The idea of a very sensitive positron emission tomography (PET) system covering a large portion of the body of a patient already dates back to the early 1990s. In the period 2000–2010, only some prototypes with long axial field of view (FOV) have been built, which never resulted in systems used for clinical research. One of the reasons was the limitations in the available detector technology, which did not yet have sufficient energy resolution, timing resolution or countrate capabilities for fully exploiting the benefits of a long axial FOV design. PET was also not yet as widespread as it is today: the growth in oncology, which has become the major application of PET, appeared only after the introduction of PET-CT (early 2000).The detector technology used in most clinical PET systems today has a combination of good energy and timing resolution with higher countrate capabilities and has now been used since more than a decade to build time-of-flight (TOF) PET systems with fully 3D acquisitions. Based on this technology, one can construct total body PET systems and the remaining challenges (data handling, fast image reconstruction, detector cooling) are mostly related to engineering. The direct benefits of long axial FOV systems are mostly related to the higher sensitivity. For single organ imaging, the gain is close to the point source sensitivity which increases linearly with the axial length until it is limited by solid angle and attenuation of the body. The gains for single organ (compared to a fully 3D PET 20-cm axial FOV) are limited to a factor 3–4. But for long objects (like body scans), it increases quadratically with scanner length and factors of 10–40 × higher sensitivity are predicted for the long axial FOV scanner. This application of PET has seen a major increase (mostly in oncology) during the last 2 decades and is now the main type of study in a PET centre. As the technology is available and the full body concept also seems to match with existing applications, the old concept of a total body PET scanner is seeing a clear revival. Several research groups are working on this concept and after showing the potential via extensive simulations; construction of these systems has started about 2 years ago. In the first phase, two PET systems with long axial FOV suitable for large animal imaging were constructed to explore the potential in more experimental settings. Recently, the first completed total body PET systems for human use, a 70-cm-long system, called PennPET Explorer, and a 2-m-long system, called uExplorer, have become reality and first clinical studies have been shown. These results illustrate the large potential of this concept with regard to low-dose imaging, faster scanning, whole-body dynamic imaging and follow-up of tracers over longer periods. This large range of possible technical improvements seems to have the potential to change the current clinical routine and to expand the number of clinical applications of molecular imaging. The J-PET prototype is a prototype system with a long axial FOV built from axially arranged plastic scintillator strips.This paper gives an overview of the recent technical developments with regard to PET scanners with a long axial FOV covering at least the majority of the body (so called total body PET systems). After explaining the benefits and challenges of total body PET systems, the different total body PET system designs proposed for large animal and clinical imaging are described in detail. The axial length is one of the major factors determining the total cost of the system, but there are also other options in detector technology, design and processing for reducing the cost these systems. The limitations and advantages of different designs for research and clinical use are discussed taking into account potential applications and the increased cost of these systems.

While the first time-of-flight (TOF)-positron emission tomography (PET) systems were already built in the early 1980s, limited clinical studies were acquired on these scanners. PET was still a research tool, and the available TOF-PET systems were experimental. Due to a combination of low stopping power and limited spatial resolution (caused by limited light output of the scintillators), these systems could not compete with bismuth germanate (BGO)-based PET scanners. Developments on TOF system were limited for about a decade but started again around 2000. The combination of fast photomultipliers, scintillators with high density, modern electronics, and faster computing power for image reconstruction have made it possible to introduce this principle in clinical TOF-PET systems. This paper reviews recent developments in system design, image reconstruction, corrections, and the potential in new applications for TOF-PET. After explaining the basic principles of time-of-flight, the difficulties in detector technology and electronics to obtain a good and stable timing resolution are shortly explained. The available clinical systems and prototypes under development are described in detail. The development of this type of PET scanner also requires modified image reconstruction with accurate modeling and correction methods. The additional dimension introduced by the time difference motivates a shift from sinogram- to listmode-based reconstruction. This reconstruction is however rather slow and therefore rebinning techniques specific for TOF data have been proposed. The main motivation for TOF-PET remains the large potential for image quality improvement and more accurate quantification for a given number of counts. The gain is related to the ratio of object size and spatial extent of the TOF kernel and is therefore particularly relevant for heavy patients, where image quality degrades significantly due to increased attenuation (low counts) and high scatter fractions. The original calculations for the gain were based on analytical methods. Recent publications for iterative reconstruction have shown that it is difficult to quantify TOF gain into one factor. The gain depends on the measured distribution, the location within the object, and the count rate. In a clinical situation, the gain can be used to either increase the standardized uptake value (SUV) or reduce the image acquisition time or administered dose. The localized nature of the TOF kernel makes it possible to utilize local tomography reconstruction or to separate emission from transmission data. The introduction of TOF also improves the joint estimation of transmission and emission images from emission data only. TOF is also interesting for new applications of PET-like isotopes with low branching ratio for positron fraction. The local nature also reduces the need for fine angular sampling, which makes TOF interesting for limited angle situations like breast PET and online dose imaging in proton or hadron therapy. The aim of this review is to introduce the reader in an educational way into the topic of TOF-PET and to give an overview of the benefits and new opportunities in using this additional information.

