Abstract. Oxidative imbalance mediates pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD) and is shown to induce mitochondrial and synaptic dysfunction in neurons. The brains of patients with MCI and AD also have increased oxidative alterations, such as protein nitration and nucleic acid modifications. Combined factors provide compelling evidence for role of oxidative imbalance in conjunction with misfolded proteins (Aβ and p-Tau) and inflammation at the front and center of AD pathogenesis resulting in functional impairment of neurons. However, noninvasive imaging tools to investigate role of oxidative imbalance in vivo have been lacking and continues to be an unmet need. Compared with other standard of care techniques, molecular imaging with radiotracers offers advantage of enabling non-invasive, quantitative, and longitudinal analysis of the biochemical status of tissues and organs. To address this need, standard clinical 18F-FDG PET/CT lacks sensitivity and diagnostic robustness. Furthermore, the mechanism of its retention and trapping poorly correlates with oxidative imbalance. To address this critical gap in armamentarium of PET tracers, we have discovered a 2ndgeneration redox-sensitive molecular PET imaging probe (identified as 18F- SLN-128) through a rational design, wherein the probe penetrates neuronal cells, gets oxidized upon encountering oxidants, and trapped within cells to report on mitochondrial function. Using live-cell fluorescence imaging analysis, we demonstrate ability of molecular imaging probe (noncarrier added SLN 128) to detect LPS- and 3-nitropropionic acid (3-NP)-induced oxidative imbalance within mitochondria of the human glioblastoma U87 cells. Moreover, in a model of LPS induced systemic inflammation of mouse brain, dynamic PET/CT scans revealed a 2-fold higher 18F- SLN128 uptake and retention in LPS-treated brains relative to uninjured saline-treated cohorts. Furthermore, studies using a stereotaxic injection of 3-NP, a mitochondrial toxin into striatum demonstrates 2-fold higher retention of the radiotracer in brains of 3-NP treated mice compared with their saline treated counterparts. These data correlate with post-imaging quantitative biodistribution studies and immunohistochemical correlations thus providing evidence for microglial cell activation and neurodegeneration. Finally, dynamic PET/MR scan indicate ability of 18F- SLN-128 to penetrate brain (SUV= 3.5) in a nontargeted rhesus monkey following intravenous injection of the radiotracer. Armed with this provocative supporting data, aims of this preclinical imaging and translational MPI RO1 project are: Aim 1. Evaluate potential of 18F-SLN-128 to serve as a noninvasive imaging agent of 3-Nitropropionic acid (3 NP) induced mitochondrial dysfunction and neurodegeneration in presence or absence of N-acetyl cysteine (NAC) in mice; Aim 1 Sub Aims. Evaluate potential of 18...