SUMMARYWe are proposing a new approach to a hybrid imaging modality that has been called b+g or pamma-positronImaging [Gri07] that promises to simultaneously overcome 1) the sensitivity limits of single-gamma-ray-photonemission imaging 2) the challenge of distinguishing between two different positron-emitting isotopes and 3) thephysics-based spatial resolution limits inherent in radioisotope imaging based on detection of positron-annihilation photons alone [Lan14]. The intent is to significantly advance molecular imaging of the human brainby allowing visualization of smaller substructures quantification of smaller amounts of radiotracer uptake andsimultaneous measurement of multiple dynamic and spatial uptake patterns in advanced multi-isotope studiesof normal brain function. The required elements to make this feasible comprise i) a detector approach forannihilation and gamma-ray photons that can yield rich data for precise energy position and timing estimationfor both photoelectric and Compton interactions ii) processing algorithms in firmware and software to sort andmake optimal use of the various combinations of signals that can occur with and without coincidence iii)reconstruction algorithms based on likelihoods that incorporate probabilities of emission detection positronrange non-collinearity and Compton kinematics and iv) detection and compensation for attenuation and subjectmotion effects that if not addressed will become limiting factors for resolution and image quality. In contrast to early efforts to accomplish b+g imaging with liquid xenon detectors [Gri07] scatteringdetectors as inserts into PET scanners [Yos20] or planar semiconductor detectors paired with scintillationcameras [Lan14] we propose instead to develop and demonstrate a single detector technology and associateddata processing methods that can be used for both 511 keV annihilation photons and the higher-energy singly-emitted gamma rays. Abbaszadeh (MPI) and Levin have pioneered an edge-on crossed-strip cadmium zinctelluride (CZT) detector approach to PET detectors that provides an ideal starting point [Abb16]. Among theirattributes are high stopping power based on the edge-on geometry 3D positioning that minimizes parallaxexcellent energy resolution and dynamic range up to 1.2 MeV in maximum photon energy deposited perinteraction. Furthermore when a photon undergoes an initial scatter followed by a photoelectric absorption thesemodules yield data vectors that allow position and energy estimation for both interactions that can be analyzedwith Compton kinematics [Abb17]. We will carry out a 2-year simulation and proof-of-principle phase (UG3) in which we demonstrate b+gdetection with edge-on CZT modules and measure detector characteristics develop simulations that supportreconstructions and demonstrate acquisitions with single and multiple isotopes. We will carry out a three-yearUH3 phase to build a tomographic system with a field of view sufficient to investigate imaging of sophisticateddynamic phantoms and in vivo imaging of rodent brain as a design study and precursor to a human brain system.