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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

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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-fluoropropylazide, 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 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

[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 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 [18F]OP-801 uptake in the 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.

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Funding

The authors would like to acknowledge Ashvattha Therapeutics, NSF GRFP Grant Number: DGE – 1656518 for funding.

Author information

Authors and Affiliations

  1. Department of Bioengineering at Stanford University, Stanford, CA, USA

    Mackenzie L. Carlson

  2. Department of Radiology at Stanford University, Stanford, CA, USA

    Isaac M. Jackson, E. Carmen Azevedo, Samantha T. Reyes, Israt S. Alam, Rowaid Kellow, Jessa B. Castillo, Sydney C. Nagy, Bin Shen & Michelle L. James

  3. Ashvattha Therapeutics, Inc., Redwood City, CA, USA

    Rishi Sharma, Matthew Brewer & Jeffrey Cleland

  4. Department of Neurology and Neurological Sciences at Stanford University, Stanford, CA, USA

    Michelle L. James

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Contributions

M.L.C. conceptualization, methodology, formal analysis, investigation, radiochemistry methodology and investigation, writing original draft, and creating figures. E.C.A., S.R., I.A., and S.N. investigation and manuscript review and editing. I.M.J. radiochemistry conceptualization, methodology, and investigation and manuscript writing and editing. R.K. radiochemistry methodology and investigation and manuscript review and editing. J.B.C. and R.S. radiochemistry conceptualization and methodology and manuscript review and editing. M.B. and J.C. supervision, funding acquisition, and manuscript review and editing. B.S. radiochemistry conceptualization, methodology, and investigation, supervision, and manuscript writing and editing. M.L.J. conceptualization, study design, data interpretation, manuscript writing and editing, supervision, and funding acquisition.

Corresponding author

Correspondence to Michelle L. James.

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Conflict of Interest

M.L.C., I.M.J., C.A., B.S., and M.L.J receive research funding and materials from Ashvattha Therapeutics. M.B., R.S., and J.C. are employees of Ashvattha Therapeutics.

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Carlson, M.L., Jackson, I.M., Azevedo, E.C. et al. 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. Mol Imaging Biol 25, 1063–1072 (2023). https://doi.org/10.1007/s11307-023-01850-5

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