ABSTRACT (30 lines) It is well established that the increasing lifespan in the US is leading to increased prevalence of brain diseases and mental illnesses, with dementia and Alzheimer’s posing significant challenges to the healthcare system. Because brain Positron Emission Tomography (PET) is a powerful noninvasive tool for clinical studies and research on fundamental mechanisms of brain maladies and metal disorders, it is expected to play an important role in addressing this challenge. However, current brain PET technologies are limited with relatively low sensitivity and low spatial resolution, constraining its usefulness in this context. Consequently, there is a critical need to improve quantitative imaging performance of brain PET. To address this need, we propose to develop advanced detector modules and associated algorithms, leveraging in particular recent progress in time-of-flight (TOF) detector technologies. These modules will lay the foundation for a follow-on project to develop an ultra-high-performance dedicated whole-brain TOF-PET camera (BRAIN PET EXPLORER) for research and clinical work. This device will overcome the current technology shortcomings by providing substantial gain in effective sensitivity and much higher spatial resolution imaging over the most current advanced brain PET system (NeuroEXPLORER commissioned in 2022). The crucial factor for improved performance of TOF-PET is better coincidence time resolution (CTR - time difference between arrival of the two annihilation photons) enabling accurate localization of the annihilation event a line-of-response. Our research is innovative because the goal of this proof-of-concept proposal is to build and demonstrate these novel and advanced thin-slab TOF-PET detector modules, and establish their suitability for scale up in a full BRAIN PET EXPLORER (future work). These detector modules will establish CTR <100 ps FWHM performance, enabling an 8× gain in effective sensitivity and outstanding 3D event localization (compared to the current state-of-art scanners) at reduced cost. An additional factor of up to 2× boost in effective sensitivity is expected to be achieved by accurate determination of the point-of-first-interaction for annihilation photons that undergo Compton scatter between detector blocks. The overall > 8× increase in the effective sensitivity can be used to reduce the activity of radiotracer administered to the patient, reduce the examination duration, increase spatial resolution, or increase the temporal resolution in dynamic brain-PET imaging. All these factors will make the brain-PET a more useful, cost-effective and affordable research and clinical tool. The advent of such innovative brain PET technology will help address growing prevalence of brain diseases and mental illnesses facing the aging population of the US. 2