Development and Initial Assessment of [18F]OP-801: a Novel Hydroxyl Dendrimer PET Tracer for Preclinical Imaging of Innate Immune Activation in the Whole Body and Brain

Purpose Innate immune activation plays a critical role in the onset and progression of many diseases. While positron emission tomography (PET) imaging provides a non-invasive means to visualize and quantify such immune responses, most available tracers are not specific for innate immune cells. To ad...

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Published in:Molecular imaging and biology 2023-12, Vol.25 (6), p.1063-1072
Main Authors: Carlson, Mackenzie L., Jackson, Isaac M., Azevedo, E. Carmen, Reyes, Samantha T., Alam, Israt S., Kellow, Rowaid, Castillo, Jessa B., Nagy, Sydney C., Sharma, Rishi, Brewer, Matthew, Cleland, Jeffrey, Shen, Bin, James, Michelle L.
Format: Article
Language:English
Subjects:
Animals
Autoradiography
Brain
Brain - diagnostic imaging
Brain stem
Computed tomography
Cortex (olfactory)
Dendrimers
Female
Fluorination
Fluorine isotopes
Imaging
Immune response
Immune system
Immunity, Innate
Inflammation
Lipopolysaccharides
Liver
Lungs
Macrophages
Medical imaging
Medicine
Medicine & Public Health
Metabolites
Mice
Mice, Inbred C57BL
Microglia
Neuroimaging
Olfactory bulb
Positron emission
Positron emission tomography
Positron Emission Tomography Computed Tomography
Positron-Emission Tomography - methods
Radioactivity
Radiochemical analysis
Radiolabelling
Radiology
Research Article
Sepsis
Spleen
Stability analysis
Substantia alba
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Summary:Purpose Innate immune activation plays a critical role in the onset and progression of many diseases. While positron emission tomography (PET) imaging provides a non-invasive means to visualize and quantify such immune responses, most available tracers are not specific for innate immune cells. To address this need, we developed [ 18 F]OP-801 by radiolabeling a novel hydroxyl dendrimer that is selectively taken up by reactive macrophages/microglia and evaluated its ability to detect innate immune activation in mice following lipopolysaccharide (LPS) challenge. Procedures OP-801 was radiolabeled in two steps: [ 18 F]fluorination of a tosyl precursor to yield [ 18 F]3-fluoropropylazide, followed by a copper-catalyzed click reaction. After purification and stability testing, [ 18 F]OP-801 (150-250 μCi) was intravenously injected into female C57BL/6 mice 24 h after intraperitoneal administration of LPS (10 mg/kg, n =14) or saline ( n =6). Upon completing dynamic PET/CT imaging, mice were perfused, and radioactivity was measured in tissues of interest via gamma counting or autoradiography. Results [ 18 F]OP-801 was produced with >95% radiochemical purity, 12–52 μCi/μg specific activity, and 4.3±1.5% decay-corrected yield. Ex vivo metabolite analysis of plasma samples ( n =4) demonstrated high stability in mice (97±3% intact tracer >120 min post-injection). PET/CT images of mice following LPS challenge revealed higher signal in organs known to be inflamed in this context, including the liver, lung, and spleen. Gamma counting confirmed PET findings, showing significantly elevated signal in the same tissues compared to saline-injected mice: the liver (p =0.009), lung ( p =0.030), and spleen ( p =0.004). Brain PET/CT images (summed 50–60 min) revealed linearly increasing [ 18 F]OP-801 uptake in the whole brain that significantly correlated with murine sepsis score ( r =0.85, p
ISSN:1536-1632
1860-2002
DOI:10.1007/s11307-023-01850-5