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Modern high-resolution PET is now more than ever in need of scrutiny into the nature and limitations of the imaging modality itself as well as image reconstruction techniques. In this work, we have reviewed, analysed and addressed the following three considerations within the particular context of state-of-the-art dynamic PET imaging:(i) the typical average numbers of events per line-of-response (LOR) are now (much) less than unity,(ii) due to the physical and biological decay of the activity distribution, one requires robust and efficient reconstruction algorithms applicable to a wide range of statistics and (iii) the computational considerations in dynamic imaging are much enhanced (ie, more frames to be stored and reconstructed). Within the framework of statistical image reconstruction, we have argued theoretically and shown experimentally that the sinogram non-negativity constraint (when using the delayed …