Skip to main content

Advertisement

SpringerLink
Log in

Preclinical evaluation and pilot clinical study of [18F]AlF-NOTA-FAPI-04 for PET imaging of rheumatoid arthritis

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Fibroblast-like synoviocytes (FLSs) are key effector cells in the inflamed joints of patients with rheumatoid arthritis (RA). Previous studies have suggested that fibroblast activation protein (FAP) is highly expressed in RA-derived FLSs and is a specific marker of activated RA FLSs. In this study, we developed aluminum-[18F]-labeled 1,4,7-triazacyclononane-N,N′,N″-triacetic acid–conjugated FAP inhibitor 04 ([18F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients.

Methods

RA FLSs and NIH3T3 cells transfected with FAP were used to perform in vitro–binding studies. Biodistribution was conducted in normal DBA1 mice. Collagen-induced arthritis (CIA) models with different arthritis scores were subjected to [18F]AlF-NOTA-FAPI-04 and 18F-FDG PET imaging. Histological examinations were performed to evaluate FAP expression and Cy3 dye–labeled FAPI-04(Cy3-FAPI-04) uptake. Blocking studies with excess unlabeled FAPI-04 in CIA mice and NIH3T3 xenografts in immunocompromised mice were used to evaluate the binding specificity of [18F]AlF-NOTA-FAPI-04. Additionally, [18F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients.

Results

The binding of [18F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/105 cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/105 cells). Compared to 18F-FDG imaging, [18F]AlF-NOTA-FAPI-04 showed high uptake in inflamed joints in the early stage of arthritis, which was positively correlated with the arthritic scores (Pearson r=0.834, P<0.001). In addition, the binding of [18F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [18F]AlF-NOTA-FAPI-04 in arthritic joints both could be blocked by excessive unlabeled FAPI-04. Fluorescent staining showed that the intensity of Cy3-FAPI-04 binding to FAP increased accordingly as the expression of FAP protein increased in cells and tissue sections. Furthermore, the uptake of [18F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [18F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints.

Conclusion

[18F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data sets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

N/A.

References

  1. Wei K, Korsunsky I, Marshall JL, Gao A, Watts GFM, Major T, Croft AP, Watts J, Blazar PE, Lange JK, et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582:259–64. https://doi.org/10.1038/s41586-020-2222-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. You S, Koh JH, Leng L, Kim WU, Bucala R. The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine. Arthritis Rheum. 2018;70:637–52. https://doi.org/10.1002/art.40406.

    Article  CAS  Google Scholar 

  3. Orange DE, Agius P, DiCarlo EF, Mirza SZ, Pannellini T, Szymonifka J, Jiang CS, Figgie MP, Frank MO, Robinson WH, et al. Histologic and Transcriptional Evidence of Subclinical Synovial Inflammation in Patients With Rheumatoid Arthritis in Clinical Remission. Arthritis Rheum. 2019;71:1034–41. https://doi.org/10.1002/art.40878.

    Article  CAS  Google Scholar 

  4. Nguyen H, Ruyssen-Witrand A, Gandjbakhch F, Constantin A, Foltz V, Cantagrel A. Prevalence of ultrasound-detected residual synovitis and risk of relapse and structural progression in rheumatoid arthritis patients in clinical remission: a systematic review and meta-analysis. Rheumatology (Oxford). 2014;53:2110–8. https://doi.org/10.1093/rheumatology/keu217.

    Article  Google Scholar 

  5. Mathew AJ, Danda D, Conaghan PG. MRI and ultrasound in rheumatoid arthritis. Curr Opin Rheumatol. 2016;28:323–9. https://doi.org/10.1097/bor.0000000000000282.

    Article  PubMed  Google Scholar 

  6. Nosrati Z, Bergamo M, Rodríguez-Rodríguez C, Saatchi K, Häfeli UO. Refinement and validation of infrared thermal imaging (IRT): a non-invasive technique to measure disease activity in a mouse model of rheumatoid arthritis. Arthritis Res Ther. 2020;22:281. https://doi.org/10.1186/s13075-020-02367-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020;39:783–803. https://doi.org/10.1007/s10555-020-09909-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bauer S, Jendro MC, Wadle A, Kleber S, Stenner F, Dinser R, Reich A, Faccin E, Gödde S, Dinges H, et al. Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res Ther. 2006;8:R171. https://doi.org/10.1186/ar2080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Wehmeyer C, Naylor AJ, Kemble S, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570:246–51. https://doi.org/10.1038/s41586-019-1263-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Syed M, Flechsig P, Liermann J, Windisch P, Staudinger F, Akbaba S, Koerber SA, Freudlsperger C, Plinkert PK, Debus J, et al. Fibroblast activation protein inhibitor (FAPI) PET for diagnostics and advanced targeted radiotherapy in head and neck cancers. Eur J Nucl Med Mol Imaging. 2020;47:2836–45. https://doi.org/10.1007/s00259-020-04859-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Altmann A, Haberkorn U, Siveke J. The Latest Developments in Imaging of Fibroblast Activation Protein. J Nucl Med. 2021;62:160–7. https://doi.org/10.2967/jnumed.120.244806.

