Since the seventies, positron emission tomography (PET) has become an invaluable medical molecular imaging modality with an unprecedented sensitivity at the picomolar level, especially for cancer diagnosis and the monitoring of its response to therapy. More recently, its combination with x-ray computed tomography (CT) or magnetic resonance (MR) has added high precision anatomic information in fused PET/CT and PET/MR images, thus compensating for the modest intrinsic spatial resolution of PET. Nevertheless, a number of medical challenges call for further improvements in PET sensitivity. These concern in particular new treatment opportunities in the context personalized (also called precision) medicine, such as the need to dynamically track a small number of cells in cancer immunotherapy or stem cells for tissue repair procedures. A better signal-to-noise ratio (SNR) in the image would allow detecting smaller size tumours together with a better staging of the patients, thus increasing the chances of putting cancer in complete remission. Moreover, there is an increasing demand for reducing the radioactive doses injected to the patients without impairing image quality. There are three ways to improve PET scanner sensitivity: improving detector efficiency, increasing geometrical acceptance of the imaging device and pushing the timing performance of the detectors. Currently, some pre-localization of the electron-positron annihilation along a line-of-response (LOR) given by the detection of a pair of annihilation photons is provided by the detection of the time difference between the two photons, also known as the time-of-flight (TOF) difference of the photons, whose accuracy is given by the coincidence time resolution (CTR). A CTR of about 10 picoseconds FWHM will ultimately allow to obtain a direct 3D volume representation of the activity distribution of a positron emitting radiopharmaceutical, at the millimetre level, thus introducing a quantum leap in PET imaging and quantification and fostering more frequent use of ¹¹ C radiopharmaceuticals. The present roadmap article toward the advent of 10 ps TOF-PET addresses the status and current/future challenges along the development of TOF-PET with the objective to reach this mythic 10 ps frontier that will open the door to real-time volume imaging virtually without tomographic inversion. The medical impact and prospects to achieve this technological revolution from the detection and image reconstruction point-of-views, together with a few perspectives beyond the TOF-PET application are discussed.

Solid state photodetectors like silicon photomultipliers (SiPMs) are playing an important role in several fields of medical imaging, life sciences and high energy physics. They are able to sense optical photons with a single photon detection time precision below 100 ps, making them ideal candidates to read the photons generated by fast scintillators in time of flight positron emission tomography (TOF-PET). By implementing novel high-frequency readout electronics, it is possible to perform a completely new evaluation of the best timing performance achievable with state-of-the-art analog-SiPMs and scintillation materials. The intrinsic SiPM single photon time resolution (SPTR) was measured with Ketek, HPK, FBK, SensL and Broadcom devices. Also, the best achieved coincidence time resolution (CTR) for these devices was measured with LSO:Ce:Ca of mm³ and mm³ size crystals. The intrinsic SPTR for all devices ranges between 70 ps and 135 ps FWHM when illuminating the entire mm² or mm² area. The obtained CTR with LSO:Ce:Ca of mm³ size ranges between 58 ps and 76 ps FWHM for the SiPMs evaluated. Bismuth Germanate (BGO), read out with state of-the-art NUV-HD SiPMs from FBK, achieved a CTR of 158 ps and 277 ps FWHM for mm³ and mm³ crystals, respectively. Other BGO geometries yielded 167 3 ps FWHM for mm³ and 235 5 ps FWHM for mm³ also coupled with Meltmount (n = 1.582) and wrapped in Teflon. Additionally, the average number of Cherenkov photons produced by BGO in each 511 keV event was measured to be 17 3 photons. Based on this measurement, we predict the limits of BGO for ultrafast timing in TOF-PET with Monte Carlo simulations. Plastic scintillators (BC422, BC418), BaF₂, GAGG:Ce codoped with Mg and CsI:undoped were also tested for TOF performance. Indeed, BC422 can achieve a CTR of 35 2 ps FWHM using only Compton interactions in the detector with a maximum deposited energy of 340 keV. BaF₂ with its fast cross-luminescence enables a CTR of 51 5 ps FWHM when coupled to VUV-HD SiPMs from FBK, with only ∼22% photon detection efficiency (PDE). We summarize the measured CTR of the various scintillators and discuss their intrinsic timing performance.

