The first time-of-flight positron emission tomography (TOF-PET) scanners were developed as early as in the 1980s. However, the poor light output and low detection efficiency of TOF-capable detectors available at the time limited any gain in image quality achieved with these TOF-PET scanners over the traditional non-TOF PET scanners. The discovery of LSO and other Lu-based scintillators revived interest in TOF-PET and led to the development of a second generation of scanners with high sensitivity and spatial resolution in the mid-2000s. The introduction of the silicon photomultiplier (SiPM) has recently yielded a third generation of TOF-PET systems with unprecedented imaging performance. Parallel to these instrumentation developments, much progress has been made in the development of image reconstruction algorithms that better utilize the additional information provided by TOF. Overall, the benefits range from a reduction in image variance (SNR increase), through allowing joint estimation of activity and attenuation, to better reconstructing data from limited angle systems. In this work, we review these developments, focusing on three broad areas: 1) timing theory and factors affecting the time resolution of a TOF-PET system; 2) utilization of TOF information for improved image reconstruction; and 3) quantification of the benefits of TOF compared to non-TOF PET. Finally, we offer a brief outlook on the TOF-PET developments anticipated in the short and longer term. Throughout this work, we aim to maintain a clinically driven perspective, treating TOF as one of multiple (and sometimes competitive) factors that can aid in the optimization of PET imaging performance.

We have recently built and characterized the performance of a monolithic scintillator detector based on a 32 mm × 32 mm × 22 mm LYSO:Ce crystal read out by digital silicon photomultiplier (dSiPM) arrays coupled to the crystal front and back surfaces in a dual-sided readout (DSR) configuration. The detector spatial resolution appeared to be markedly better than that of a detector consisting of the same crystal with conventional back-sided readout (BSR). Here, we aim to evaluate the influence of this difference in the detector spatial response on the quality of reconstructed images, so as to quantify the potential benefit of the DSR approach for high-resolution, whole-body time-of-flight (TOF) positron emission tomography (PET) applications. We perform Monte Carlo simulations of clinical PET systems based on BSR and DSR detectors, using the results of our detector characterization experiments to model the detector spatial responses. We subsequently quantify the improvement in image quality obtained with DSR compared to BSR, using clinically relevant metrics such as the contrast recovery coefficient (CRC) and the area under the localized receiver operating characteristic curve (ALROC). Finally, we compare the results with simulated rings of pixelated detectors with DOI capability. Our results show that the DSR detector produces significantly higher CRC and increased ALROC values than the BSR detector. The comparison with pixelated systems indicates that one would need to choose a crystal size of 3.2 mm with three DOI layers to match the performance of the BSR detector, while a pixel size of 1.3 mm with three DOI layers would be required to get on par with the DSR detector.