PROJECT SUMMARY This application is a competitive renewal of R01-CA-113941 to develop technology and methodologies for time- of-flight (TOF) imaging to advance the performance of positron emission tomography (PET) instruments and their utilization in the management of cancer and other diseases. In this renewal we propose to continue a systematic approach to TOF PET scanner design, but with a shift towards combining advanced TOF technology with longer axial field-of-view (AFOV) scanner designs. Both the uEXPLORER at UC Davis and the PennPET Explorer have produced qualitatively superior images, unmatched by modern clinical scanners, and there is enormous excitement in the field for the opportunities that such total-body (TB) PET instruments offer. However, the success of TB-PET will ultimately depend on integration and utilization at multiple sites, which, in turn depends on the cost as well as performance of the instrument. We propose to perform studies to demonstrate how to achieve improved performance while also considering ways to constrain the cost of the design. Our goal is to study scanner configurations, with varied axial field-of-view (AFOV) and advanced detector designs that offer different trade-offs in performance and to judge the merits of these choices by their impact on a variety of potential TB-PET clinical/research applications. Our studies will include development of enabling technology for two TOF detector concepts: one (with LYSO) emphasizing TOF performance with a target of 150 ps, below that of any existing PET scanner, with the other (with BGO) emphasizing higher intrinsic sensitivity. These detectors will be studied in the context of scanner geometries with full detector coverage, or with inter-ring gaps that permit extending the AFOV while constraining the number of detectors. A TB-PET scanner has a dramatic increase in the number of lines-of-response (LORs), so we can leverage the advantages of improved TOF (and spatial) resolutions to optimize the number of LYSO detectors, or alternatively, use the higher sensitivity, but less-costly BGO detectors. Human clinical/research studies performed on the PennPET Explorer scanner will be complemented by simulations of varying scanner designs and advanced detector technology. The new detector concepts will be tested both on the benchtop and with a scanner demonstrator setup using a small number of detectors operating in coincidence. Our work will be guided with consideration of scalability to a full system and the impact of new methods on system performance and clinical benefit. Our access to clinical research data from a TB-PET system provides us a unique advantage in achieving our goals. The outcome of this project will provide guidance to prioritize the design of future TB-PET systems.