Advancing positron lifetime tomography for clinical translation - Project Summary/Abstract This project proposes to advance positronium lifetime tomography (PLT) as a novel, quantitative imaging modality for mapping tissue microenvironment in vivo. Complementary to positron emission tomography (PET), which measures the spatial distribution of tracer uptake, PLT provides additional information about the local chemical environment by measuring the lifetime of ortho-positronium (o-Ps) atoms before annihilation. The o-Ps lifetime is sensitive to oxygen concentration, free radicals, and tissue composition, making it a promising biomarker for hypoxia and cellular stress, with broad implications for cancer, cardiovascular, and neurodegenerative diseases. A unique advantage of PLT is that it utilizes data readily acquirable on existing TOF PET scanners during routine PET scans, requiring no new hardware or additional scanning. However, despite its promise, there is currently no practical method for obtaining high-resolution, quantitative o- Ps lifetime images in vivo. To fill this critical gap, we propose to develop the first robust and fully quantitative PLT framework and demonstrate its performance using the PennPET Explorer, a state-of-the-art total-body TOF PET scanner. Building on innovations from our prior NIH R21 grant, we will enhance statistical efficiency of our lifetime image reconstruction method, incorporate advanced regularization, and implement comprehensive corrections for scatter, randoms, attenuation, and normalization. Optimized acquisition protocols will be developed through Monte Carlo simulations and phantom studies. We will validate the accuracy and utility of PLT in large animal models (pigs) under controlled hypoxic conditions, using multiple radioisotopes (⁴⁴Sc, ⁶⁸Ga, ⁸²Rb) and comparing o-Ps lifetime measurements with direct pO₂ readings from invasive probes. Following successful preclinical validation, we will conduct human imaging studies using ⁶⁸Ga-PSMA and benchmark PLT-derived hypoxia metrics against ¹⁸F-MISO PET, a gold standard for hypoxia imaging. This work will demonstrate the feasibility and clinical potential of high-resolution PLT and establish it as a complementary imaging modality to PET. The integration of PET and PLT enables simultaneous assessment of molecular tracer uptake and tissue oxygenation in a single scan. The ability to noninvasively localize hypoxic and stressed tissue with high resolution has the potential to enhance diagnosis, personalize therapy, and improve outcomes in oncology and beyond. Upon successful development, these technologies will be readily translatable to commercial PET systems through partnerships with industry leaders, paving the way for widespread clinical adoption.
