Document text
Principal Investigator: Tammie Lee Smith Benzinger
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $748,349
Funding agency: National Institute on Aging
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.
Terms: <18-FDG><18F- FDG><18FDG><2 Fluoro 2 deoxy D glucose><2-Fluoro-2-deoxyglucose><3-NP acid><3-nitropropanoic acid><3-nitropropionic acid><4 hydroxynonenal><4-HNE cpd><4-hydroxy-2,3-nonenal><4-hydroxy-2-nonenal><4-hydroxynonen-2-al><AD dementia><AD related dementia><AD transgenic mice><ADRD><APP-PS1><APP/PS1><Address><Aducanumab><Age><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimer's disease transgenic mice><Alzheimer's transgenic mice><Alzheimers Dementia><Amyloid><Amyloid (Aβ) plaques><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Apoplexy><Atomic Medicine><Authorization><Authorization documentation><Aβ><BIIB037><Biochemical><Biodistribution><Biological><Biological Markers><Body Tissues><Brain><Brain Inflammation><Brain Nervous System><Brain Trauma><Brain Vascular Accident><Brain imaging><Brain region><CAT scan><CT X Ray><CT Xray><CT imaging><CT scan><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Causality><Cell Body><Cell Culture Techniques><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Characteristics><Chemistry><Chronic><Classification><Clinical><Clinical Data><Complex><Computed Tomography><Corpus Striatum><Corpus striatum structure><Cysteine><Data><Data Correlations><Degenerative Neurologic Disorders><Deposit><Deposition><Development><Diagnosis><Diagnostic><Discipline of Nuclear Medicine><Disease><Disorder><Disseminated Sclerosis><Dose><Drug Kinetics><Dysfunction><Encephalitis><Encephalon><Etiology><Excretory function><FDA approved><Free Radicals><Functional Imaging><Functional disorder><Functional impairment><Gehrig's Disease><Generations><Glioblastoma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Half-Cystine><Heart Vascular><Hortega cell><Human><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><IRB><IRBs><Image><Imaging Device><Imaging Instrument><Imaging Tool><Impairment><Inflammation><Injections><Innate Immune System><Institution><Institutional Review Boards><L-Cysteine><Life Style><Lifestyle><Lipid Peroxidation><Location><Lou Gehrig Disease><M mulatta><M. mulatta><MT-bound tau><Macaca mulatta><Mediating><Messenger RNA><Mice><Mice Mammals><Microglia><Mitochondria><Mitochondrial DNA><Modeling><Modern Man><Modification><Mole the mammal><Molecular><Moles><Monoclonal Antibody Therapy><Multiple Sclerosis><Murine><Mus><Muscular Dystrophies><Myodystrophica><Myodystrophy><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuritic Plaques><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Nuclear><Nuclear Medicine><Nucleic Acids><Organ><Outcome><Output><Oxidants><Oxidation-Reduction><Oxidizing Agents><PET><PET Scan><PET imaging><PET/CT><PET/CT scan><PETSCAN><PETT><Paralysis Agitans><Parkinson><Parkinson Disease><Participant><Pathogenesis><Patients><Penetration><Peripheral><Permission><Pharmacokinetics><Physiologic Imaging><Physiopathology><Pilot Projects><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Parkinsonism><Primary Senile Degenerative Dementia><Production><Proteins><Qualifying><Rad.-PET><Radiation Dosimetry><Radiology / Radiation Biology / Nuclear Medicine><Radiometry><Radiopharmaceutical Compound><Radiopharmaceuticals><Redox><Reporting><Rhesus Macaque><Rhesus Monkey><Role><Running><Safety><Saline><Saline Solution><Scanning><Senile Plaques><Site><Striate Body><Striatum><Stroke><Structure-Activity Relationship><Superoxide Anion><Superoxide Radical><Superoxides><Synapses><Synaptic><Systematics><Techniques><Therapeutic><Therapeutic Intervention><Time><Tissues><Tomodensitometry><Toxicology><Toxin><Tracer><Translations><Traumatic Brain Injury><Treatment Efficacy><Validation><Venous><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><a beta peptide><aberrant folded protein><aberrant folded proteins><aberrant protein folding><abeta><abeta deposition><abnormal folded protein><abnormal folded proteins><abnormal protein folding><aduhelm><ages><amyloid beta><amyloid beta deposition><amyloid beta plaque><amyloid β deposition><amyloid-b plaque><amyloid-b protein><analyzing longitudinal><aβ deposition><aβ plaques><base><bases><beta amyloid fibril><beta-nitropropionic acid><bio-markers><biologic><biologic marker><biomarker><biomarker evaluation><brain attack><brain visualization><catscan><causation><cell culture><cell cultures><cerebral vascular accident><cerebrovascular accident><chemical structure function><circulating biomarkers><circulating markers><circulatory system><cohort><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><cored plaque><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><denitration><design><designing><developmental><diffuse plaque><disease causation><dosimetry><electron acceptor><excretion><first in man><first-in-human><fluorescence imaging><fluorescent imaging><fluorodeoxyglucose><gitter cell><glial activation><glial cell activation><glioblastoma multiforme><glucose metabolism><health care management><health management><healthcare management><imaging><imaging agent><imaging probe><in vivo><insoluble aggregate><insular sclerosis><intervention efficacy><intervention therapy><intravenous injection><kinetic model><longitudinal analysis><mAB-based therapy><mAb therapy><mAb-based therapeutics><mRNA><manufacture><marker evaluation><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><misfolded protein><misfolded proteins><mitochondrial><mitochondrial dysfunction><molecular imaging><molecule imaging><mouse model><mtDNA><murine model><muscle dystrophy><nano><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><nitration><non-contrast CT><non-human primate><non-invasive imaging><noncontrast CT><noncontrast computed tomography><nonhuman primate><noninvasive imaging><novel><oxidation><oxidation reduction reaction><p-tau><p-τ><pathologic protein folding><pathophysiology><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><physiological imaging><pilot study><positron emission computed tomography><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><post-translational modification of tau><posttranslational modification of tau><pre-clinical imaging><preclinical imaging><primary degenerative dementia><protein aggregate><protein aggregation><protein misfolding><proteotoxic protein><proteotoxin><quantitative imaging><radioactive drugs><radioassay><radiolabel><radiolabels><radiotherapeutic drugs><radiotracer><rational design><senile dementia of the Alzheimer type><side effect><social role><soluble amyloid precursor protein><spongioblastoma multiforme><standard of care><striatal><stroked><strokes><structure function relationship><synapse><systemic inflammation><systemic inflammatory response><tau><tau Proteins><tau factor><tau phosphorylation><tau posttranslational modification><tau-1><therapeutic efficacy><therapeutic stratification><therapy efficacy><translation><traumatic brain damage><treatment stratification><uptake><validations><τ Proteins><τ phosphorylation>