Time-of-flight: The last frontier in positron emission tomography instrumentation.

Positron emission tomography (PET) instrumentation has seen significant advances over the last 20 years. In particular, substantial improvement in electronics and scalability have allowed new clinical scanners to combine high gamma stopping power and patient geometrical coverage in the total body PET paradigm. Similarly, spatial resolution has almost reached its physical limit imposed by the uncertainty caused by the positron range and acollinearity of emitted annihilation gamma rays. Time-of-flight (ToF) offers an improvement to effective sensitivity, proportional to the reverse square of detector timing resolution. In contrast to the aforementioned, this is a development direction that has not yet been sufficiently harnessed, with state of the art remaining far from the physical limit of ToF resolution. Nevertheless, existing scanners offer a glimpse of the advantages of ToF for imaging and diagnosis. In this review, analyse the limiting factors; describe the motivation for enhancing detector ToF capabilities; explore the physical mechanisms related to ToF application; describe the state-of-the-art in clinical, prototyping and laboratory stages; offer insights on emerging approaches and their capabilities to provide scalable, and cost-effective ToF; and finally envision the future of medicine, once ultraToF of the order of 10 ps has become the standard in clinically deployed scanners.