivity of the 176Lu contained in the LSO compound. Our aim is to examine the feasibility of using an LSO-based clinical PET scanner for imaging activity distributions of 4nCi/mm 3 or less. In this study the parameter of minimum detectable activity (MDA) has been used for the quantification of the detection threshold of a system. A series of acquisitions was simulated using the Monte Carlo simulation software package of GATE. Existing validated GATE models of the clinical Siemens Biograph 6 PET/CT and pre-clinical microPET Focus 220 scanners have been applied to quantify and compare the effect of the LSO background and the energy window on the MDA performance of the systems. Four square regions, each with a unique signal-to-background activity concentration ratio (SBR), were scanned simultaneously. The intrinsic LSO background spectrum and the total energy spectrum, as well as their relative positions and intensities were estimated. The simulated data were histogrammed on various time frames, which were later reconstructed using a filtered back-projection algorithm. Detectability in every image was quantified using a modified Currie equation to associate an MDA value with a specific region and frame length. In the case of Biograph an MDA of 4nCi/mm3 can be reliably detected for frame lengths longer than 5min and in regions where the SBR was higher than 4. When higher contrast regions are imaged, detection can be achieved even for frame lengths down to 1min. The previous analysis was repeated by using a GATE model of a hypothetical BGO-based clinical PET scanner. The results between the two scanner models were compared with each other as well as with those of a previous MDA study on a preclinical microPET Focus 220 scanner.