PROJECT SUMMARY/ABSTRACT Positron emission tomography (PET) is an important in vivo molecular imaging modality that has been widely used for diagnosis and treatment response evaluation of many serious diseases including cancers, cardiovascular diseases and neurological disorders. It is also useful for studying disease pathogenesis, progression and treatment. It can accelerate drug discovery and development, and has a key role in precision and personalized medicine. To realize its full potentials, there are active ongoing research efforts to improve all areas of PET. this research is concerned with the detector technology. Ideally, PET detectors shall have high detection efficiency, high spatial resolution and good energy resolution while also producing time-of-flight (TOF) and depth-of-interaction (DOI) measurements. Many groups have proposed various detector designs by using scintillators such as LYSO and silicon photomultipliers (SiPM) to yield high spatial, TOF and/or DOI resolution. However, they either are rather complex and hence too difficult and expensive to implement in quantity, have inadequately compromised certain performance aspects when optimizing the other(s), or require electronics that are not yet suitable for building systems. Therefore, no practical PET system have used these detectors. We propose to validate a design for building detectors of the above kind that is practical in terms of complexity, technology readiness, and other engineering features such as compactness, physical/functional modularity, and low power consumption and heat generation of the electronics. The basic detector unit will be comparable with the conventional photomultiplier (PMT) based non-DOI clinic block detectors in size (~2?x2?) and electronic complexity (having 4 analog outputs). It has minimal detection-inactive edges so that it is tileable. Its electronics efficiently sample the analog outputs and support digital event processing and transmission using modern commodity digital electronics. The project has the following specific aims (SA): SA1 develops and validates the detector unit. SA2 develops a 60-channel sampling/digital board to receive 3x5 detector units to yield a panel detector of ~6.3?x10.5? in size when fully populated, as well as processing algorithms suitable for embedding in electronics. The board will employ an Ethernet interface for I/O. Therefore, the resulting panel detector will have high physical and functional modularity so that researchers can employ it to rapidly develop new PET systems. SA3 measures and validates the detector performance, including the detection efficiency, accuracy in pixel discrimination, energy resolution, DOI resolution, TOF resolution, and count rate capability. This research will demonstrate a performant detector unit having practical size and complexity, the use of a sampling/digital electronics to handle its output, and a highly modularized panel detector based on the detector units and electronics. In future R01?s, we will seek to develop and use such panel detectors for developing PET imagers to complement the current clinical systems to provide superior PET imaging of specific orangs (e.g. breast and brain) and to create new uses of PET to advance medicine (e.g. in critical care and surgery).