Recent Progress and Perspectives in Positronium Imaging with the 3γ/2γ Ratio

Positronium imaging represents an extension of conventional positron emission tomography, providing information not only about the spatial distribution of the radiopharmaceutical in the human body but also about the molecular environment and tissue architecture. The positronium lifetime and the 3$\gamma$/2$\gamma$ annihilation rate ratio are observables sensitive to the local molecular environment, including the intramolecular free-volume size and oxygen concentration, and may therefore indicate tissue hypoxia. Recent developments in multi-photon detection and event reconstruction have strengthened the feasibility of positronium imaging. Positronium lifetime imaging has already been demonstrated in vivo and is being investigated in clinical and preclinical studies. In contrast, 3$\gamma$/2$\gamma$ ratio imaging remains at the proof-of-concept stage, supported by physical modeling and experimental demonstrations of relative ratio imaging, while quantitative imaging has yet to be validated. This review summarizes recent progress in 3$\gamma$/2$\gamma$ positronium ratio imaging, discusses the main challenges, and outlines its future perspectives and potential applications.