The silicon photomultiplier (SiPM) is an established device of choice for a variety of applications, e.g. in time of flight positron emission tomography (TOF-PET), lifetime fluorescence spectroscopy, distance measurements in LIDAR applications, astrophysics, quantum-cryptography and related applications as well as in high energy physics (HEP). To fully utilize the exceptional performances of the SiPM, in particular its sensitivity down to single photon detection, the dynamic range and its intrinsically fast timing properties, a qualitative description and understanding of the main SiPM parameters and properties is necessary. These analyses consider the structure and the electrical model of a single photon avalanche diode (SPAD) and the integration in an array of SPADs, i.e. the SiPM. The discussion will include the front-end readout and the comparison between analog-SiPMs, where the array of SPADs is connected in parallel, and the digital SiPM, where each SPAD is read out and digitized by its own electronic channel. For several applications a further complete phenomenological view on SiPMs is necessary, defining several SiPM intrinsic parameters, i.e. gain fluctuation, afterpulsing, excess noise, dark count rate, prompt and delayed optical crosstalk, single photon time resolution (SPTR), photon detection effieciency (PDE) etc. These qualities of SiPMs influence directly and indirectly the time and energy resolution, for example in PET and HEP. This complete overview of all parameters allows one to draw solid conclusions on how best performances can be achieved for the various needs of the different applications.

Scintillator based radiation detectors readout by SiPMs successively break records in their reached time resolution. Nevertheless, new challenges in time of flight positron emission tomography (TOF-PET) and high energy physics are setting unmatched goals in the 10 ps range. Recently it was shown that high frequency (HF) readout of SiPMs significantly improves the measured single photon time resolution (SPTR), allowing to evaluate the intrinsic performance of large area devices; e.g. FBK NUV-HD SiPMs of mm ² area and 40 m single photon avalanche diode (SPAD) size achieve 90 ps FWHM. In TOF-PET such readout allows to lower the leading edge detection threshold, so that the fastest photons produced in the crystal can be utilized. This is of utmost importance if a high SPTR and prompt Cherenkov light generated by the hot-recoil electron upon 511 keV photo-absorption should improve timing. This paper shows that high-frequency bipolar transistor readout of state-of-the-art SiPMs coupled to high-performance scintillators can substantially improve the best achievable coincidence time resolution (CTR) in TOF-PET. In this context a CTR of 158 3 ps FWHM with mm ³ BGO crystals coupled to FBK SiPMs is achieved. This faint Cherenkov signal is as well present in standard LSO scintillators, which together with low SPTR values (<90 ps FWHM) improves the CTR of mm ³ LSO:Ce:Ca coupled to FBK NUV-HD mm ² with 25 m SPAD size to 61 2 ps FWHM using HF-electronics, as compared to 73 2 ps when readout by the NINO front-end ASIC. When coupling the LSO:Ce:Ca crystals to FBK NUV-HD SiPMs of mm ² and 40 m SPAD size, using HF-electronics, a CTR of even 58 3 ps for mm ³ and 98 3 ps for mm ³ is achieved. This new experimental data will allow to further discuss the timing limits in scintillator-based detectors.

The coincidence time resolution (CTR) of scintillator based detectors commonly used in positron emission tomography is well known to be dependent on the scintillation decay time ( ) and the number of photons detected ( ), i.e. . However, it is still an open question to what extent the scintillation rise time ( ) and other fast or prompt photons, e.g. Cherenkov photons, at the beginning of the scintillation process influence the CTR. This paper presents measurements of the scintillation emission rate for different LSO type crystals, i.e. LSO:Ce, LYSO:Ce, LSO:Ce codoped Ca and LGSO:Ce. For the various LSO-type samples measured we find an average value of 70 ps for the scintillation rise time, although some crystals like LSO:Ce codoped Ca seem to have a much faster rise time in the order of 20 ps. Additional measurements for LuAG:Ce and LuAG:Pr show a rise time of 535 ps and 251 ps, respectively. For these crystals, prompt photons (Cherenkov) can be observed at the beginning of the scintillation event. Furthermore a significantly lower rise time value is observed when codoping with calcium. To quantitatively investigate the influence of the rise time to the time resolution we measured the CTR with the same L(Y)SO samples and compared the values to Monte Carlo simulations. Using the measured relative light yields, rise- and decay times of the scintillators we are able to quantitatively understand the measured CTRs in our simulations. Although the rise time is important to fully explain the CTR variation for the different samples tested we determined its influence on the CTR to be in the order of a few percent only. This result is surprising because, if only photonstatistics of the scintillation process is considered, the CTR would be proportional to the square root of the rise time. The unexpected small rise time influence on the CTR can be explained by the convolution of the scintillation rate with the single photon time resolution (SPTR) of the photodetector and the photon travel spread (PTS) in the crystal. The timing benefits of prompt photons at the beginning of the scintillation process (Cherenkov etc) are further studied, which leads to the conclusion that the scintillation rise time, SPTR and PTS have to be lowered simultaneously to fully profit from these fast photons in order to improve the CTR significantly.