Novel Non-Invasive PET Imaging of Reactive Oxygen Species Using [18 F]ROStrace in Three Proteinopathy-Associated Neurodegenerative Mouse Models.

Abstract

RATIONALE AND OBJECTIVES: Prolonged oxidative stress, driven by aggregation of misfolded proteins such as amyloid beta (Aβ), alpha-synuclein (aSyn), and tau, plays a key role in neurodegenerative disease (ND) progression. Yet, the lack of noninvasive tools to monitor oxidative stress in vivo limits clinical tracking of disease. To address this, we evaluated [18 F]ROStrace, a novel superoxide (O₂·⁻)-sensitive PET tracer, in three proteinopathy-associated ND mouse models. MATERIALS AND METHODS: To validate [18 F]ROStrace's reactive oxygen species (ROS)-detecting ability across different types of NDs, we used three proteinopathy-associated ND mouse models: APP/PS1 (Alzheimer's disease, [AD]), A53T (Parkinson's disease, [PD]), and PS19 (4R tauopathy, [AD]). Each group of mice received [18 F]ROStrace injections at various ages, followed by 60 min dynamic micro-PET scans. Brain tissues were collected 24 h later for immunofluorescence to correlate tracer retention with proteinopathy-induced oxidative damage. RESULTS: [18 F]ROStrace is highly sensitive in detecting increased oxidative stress in all three ND animal models. Furthermore, region-specific elevations in [18 F]ROStrace retention strongly correlated with the abnormal aggregation of misfolded proteins and oxidative damage, highlighting the tracer's ability to pinpoint affected brain areas in different neurodegenerative conditions. CONCLUSIONS: By enabling early identification of oxidative stress, [18 F]ROStrace holds significant potential for improving ND diagnosis, monitoring disease trajectory, and evaluating therapeutic interventions targeting oxidative damage.