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PET/CT imaging of CSF1R in a mouse model of tuberculosis

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Macrophages represent an essential means of sequestration and immune evasion for Mycobacterium tuberculosis. Pulmonary tuberculosis (TB) is characterized by dense collections of tissue-specific and recruited macrophages, both of which abundantly express CSF1R on their outer surface. 4-Cyano-N-(5-(1-(dimethylglycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide (JNJ-28312141) is a reported high affinity, CSF1R-selective antagonist. We report the radiosynthesis of 4-cyano-N-(5-(1-(N-methyl-N-([11C]methyl)glycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide ([11C]JNJ-28312141) and non-invasive detection of granulomatous and diffuse lesions in a mouse model of TB using positron emission tomography (PET).

Methods

Nor-methyl-JNJ-28312141 precursor was radiolabeled with [11C]iodomethane to produce [11C]JNJ-28312141. PET/CT imaging was performed in the C3HeB/FeJ murine model of chronic pulmonary TB to co-localize radiotracer uptake with granulomatous lesions observed on CT. Additionally, CSF1R, Iba1 fluorescence immunohistochemistry was performed to co-localize CSF1R target with reactive macrophages in infected and healthy mice.

Results

Radiosynthesis of [11C]JNJ-28312141 averaged a non-decay-corrected yield of 18.7 ± 2.1%, radiochemical purity of 99%, and specific activity averaging 658 ± 141 GBq/µmol at the end-of-synthesis. PET/CT imaging in healthy mice showed hepatobiliary [13.39–25.34% ID/g, percentage of injected dose per gram of tissue (ID/g)] and kidney uptake (12.35% ID/g) at 40–50 min post-injection. Infected mice showed focal pulmonary lesion uptake (5.58–12.49% ID/g), hepatobiliary uptake (15.30–40.50% ID/g), cervical node uptake, and renal uptake (11.66–29.33% ID/g). The ratio of infected lesioned lung/healthy lung uptake is 5.91:1, while the ratio of lesion uptake to adjacent infected radiolucent lung is 2.8:1. Pre-administration of 1 mg/kg of unlabeled JNJ-28312141 with [11C]JNJ-28312141 in infected animals resulted in substantial blockade. Fluorescence microscopy of infected and uninfected whole lung sections exclusively co-localized CSF1R staining with abundant Iba1 + macrophages. Healthy lung exhibited no CSF1R staining and very few Iba1 + macrophages.

Conclusion

[11C]JNJ-28312141 binds specifically to CSF1R + macrophages and delineates granulomatous foci of disease in a murine model of pulmonary TB.

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Acknowledgements

The authors would like to acknowledge funding from the following sources: R01AG066464, R01-AI153349, R01 EB020539, R01-AI145435-A1 and P41 EB024495. We would like to acknowledge Mariah Klunk for operating the scanner.

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Authors and Affiliations

  1. The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA

    Catherine A. Foss, Ravi Naik, Deepankar Das, Andrew Hall, Yunkou Wu, Robert F. Dannals, Sanjay K. Jain, Martin G. Pomper & Andrew G. Horti

  2. Department of Pediatrics, Center for Infection and Inflammation Imaging Research, Baltimore, MD, USA

    Catherine A. Foss, Alvaro A. Ordonez & Sanjay K. Jain

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  1. Catherine A. Foss
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  2. Alvaro A. Ordonez
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Contributions

CAF designed, conducted, analyzed, and prepared the manuscript. AAO kindly provided the mouse model, RN and DD synthesized the precursor, SKJ oversees the Ci3R where scans took place and provided funds for generation of the model (R01 EB020539), MGP provided funds (P41) and helped critically revise the manuscript and AGH designed the radiotracer and performed the radiochemistry, helped fund the work (R01AG066464) and helped revise the manuscript.

Corresponding author

Correspondence to Catherine A. Foss.

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None of the authors have anything to disclose. All animal protocols were approved by the Johns Hopkins Biosafety, Radiation Safety and Animal Care and Use Committees. No human subjects or tissues were used in this work.

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The authors declare no competing interests.

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This article is part of the Topical Collection on Infection and inflammation

Supplementary Information

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259_2022_5862_MOESM1_ESM.pdf

Supplementary file1 (PDF 118 KB) Figure SI 1. PET/CT images of three additional TB infected mice pre-administered with 1 mg/kg JNJ-28312141 by gavage 1.5 h before I.V. radiotracer administration. Red crosshairs indicate CT apparent lesions in each mouse. Radiotracer is limited to hepatobiliary clearance tissues.

259_2022_5862_MOESM2_ESM.pdf

Supplementary file2 (PDF 58 KB) Figure SI 2. Immunofluorescence microscopy of infected lung (n = 1). Fluorescence channels are as indicated. Top left is a composite of all channels. Iba1+ alveolar macrophages (red, arrows) are abundant, are very large and are associated with CSF1R staining (red). Bar = 50 µm.

259_2022_5862_MOESM3_ESM.pdf

Supplementary file3 (PDF 93 KB) Figure SI 3. Immunofluorescence microscopy of uninfected lung (n = 1).Fluorescence channels are as indicated. Top left is a composite of all channels. Iba1+ macrophages are absent. All other green and red signals exclusively co-localize as red blood cell autofluorescence in all but UV channels (bottom left panel). No red CSF1R staining is observed in healthy lung parenchyma. Bar = 50 µm

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Foss, C.A., Ordonez, A.A., Naik, R. et al. PET/CT imaging of CSF1R in a mouse model of tuberculosis. Eur J Nucl Med Mol Imaging 49, 4088–4096 (2022). https://doi.org/10.1007/s00259-022-05862-1

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  • DOI: https://doi.org/10.1007/s00259-022-05862-1

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