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[68 Ga]Ga-FAPI-46 PET for non-invasive detection of pulmonary fibrosis disease activity

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Abstract

Purpose

The lack of effective molecular biomarkers to monitor idiopathic pulmonary fibrosis (IPF) activity or treatment response remains an unmet clinical need. Herein, we determined the utility of fibroblast activation protein inhibitor for positron emission tomography (FAPI PET) imaging in a mouse model of pulmonary fibrosis.

Methods

Pulmonary fibrosis was induced by intratracheal administration of bleomycin (1 U/kg) while intratracheal saline was administered to control mice. Subgroups from each cohort (n = 3–5) underwent dynamic 1 h PET/CT after intravenously injecting FAPI-46 radiolabeled with gallium-68 ([68 Ga]Ga-FAPI-46) at 7 days and 14 days following disease induction. Animals were sacrificed following imaging for ex vivo gamma counting and histologic correlation. [68 Ga]Ga-FAPI-46 uptake was quantified and reported as percent injected activity per cc (%IA/cc) or percent injected activity (%IA). Lung CT density in Hounsfield units (HU) was also correlated with histologic examinations of lung fibrosis.

Results

CT only detected differences in the fibrotic response at 14 days post-bleomycin administration. [68 Ga]Ga-FAPI-46 lung uptake was significantly higher in the bleomycin group than in control subjects at 7 days and 14 days. Significantly (P = 0.0012) increased [68 Ga]Ga-FAPI-46 lung uptake in the bleomycin groups at 14 days (1.01 ± 0.12%IA/cc) vs. 7 days (0.33 ± 0.09%IA/cc) at 60 min post-injection of the tracer was observed. These findings were consistent with an increase in both fibrinogenesis and FAP expression as seen in histology.

Conclusion

CT was unable to assess disease activity in a murine model of IPF. Conversely, FAPI PET detected both the presence and activity of lung fibrogenesis, making it a promising tool for assessing early disease activity and evaluating the efficacy of therapeutic interventions in lung fibrosis patients.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors wish to acknowledge the Small Animal Imaging and Radiotherapy (SAIRF) facility at UW-Madison maintaining facilities for acquiring PET/CT, including support through the Cancer Center Support Grant NCI P30CA014520. The author(s) thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520) and the Office of The Director- NIH (S10 OD023526) for use of its facilities and services.”

Funding

This work was supported in part by the University of Wisconsin-Madison, the National Institutes of Health (R01HL146402), and the Department of Defense (Early Investigator Award, W81XWH1910285). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA009206. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medical Physics, University of Wisconsin-Madison, 1111 Highland Ave., Room 7137, WI, 53705, Madison, USA

    Zachary T. Rosenkrans, Christopher F. Massey, Carolina A. Ferreira, Jeanine M. Batterton, Alan B. McMillan, Ali Pirasteh & Reinier Hernandez

  2. Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA

    Ksenija Bernau & Nathan Sandbo

  3. University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA

    Justin J. Jeffery & Reinier Hernandez

  4. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA

    Jefree J. Schulte

  5. SOFIE, Dulles, VA, USA

    Melissa Moore, Frank Valla & Christopher R. Drake

  6. Department of Radiology, University of Wisconsin-Madison, 1111 Highland Ave., Room 2423, WI, 53705, Madison, USA

    Ali Pirasteh & Reinier Hernandez

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  1. Zachary T. Rosenkrans
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Contributions

All authors have contributed to, read, and approved the manuscript. Z. T. R. and R. H. conceived the idea and designed the study. Z. T. R., C. F. M., and C. A. F. conducted the imaging experiments. K. B. and N. S. established the pulmonary fibrosis model. J. J. S. analyzed tissue staining. J. M. B. produced Ga-68. M. M., F. V., and C. R. D. prepared the FAPI-46 compound. J. J. J., A. B. M., and A. P. contributed through discussion.

Corresponding authors

Correspondence to Ali Pirasteh or Reinier Hernandez.

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All animal studies were conducted under protocols approved by the Institutional Animal Care and Use Committee at the University of Wisconsin-Madison.

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Not applicable.

Competing interests

A. P. receives departmental research support from GE Healthcare. A. P. serves as a consultant for TheraCea and Sanofi Genzyme. M. M., F. V., and C. R. D. are all current (F. V.) or former employees (M. M., C. R. D.) at SOFIE. All other authors declare no conflicts of interest.

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Rosenkrans, Z.T., Massey, C.F., Bernau, K. et al. [68 Ga]Ga-FAPI-46 PET for non-invasive detection of pulmonary fibrosis disease activity. Eur J Nucl Med Mol Imaging 49, 3705–3716 (2022). https://doi.org/10.1007/s00259-022-05814-9

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