Skip to main content

Gallium Imaging of Infection and Inflammation

  • Chapter
  • First Online:
Nuclear Medicine and Immunology
  • 1274 Accesses

Abstract

Infection and inflammation are both important causes of morbidity and mortality and often co-exist not just with each other but also with other disease entities. In instances where a definite distinction between the two processes is required in order to best manage the patient, time may not be sufficient to wait for the results of time-consuming cultures. Imaging provides a noninvasive diagnostic tool, which, when applied as positron emission tomography/computed tomography (PET/CT), is able to image the whole body in one investigation and to provide detailed morphological information combined with molecular information on the pathophysiology in one convenient study. Application of gallium-68-based tracers provides further important advantages with regard to costs, availability, and versatility. These advancements developed from earlier infection and inflammation single-photon emission computed tomography (SPECT) imaging performed with [67Ga]Ga-citrate, which has supplied physicians over many decades with a versatile diagnostic tool, commonly referred to as “the poor man’s alternative to PET.” In this chapter, inflammation and infection imaging will be discussed and further divided into preclinical developments, clinical applications, and possible future applications.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. MacNeil A, Glaziou P, Sismanidis C, Maloney S, Floyd K. Global epidemiology of tuberculosis and progress toward achieving global targets - 2017. MMWR Morb Mortal Wkly Rep. 2019;68:263–6.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Espinoza J. Malaria resurgence in the Americas: an underestimated threat. Pathogens. 2019;8:11–4.

    Article  PubMed Central  Google Scholar 

  3. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.

    Article  CAS  PubMed  Google Scholar 

  4. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Decristoforo C. Gallium-68—a new opportunity for PET available from a long shelf-life generator - automation and applications. Curr Radiopharm. 2012;5:212–20.

    Article  CAS  PubMed  Google Scholar 

  6. Roesch F. Maturation of a key resource - the germanium-68/gallium-68 generator: development and new insights. Curr Radiopharm. 2012;5:202–11.

    Article  CAS  PubMed  Google Scholar 

  7. Tsuchiya Y, Nakao A, Komatsu T, Yamamoto M, Shimokata K. Relationship between gallium 67 citrate scanning and transferrin receptor expression in lung diseases. Chest. 1992;102:530–4.

    Article  CAS  PubMed  Google Scholar 

  8. Spang P, Herrmann C, Roesch F. Bifunctional Gallium-68 chelators—past, present, and future. Semin Nucl Med. 2016;46:373–94.

    Article  PubMed  Google Scholar 

  9. Vorster M, Maes A, Van deWiele C, Sathekge M. Gallium-68: a systematic review of its nononcological applications. Nucl Med Commun. 2013;34:834–54.

    Article  CAS  PubMed  Google Scholar 

  10. Vorster M, Maes A, Van de Wiele C, Sathekge M. Gallium-68 PET—a powerful generator-based alternative to infection and inflammation imaging. Semin Nucl Med. 2016;46:436–47.

    Article  PubMed  Google Scholar 

  11. Velikyan I. Prospective of 68Ga radionuclide contribution to the development of imaging agents for infection and inflammation. Contrast Media Mol Imaging. 2018;2018:1–24.

    Article  CAS  Google Scholar 

  12. Siemsen JK, Grebe SF, Waxman AD. The use of gallium-67 in pulmonary disorders. Semin Nucl Med. 1978;8:235–49.

    Article  CAS  PubMed  Google Scholar 

  13. Auletta S, Varani M, Horvat R, Galli F, Signore A, Hess S. PET radiopharmaceuticals for specific bacteria imaging: a systematic review. JCM. 2019;8:197–25.

    Article  CAS  PubMed Central  Google Scholar 

  14. Ebenhan T, Chadwick N, Sathekge MM, Govender P, Govender T, Kruger HG, Marjanovic-Painter B, Zeevaart JR. Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT. Nucl Med Biol. 2014;41:390–400.

    Article  CAS  PubMed  Google Scholar 

  15. Satpati D, Arjun C, Krishnamohan R, Samuel G, Banerjee S. 68Ga-labeled ciprofloxacin conjugates as radiotracers for targeting bacterial infection. Chem Biol Drug Des. 2015;87:680–6.