    Article  CAS  PubMed  Google Scholar 

  12. Song G, Feng T, Zhao R, Lu Q, Diao Y, Guo Q, Wang Z, Zhang Y, Ge L, Pan J, et al. CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis. Ann Rheum Dis. 2019;78:1632–41. https://doi.org/10.1136/annrheumdis-2019-215473.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, Goodman SM, Tabechian D, Hughes LB, Salomon-Escoto K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20:928–42. https://doi.org/10.1038/s41590-019-0378-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Winer J, Jung CK, Shackel I, Williams PM. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem. 1999;270:41–9. https://doi.org/10.1006/abio.1999.4085.

    Article  CAS  PubMed  Google Scholar 

  15. Liao KP, Batra KL, Chibnik L, Schur PH, Costenbader KH. Anti-cyclic citrullinated peptide revised criteria for the classification of rheumatoid arthritis. Ann Rheum Dis. 2008;67:1557–61. https://doi.org/10.1136/ard.2007.082339.

    Article  CAS  PubMed  Google Scholar 

  16. Wagner L, Klemann C, Stephan M, von Hörsten S. Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins. Clin Exp Immunol. 2016;184:265–83. https://doi.org/10.1111/cei.12757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl. 2014;8:454–63. https://doi.org/10.1002/prca.201300095.

    Article  CAS  PubMed  Google Scholar 

  18. Laverman P, van der Geest T, Terry SY, Gerrits D, Walgreen B, Helsen MM, Nayak TK, Freimoser-Grundschober A, Waldhauer I, Hosse RJ, et al. Immuno-PET and Immuno-SPECT of Rheumatoid Arthritis with Radiolabeled Anti-Fibroblast Activation Protein Antibody Correlates with Severity of Arthritis. J Nucl Med. 2015;56:778–83. https://doi.org/10.2967/jnumed.114.152959.

    Article  CAS  PubMed  Google Scholar 

  19. van der Geest T, Roeleveld DM, Walgreen B, Helsen MM, Nayak TK, Klein C, Hegen M, Storm G, Metselaar JM, van den Berg WB, et al. Imaging fibroblast activation protein to monitor therapeutic effects of neutralizing interleukin-22 in collagen-induced arthritis. Rheumatology (Oxford). 2018;57:737–47. https://doi.org/10.1093/rheumatology/kex456.

    Article  CAS  Google Scholar 

  20. van der Geest T, Laverman P, Gerrits D, Walgreen B, Helsen MM, Klein C, Nayak TK, Storm G, Metselaar JM, Koenders MI, et al. Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody. J Nucl Med. 2017;58:151–5. https://doi.org/10.2967/jnumed.116.177931.

    Article  CAS  PubMed  Google Scholar 

  21. Niemeijer AN, Leung D, Huisman MC, Bahce I, Hoekstra OS, van Dongen G, Boellaard R, Du S, Hayes W, Smith R, et al. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018;9:4664. https://doi.org/10.1038/s41467-018-07131-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fanti S, Goffin K, Hadaschik BA, Herrmann K, Maurer T, MacLennan S, Oprea-Lager DE, Oyen WJ, Rouvière O, Mottet N, et al. Consensus statements on PSMA PET/CT response assessment criteria in prostate cancer. Eur J Nucl Med Mol Imaging. 2021;48:469–76. https://doi.org/10.1007/s00259-020-04934-4.

    Article  PubMed  Google Scholar 

  23. Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert C, Vanhoeij M, Duhoux FP, Gevaert T, Simon P, et al. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma. J Nucl Med. 2016;57:27–33. https://doi.org/10.2967/jnumed.115.162024.

    Article  CAS  PubMed  Google Scholar 

  24. Sharma P, Singh SS, Gayana S. Fibroblast Activation Protein Inhibitor PET/CT: A Promising Molecular Imaging Tool. Clin Nucl Med. 2021;46:e141–50. https://doi.org/10.1097/rlu.0000000000003489.

