Affiliation:
1. Stanford University School of Medicine
2. Ashvattha Therapeutics
3. Stanford University
Abstract
Abstract
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 [18F]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: [18F]fluorination of a tosyl precursor to yield [18F]3-fluoropropyl azide, followed by a copper-catalyzed click reaction. After purification and stability testing, [18F]OP-801 (150–250 µCi) was intravenously injected into female C57BL/6 mice 24 hours 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
[18F]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 liver, lung, and spleen. Gamma counting confirmed PET findings, showing significantly elevated signal in the same tissues compared to saline-injected mice: liver (p = 0.009), lung (p = 0.030), and spleen (p = 0.004). Brain PET/CT images (summed 50–60 min) revealed linearly increasing [18F]OP-801 uptake in whole brain that significantly correlated with murine sepsis score (r = 0.85, p < 0.0001). Specifically, tracer uptake was significantly higher in the brain stem, cortex, olfactory bulb, white matter, and ventricles of LPS-treated mice compared to saline-treated mice (p < 0.05).
Conclusion
[18F]OP-801 is a promising new PET tracer for sensitive and specific detection of activated macrophages and microglia that warrants further investigation.
Publisher
Research Square Platform LLC
Reference31 articles.
1. Recent developments in TSPO PET imaging as a biomarker of neuroinflammation in neurodegenerative disorders;Werry EL;Int J Mol Sci,2019
2. Krause DL, Müller N (2010) Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. International journal of Alzheimer’s disease. ;2010
3. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease;Lambert J-C;Nat Genet,2009
4. Recent Progress in the Development of TSPO PET Ligands for Neuroinflammation Imaging in Neurological Diseases;Alam MM;Nuclear Med Mol Imaging,2017
5. Chaney A, Becker E, Jackson IM, James ML (2020) PET Imaging of Neuroinflammation. In: Ross, Gambhir, editors. Molecular Imaging.