    Article  PubMed  CAS  Google Scholar 

  16. Mokaleng BB, Ebenhan T, Ramesh S, et al. Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent. Biomed Res Int. 2015;2015:1–12.

    Article  CAS  Google Scholar 

  17. Lankinen P, Mäkinen TJ, Pöyhönen TA, Virsu P, Salomäki S, Hakanen AJ, Jalkanen S, Aro HT, Roivainen A. 68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phase of inflammation in healing bones and the progress of infection in osteomyelitic bones. Eur J Nucl Med Mol Imaging. 2007;35:352–64.

    Article  PubMed  CAS  Google Scholar 

  18. Kumar V, Boddeti DK, Evans SG, Roesch F, Howman-Giles R. Potential use of 68Ga-apo-transferrin as a PET imaging agent for detecting Staphylococcus aureus infection. Nucl Med Biol. 2011;38:393–8.

    Article  CAS  PubMed  Google Scholar 

  19. Welling MM, Bunschoten A, Kuil J, Nelissen RGHH, Beekman FJ, Buckle T, van Leeuwen FWB. Development of a hybrid tracer for SPECT and optical imaging of bacterial infections. Bioconjug Chem. 2015;26:839–49.

    Article  CAS  PubMed  Google Scholar 

  20. Nanni C, Marangoni A, Quarta C, et al. Small animal PET for the evaluation of an animal model of genital infection. Clin Physiol Funct Imaging. 2009;29:187–92.

    Article  PubMed  Google Scholar 

  21. Petrik M, Haas H, Dobrozemsky G, Lass-Florl C, Helbok A, Blatzer M, Dietrich H, Decristoforo C. 68Ga-siderophores for PET imaging of invasive pulmonary aspergillosis: proof of principle. J Nucl Med. 2010;51:639–45.

    Article  CAS  PubMed  Google Scholar 

  22. Petrik M, Franssen GM, Haas H, Laverman P, Hörtnagl C, Schrettl M, Helbok A, Lass-Flörl C, Decristoforo C. Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging. Eur J Nucl Med Mol Imaging. 2012;39:1175–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Petrik M, Haas H, Laverman P, Schrettl M, Franssen GM, Blatzer M, Decristoforo C. 68Ga-Triacetylfusarinine C and 68Ga-ferrioxamine E for Aspergillus infection imaging: uptake specificity in various microorganisms. Mol Imaging Biol. 2013;16:102–8.

    Article  PubMed Central  Google Scholar 

  24. Rizzello A, Di Pierro D, Lodi F, et al. Synthesis and quality control of 68Ga citrate for routine clinical PET. Nucl Med Commun. 2009;30:542–5.

    Article  CAS  PubMed  Google Scholar 

  25. Palestro CJ, Torres MA. Radionuclide imaging in orthopedic infections. Semin Nucl Med. 1997;27:334–45.

    Article  CAS  PubMed  Google Scholar 

  26. Palestro CJ. The current role of gallium imaging in infection. Semin Nucl Med. 1994;24:128–41.

    Article  CAS  PubMed  Google Scholar 

  27. Vorster M, Buscombe J, Saad Z, Sathekge M. Past and future of Ga-citrate for infection and inflammation imaging. Curr Pharm Des. 2018;24:787–94.

    Article  CAS  PubMed  Google Scholar 

  28. Nanni C, Errani C, Boriani L, et al. 68Ga-citrate PET/CT for evaluating patients with infections of the bone: preliminary results. J Nucl Med. 2010;51:1932–6.

    Article  PubMed  Google Scholar 

  29. Vorster M, Maes A, Jacobs A, Malefahlo S, Pottel H, Van de Wiele C, Sathekge MM. Evaluating the possible role of 68Ga-citrate PET/CT in the characterization of indeterminate lung lesions. Ann Nucl Med. 2014;20:303–8.

    Google Scholar 

  30. Mukherjee A, Bhatt J, Shinto A, Korde A, Kumar M, Kamaleshwaran K, Joseph J, Sarma HD, Dash A. 68Ga-NOTA-ubiquicidin fragment for PET imaging of infection: from bench to bedside. J Pharm Biomed Anal. 2018;159:245–51.