    Article  PubMed  Google Scholar 

  25. Meyer C, Dahlbom M, Lindner T, Vauclin S, Mona C, Slavik R, Czernin J, Haberkorn U, Calais J. Radiation Dosimetry and Biodistribution of (68)Ga-FAPI-46 PET Imaging in Cancer Patients. J Nucl Med. 2020;61:1171–7. https://doi.org/10.2967/jnumed.119.236786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kubota K, Yamashita H, Mimori A. Clinical Value of FDG-PET/CT for the Evaluation of Rheumatic Diseases: Rheumatoid Arthritis, Polymyalgia Rheumatica, and Relapsing Polychondritis. Semin Nucl Med. 2017;47:408–24. https://doi.org/10.1053/j.semnuclmed.2017.02.005.

    Article  PubMed  Google Scholar 

  27. Irmler IM, Opfermann T, Gebhardt P, Gajda M, Bräuer R, Saluz HP, Kamradt T. In vivo molecular imaging of experimental joint inflammation by combined (18)F-FDG positron emission tomography and computed tomography. Arthritis Res Ther. 2010;12:R203. https://doi.org/10.1186/ar3176.

    Article  PubMed  PubMed Central  Google Scholar 

  28. van der Geest T, Metselaar JM, Gerrits D, van Lent PL, Storm G, Laverman P, Boerman OC. [(18)]F FDG PET/CT imaging to monitor the therapeutic effect of liposome-encapsulated prednisolone in experimental rheumatoid arthritis. J Control Release. 2015;209:20–6. https://doi.org/10.1016/j.jconrel.2015.04.019.

    Article  CAS  PubMed  Google Scholar 

  29. Chung SJ, Yoon HJ, Youn H, Kim MJ, Lee YS, Jeong JM, Chung JK, Kang KW, Xie L, Zhang MR, et al. (18)F-FEDAC as a Targeting Agent for Activated Macrophages in DBA/1 Mice with Collagen-Induced Arthritis: Comparison with (18)F-FDG. J Nucl Med. 2018;59:839–45. https://doi.org/10.2967/jnumed.117.200667.

    Article  CAS  PubMed  Google Scholar 

  30. Elzinga EH, van der Laken CJ, Comans EF, Lammertsma AA, Dijkmans BA, Voskuyl AE. 2-Deoxy-2-[F-18]fluoro-D-glucose joint uptake on positron emission tomography images: rheumatoid arthritis versus osteoarthritis. Mol Imaging Biol. 2007;9:357–60. https://doi.org/10.1007/s11307-007-0113-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wong KP, Sha W, Zhang X, Huang SC. Effects of administration route, dietary condition, and blood glucose level on kinetics and uptake of 18F-FDG in mice. J Nucl Med. 2011;52:800–7. https://doi.org/10.2967/jnumed.110.085092.

    Article  PubMed  Google Scholar 

  32. Dorst DN, Rijpkema M, Buitinga M, Walgreen B, Helsen MMA, Brennan E, Klein C, Laverman P, Ramming A, Schmidkonz C, et al. Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy. Rheumatology (Oxford). 2021. https://doi.org/10.1093/rheumatology/keab664.

  33. Schmidkonz C, Rauber S, Atzinger A, Agarwal R, Götz TI, Soare A, Cordes M, Prante O, Bergmann C, Kleyer A, et al. Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging. Ann Rheum Dis. 2020;79:1485–91. https://doi.org/10.1136/annrheumdis-2020-217408.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the staff at PET/CT center, Shandong Cancer Hospital, for their contributions to tracer preparation and PET/CT imaging.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81772760, 82072850, 81901666, 82101903), The Shandong Taishan Scholarship (Grant NO. tsqn20161076), Natural Science Foundation of Shandong Province (Grant No. ZR2020YQ55), Key Research and Development project of Shandong Province (No. 2021ZDSYS27), The Innovation Project of Shandong Academy of Medical Sciences (2021), The Youth Innovation Technology Plan of Shandong University (Grant No. 2019KJK003), and Academic Promotion Programme of Shandong First Medical University (Grant No. 2019LJ001).

