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 i...

The MOLECUBES β-CUBE scanner is the newest amongst commercially available preclinical PET scanners for dedicated small animal imaging. The scanner is compact, lightweight and utilizes a small footprint to facilitate bench-top imaging. It can be used individually, or in combination with the X-CUBE CT scanner, which provides the ability to perform all necessary PET data corrections and provide fully quantitative PET images. The PET detector comprises of an 8 mm thick monolithic LYSO scintillator read-out by an array of 3 mm  ×  3 mm Hamamatsu silicon photomultipliers. The monolithic scintillator provides the ability to measure depth-of-interaction which aids in the development of such a compact scanner. With a scanner diameter of 7.6 cm and axial length of 13 cm it is suitable for imaging both whole-body mice and rats. This paper presents the design and imaging performance of the β-CUBE scanner. NEMA NU4-2008 characterization and a variety of phantom and animal imaging studies to demonstrate the quantitative imaging performance of the PET scanner are presented. Spatial resolution of 1 mm is measured with a filtered-back projection reconstruction algorithm at the center of the scanner and DOI measurement helps maintain the excellent spatial resolution over the entire imaging FOV. An absolute peak sensitivity of 12.4% is measured with a 255-765 keV energy window. The scanner demonstrates good count-rate performance, with a peak NEC of 300 kcps and 160 kcps measured with ~900 µCi in the NEMA mouse and rat phantoms, respectively. Imaging data with the NEMA image quality phantom and Micro Derenzo phantoms demonstrate the ability to achieve good image quality and accurate quantitative data. Image uniformity of 7.4% and spill-over ratio of 8% were measured. The superior spatial resolution, excellent energy resolution and sensitivity also provide superior contrast recovery, with ~70% recovery for the 2 mm rods. While current commercial preclinical PET scanners have spatial resolution in the 1-2 mm range, the 1 mm volumetric resolution presents significant improvement over current commercially available preclinical PET scanners. In combination with the X-CUBE scanner it provides the ability to perform fully quantitative imaging with spatially co-registered high-resolution 3D PET-CT images.

Quantitative PET imaging requires an attenuation map to correct for attenuation. In stand-alone PET or PET/CT, the attenuation map is usually derived from a transmission scan or CT image, respectively. In PET/MR, these methods will most likely not be used. Therefore, attenuation correction has long been regarded as one of the major challenges in the development of PET/MR. In the past few years, much progress has been made in this field. In this review, the challenges faced in attenuation correction for PET/MR are discussed. Different methods have been proposed to overcome these challenges. An overview of the MR-based (template-based and voxel-based), transmission-based and emission-based methods and the results that have been obtained is provided. Although several methods show promising results, no single method fulfils all of the requirements for the ideal attenuation correction method for PET/MR. Therefore, more work is still necessary in this field. To allow implementation in routine clinical practice, extensive evaluation of the proposed methods is necessary to demonstrate robustness and automation.

When using a segmented attenuation map, at least five different tissue types should be considered: cortical bone, spongeous bone, soft tissue, lung, and air. Furthermore, the interpatient variability of lung attenuation coefficients should be taken into account. Limited misclassification from bone to soft tissue and from lung to air is acceptable, as these do not lead to relevant errors.