    Article  CAS  PubMed  Google Scholar 

  31. Besson FL, Chaumet-Riffaud P, Playe M, Noel N, Lambotte O, Goujard C, Prigent A, Durand E. Contribution of 18F-FDG PET in the diagnostic assessment of fever of unknown origin (FUO): a stratification-based meta-analysis. Eur J Nucl Med Mol Imaging. 2016;43(10):1887–95.

    Article  CAS  PubMed  Google Scholar 

  32. Chen C-J, Kono H, Golenbock D, Reed G, Akira S, Rock KL. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med. 2007;13:851–6.

    Article  CAS  PubMed  Google Scholar 

  33. Tsan M-F. Mechanism of gallium-67 accumulation in inflammatory lesions. J Nucl Med. 1985;26:88–92.

    CAS  PubMed  Google Scholar 

  34. Elliott DE, Li J, Blum AM, Metwali A, Patel YC, Weinstock JV. SSTR2A is the dominant somatostatin receptor subtype expressed by inflammatory cells, is widely expressed and directly regulates T cell IFN-gamma release. Eur J Immunol. 1999;29:2454–63.

    Article  CAS  PubMed  Google Scholar 

  35. Prevete N, Liotti F, Marone G, Melillo RM, de Paulis A. Formyl peptide receptors at the interface of inflammation, angiogenesis and tumor growth. Pharmacol Res. 2015;102:184–91.

    Article  CAS  PubMed  Google Scholar 

  36. Uddin MJ, Crews BC, Ghebreselasie K, Huda I, Kingsley PJ, Ansari MS, Tantawy MN, Reese J, Marnett LJ. Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer. Cancer Prev Res. 2011;4:1536–45.

    Article  CAS  Google Scholar 

  37. Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149–60.

    Article  CAS  PubMed  Google Scholar 

  38. Hodivala-Dilke K. αvβ3 integrin and angiogenesis: a moody integrin in a changing environment. Curr Opin Cell Biol. 2008;20:514–9.

    Article  CAS  PubMed  Google Scholar 

  39. Jalkanen S, Salmi M. VAP-1 and CD73, endothelial cell surface enzymes in leukocyte extravasation. Arterioscler Thromb Vasc Biol. 2008;28:18–26.

    Article  CAS  PubMed  Google Scholar 

  40. Roivainen A, Jalkanen S, Nanni C. Gallium-labelled peptides for imaging of inflammation. Eur J Nucl Med Mol Imaging. 2012;39:68–77.

    Article  CAS  Google Scholar 

  41. Autio A, Henttinen T, Sipilä HJ, Jalkanen S, Roivainen A. Mini-PEG spacering of VAP-1-targeting 68 Ga-DOTAVAP-P1 peptide improves PET imaging of inflammation. EJNMMI Res. 2011;1:1–7.

    Article  CAS  Google Scholar 

  42. Brennan TV, Rendell VR, Yang Y. Innate immune activation by tissue injury and cell death in the setting of hematopoietic stem cell transplantation. Front Immunol. 2015;6:1813–9.

    Article  CAS  Google Scholar 

  43. Watanabe H, Ono M, Iikuni S, Yoshimura M, Matsumura K, Kimura H, Saji H. A 68Ga complex based on benzofuran scaffold for the detection of Î2-amyloid plaques. Bioorg Med Chem Lett. 2014;24:4834–7.

    Article  CAS  PubMed  Google Scholar 

  44. Choi H, Phi JH, Paeng JC, Kim S-K, Lee Y-S, Jeong JM, Chung J-K, Lee DS, Wang K-C. Imaging of integrin α(v)β(3) expression using 68Ga-RGD positron emission tomography in pediatric cerebral infarct. Mol Imaging. 2013;12:213–7.

    Article  CAS  PubMed  Google Scholar 

  45. Haukkala J, Laitinen I, Luoto P, et al. 68Ga-DOTA-RGD peptide: biodistribution and binding into atherosclerotic plaques in mice. Eur J Nucl Med Mol Imaging. 2009;36:2058–67.

    Article  CAS  Google Scholar 

  46. Eo JS, Paeng JC, Lee S, Lee Y-S, Jeong JM, Kang KW, Chung J-K, Lee DS. Angiogenesis imaging in myocardial infarction using 68Ga-NOTA-RGD PET. Coron Artery Dis. 2013;24:303–11.