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.

Faster scintillators like LaBr(3) and LSO have sparked renewed interest in PET scanners with time-of-flight (TOF) information. The TOF information adds another dimension to the data set compared to conventional three-dimensional (3D) PET with the size of the projection data being multiplied by the number of TOF bins. Here we show by simulations and analytical reconstruction that angular sampling for two-dimensional (2D) TOF PET can be reduced significantly compared to what is required for conventional 2D PET. Fully 3D TOF PET data, however, have a wide range of oblique and transverse angles. To make use of the smaller necessary angular sampling we reduce the 3D data to a set of 2D histoprojections. This is done by rebinning the 3D data to 2D data and by mashing these 2D data into a limited number of angles. Both methods are based on the most likely point given by the TOF measurement. It is shown that the axial resolution loss associated with rebinning reduces with improved timing resolution and becomes less than 1 mm for a TOF resolution below 300 ps. The amount of angular mashing that can be applied without tangential resolution loss increases with improved TOF resolution. Even quite coarse angular mashing (18 angles out of 324 measured angles for 424 ps) does not significantly reduce image quality in terms of the contrast or noise. The advantages of the proposed methods are threefold. Data storage is reduced to a limited number of 2D histoprojections with TOF information. Compared to listmode format we have the advantage of a predetermined storage space and faster reconstruction. The method does not require the normalization of projections prior to rebinning and can be applied directly to measured listmode data.

Targeted radionuclide therapy (TRT) is a promising technique for cancer therapy. However, in order to deliver the required dose to the tumor, minimize potential toxicity in normal organs, as well as monitor therapeutic effects, it is important to assess the individualized internal dosimetry based on patient-specific data. Advanced imaging techniques, especially radionuclide imaging, can be used to determine the spatial distribution of administered tracers for calculating the organ-absorbed dose. While planar scintigraphy is still the mainstream imaging method, SPECT, PET and bremsstrahlung imaging have promising properties to improve accuracy in quantification. This article reviews the basic principles of TRT and discusses the latest development in radionuclide imaging techniques for different theranostic agents, with emphasis on their potential to improve personalized TRT dosimetry.

Peptide receptor radionuclide therapy with 177Lu-DOTATATE has become a standard treatment modality in neuroendocrine tumours (NETs). No consensus has yet been reached however regarding the absorbed dose threshold for lesion response, the absorbed dose limit to organs-at-risk, and the optimal fractionation and activity to be administered. This is partly due to a lack of uniform and comparable dosimetry protocols. The present article details the development of an organ-at-risk dosimetry procedure, which could be implemented and used routinely in a clinical context. Forty-seven patients with NETs underwent 177Lu-DOTATATE therapy. Three SPECT/CT images were acquired at 4, 24 and 144-192 h post-injection. Three blood samples were obtained together with the SPECT/CT acquisitions and 2 additional samples were obtained around 30 min and 1 h post-injection. A bi-exponential fit was used to compute the source organ time-integrated activity coefficients. Coefficients were introduced into OLINDA/EXM software to compute organ-at-risk absorbed doses. Median values for all patients were computed for absorbed dose coefficient D/A0 and for late effective half-life T1/2eff for kidneys, spleen and red marrow. Dosimetry resulted in a median[interquartile range] of 0.78[0.35], 1.07[0.58] and 0.028[0.010] Gy/GBq for D/A0 and of 55[9], 71[9] and 52[18] h for T1/2eff for kidneys, spleen and red marrow respectively. A dosimetry procedure for organs-at-risk in 177Lu-DOTATATE therapy based on serial SPECT/CT images and blood samples can be implemented routinely in a clinical context with limited patient burden. The results obtained were in accordance with those of other centres.