Author information

Authors and Affiliations

  1. Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Ji’nan, 250014, Shandong, China

    Luna Ge, Yuang Zhang, Jihong Pan & Lin Wang

  2. Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji’nan, 250117, Shandong, China

    Luna Ge, Dandan Shi, Huancai Fan, Ruojia Zhang, Yuang Zhang, Jihong Pan & Lin Wang

  3. Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji’nan, 250117, Shandong, China

    Zheng Fu & Kai Cheng

  4. Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji’nan, 250117, Shandong, China

    Yuchun Wei & Shijie Wang

  5. Shandong First Medical University & Shandong Academy of Medical Sciences, Ji’nan, 250117, Shandong, China

    Yun Geng

  6. Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Ji’nan, 250014, Shandong, China

    Shufeng Li

  7. The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China

    Haojun Shi

  8. Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji’nan, 250117, Shandong, China

    Guanhua Song

Authors
  1. Luna Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zheng Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuchun Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dandan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yun Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huancai Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ruojia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shufeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shijie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Haojun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guanhua Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jihong Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kai Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: LW, KC.

Acquiring data: LG, FZ, YW, DS, SL, HS, GS, JP.

Analyzing data: HF, YZ, YG, SW, RZ.

Drafting manuscript: LG, KC.

Revising the manuscript: ZF, LG, YW, LW.

Approving the final content of the manuscript: All authors.

Corresponding authors

Correspondence to Kai Cheng or Lin Wang.

Ethics declarations

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication

All authors approved the article for publication.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Translational research

Supplementary Information

Fig. S1

Structural formula and quality control of the probe used in this study. (a) Synthesis of [18F]AlF-NOTA-FAPI-04. (b) Analytical HPLC chromatogram of purified [18F]AlF-NOTA-FAPI-04 at 220 nm. (c) Structural formula of Cy3-FAPI-04. (PNG 155 kb)

High Resolution Image (TIF 879 kb)

Fig. S2

In vitro stability of [18F]AlF-NOTA-FAPI-04. Radiochemical purity of [18F]AlF-NOTA-FAPI-04 in saline and 5% HSA. HSA, human serum albumin. The data are expressed as the mean ± SEM (n=6). (PNG 36 kb)

High Resolution Image (TIF 199 kb)

Fig. S3

Characterization of NIH3T3 cells stably transfected with FAP overexpression or negative control adenovirusd. (a) GFP fluorescence was observed by confocal microscopy (400×). The FAP and DPP4 expression levels were determined by qPCR (b, c) and western blotting (d). The data are expressed as the mean ± SEM (n=6). ***P<0.001. (PNG 162 kb)

High Resolution Image (TIF 866 kb)

Fig. S4

The expression of FAP in different cells. (a) The expression of FAP in OA-derived FLSs and RA-derived FLSs obtained from disaggregated synovial tissue. (b) The expression of FAP in RA-derived FLSs, monocytes, B cells and T cells. The data are expressed as the mean ± SEM (n=6). ***P<0.001. (PNG 38 kb)

High Resolution Image (TIF 171 kb)

Fig. S5

Specificity of FAPI-04. (a) FAP expression and the fluorescence intensity of Cy3-FAPI-04 in GFP-NIH3T3 and FAP-GFP-NIH3T3 cells (400×). (b) DPP4 expression and the fluorescence intensity of Cy3-FAPI-04 in FAP-GFP-NIH3T3 cells (400×). (PNG 610 kb)

High Resolution Image (TIF 2984 kb)

Fig. S6

Organ uptake of [18F]AlF-NOTA-FAPI-04 in healthly DBA/1 mice and CIA mice. (a) Normal DBA/1 mice were intravenously injected with [18F]AlF-NOTA-FAPI-04 (4.2 MBq). The organs of interest were collected at 30 min, 1 h, 2 h, and 4 h, and radioactivity was measured with a gamma counter. (b) The uptake of [18F]AlF-NOTA-FAPI-04 in CIA mice during dynamic scanning was acquired by automatic delineation of target area. The data were converted to the percentage of injected dose per mL (% ID/mL). Joint/muscle (c) and joint/blood uptake ratios (d) were calculated. The data are expressed as the mean±SEM (n=3). ***P<0.001. (PNG 316 kb)

High Resolution Image (TIF 1541 kb)

Supplementary Table 1

Primer sequences used in this study. (DOCX 13 kb)

Supplementary Table 2

Quality control analysis of [18F]AlF-NOTA-FAPI-04. (DOCX 13 kb)

Supplementary Table 3

Clinical data of the two patients. (DOCX 12 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ge, L., Fu, Z., Wei, Y. et al. Preclinical evaluation and pilot clinical study of [18F]AlF-NOTA-FAPI-04 for PET imaging of rheumatoid arthritis. Eur J Nucl Med Mol Imaging 49, 4025–4036 (2022). https://doi.org/10.1007/s00259-022-05836-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-022-05836-3

Keywords

Search

Navigation