Project Summary/Abstract We propose to study a promising candidate for the next generation time-of-flight (TOF)-positron emission tomography (PET) annihilation photon detector. By enabling significant increases in the reconstructed image signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), TOF-PET has demonstrated substantial clinical impact on the visualization and quantification of molecular signatures of cancer in patients. In particular it has been shown to improve image quality and accuracy in count starved and contrast limited lesion detection scenarios. The effective photon sensitivity boost provided by TOF can also be exploited to significantly reduce injected dose to the patient and/or study duration, factors that would make PET more practical, cost-effective, and safe for a variety of clinical cancer imaging applications. Thus, studies that further advance the TOF-PET technique, and photon sensitivity in general, are highly worthwhile. The key to better TOF-PET performance is to improve the annihilation photon pair coincidence time resolution (CTR) measured between any two detection elements in the system, which has been a focus of research for the past two decades. Current commercially available PET systems achieve a CTR of roughly 350 to 800 ps full-width-at-half-maximum (FWHM). A goal of this proposal is to employ a novel scintillation detection configuration in order to achieve 100 ps FWHM CTR, without compromising other important performance parameters. This novel configuration also enables another capability not possible with the conventional PET detector: The ability to measure the energy and three-dimensional (3D) position of one or more annihilation photon interactions in the detector. Owing to the fact that most incoming 511 keV photons undergo inter-crystal Compton scatter in the detectors, we can exploit the kinematics of that process to estimate the photon angle-of-incidence. If successful, that capability enables us to accurately position the first interaction of such multi-crystal events, but also offers the potential to retain a high fraction of photon events that are normally rejected by a conventional PET system, such as single (unpaired) photons, random coincidences, tissue-scatter coincidences, and multiple (>2) photon coincidences. Since these normally-discarded events are over 10-fold more probable than true coincidence events in a standard PET study, this 3D position sensitive detector shows promise as another method to greatly boost photon sensitivity. If successful, this resulting substantial photon sensitivity increase, along with the substantial image SNR enhancement possible with 100 ps CTR would enable PET to be more sensitive, accurate, and practical for cancer imaging. In this project we will design and develop these next-generation detectors, integrate these modules into a prototype partial-ring PET system, and compare image quality and accuracy available with this partial-ring system to a state-of-the-art whole body TOF-PET system currently installed in our imaging clinic.