Thursday, December 26, 2024
12/26/2024
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 18F-SLN-128 to serve as a noninvasive imaging agent of ROS-mediated inflammation: 1.1. APP/PS1 (Aβ); mice and their age-matched control counterparts as a function of aging (pre-plaques (3 months), mild-moderate plaques, and severe plaques (12 months) through PET/CT imaging using 3-tracer paradigm imaging (11C-PiB for Aβ; 18F-SLN-128 for ROS; and 18F-FDG for glucose metabolism); Aim 2. Evaluate pharmacokinetics of 18F-SLN128, perform metabolite analysis from both venous and arterial outputs, and kinetic modeling in non-human primates; Aim 3. Perform radiation dosimetry to determine human effective dose equivalent (HED) and toxicology studies for 18F-SLN128 to prepare for GMP production of the PET tracer; and Aim 4. Perform three qualifying runs under GMP conditions to ascertain chemistry manufacturing controls (CMCs) to produce clinical doses of the PET radiopharmaceutical for compiling data for eIND filing; Aim 5: Perform first- in-human studies using 18F-SLN128: evaluate dosimetry, biodistribution, safety, and imaging characteristics of inflammation in AD participants compared to healthy controls. Successful accomplishment of proposed aims could deliver redox-sensitive PET molecular imaging agent for management of ROS-mediated pathogenesis in Parkinson’s disease, muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, traumatic brain injury, and chronic inflammation, thus extending benefits for functional imaging of mitochondrial function in vivo well-beyond its immediate utility in Alzheimer’s disease and ADRDs.
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