    Article  PubMed  Google Scholar 

  47. Silvola JM, Laitinen I, Sipilä HJ, Laine VJO, Leppänen P, Ylä-Herttuala S, Knuuti J, Roivainen A. Uptake of 68 gallium in atherosclerotic plaques in LDLR−/− ApoB 100/100 mice. EJNMMI Res. 2011;1:1–8.

    Article  CAS  Google Scholar 

  48. Li X, Bauer W, Israel I, Kreissl MC, et al. Targeting P-selectin by gallium-68–labeled fucoidan positron emission tomography for noninvasive characterization of vulnerable plaques: correlation with in vivo. Am Heart Assoc. 2014; https://doi.org/10.1161/ATVBAHA.114.303485/-/DC1.

  49. Lapa C, Reiter T, Li X, Werner RA, Samnick S, Jahns R, Buck AK, Ertl G, Bauer WR. Imaging of myocardial inflammation with somatostatin receptor based PET/CT—a comparison to cardiac MRI. Int J Cardiol. 2015;194:44–9.

    Article  PubMed  Google Scholar 

  50. Kiugel M, Dijkgraaf I, Kytö V, et al. Dimeric [68Ga]DOTA-RGD peptide targeting αvβ3 integrin reveals extracellular matrix alterations after myocardial infarction. Mol Imaging Biol. 2014;16:793–801.

    Article  PubMed  Google Scholar 

  51. Thackeray JT, Bankstahl JP, Wang Y, Korf-Klingebiel M, Walte A, Wittneben A, Wollert KC, Bengel FM. Targeting post-infarct inflammation by PET imaging: comparison of 68Ga-citrate and 68Ga-DOTATATE with 18F-FDG in a mouse model. Eur J Nucl Med Mol Imaging. 2014;42:317–27.

    Article  PubMed  CAS  Google Scholar 

  52. Zhou J, Hao G, Weng H, Tsai Y-T, Baker DW, Sun X, Tang L. In vivo evaluation of medical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging probe. Bioorg Med Chem Lett. 2013;23:2044–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rominger A, Saam T, Vogl E, et al. In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. J Nucl Med. 2010;51:193–7.

    Article  PubMed  Google Scholar 

  54. Bekerman C, Bitran J. Gallium-67 scanning in the clinical evaluation of human immunodeficiency virus infection: indications and limitations. Semin Nucl Med. 1988;18:273–86.

    Article  CAS  PubMed  Google Scholar 

  55. Sathekge MM, Maes A, Pottel H, Stoltz A, Van de Wiele C. Dual time-point FDG PET-CT for differentiating benign from malignant solitary pulmonary nodules in a TB endemic area. S Afr Med J. 2010;100:598–601.

    Article  PubMed  Google Scholar 

  56. Allard AB, Buscombe J, Kidd DP. The role of gallium (Ga-67) scintigraphy in the diagnosis of sarcoidosis. MRI. 2014;03:99–107.

    Article  Google Scholar 

  57. Sobic-Saranovic D, Artiko V, Obradovic V. FDG PET imaging in sarcoidosis. Semin Nucl Med. 2013;43:404–11.

    Article  PubMed  Google Scholar 

  58. Soydal C, Kucuk ON, Ozkan E, Metin KK. Ga-68 DOTATATE accumulation in sarcoidosis. Int J Nucl Med Res. 2015;2:1–4.

    Article  Google Scholar 

  59. Ambrosini V, Zompatori M, De Luca F, et al. 68Ga-DOTANOC PET/CT allows somatostatin receptor imaging in idiopathic pulmonary fibrosis: preliminary results. J Nucl Med. 2010;51:1950–5.

    Article  PubMed  Google Scholar 

  60. Jensen SB, Käkelä M, Jødal L, Moisio O, Alstrup AKO, Jalkanen S, Roivainen A. Exploring the radiosynthesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9. J Label Compd Radiopharm. 2017;60:439–49.

    Article  CAS  Google Scholar 

  61. Buechler C, Ritter M, Orsó E, Langmann T, Klucken J, Schmitz G. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol. 2000;67:97–103.

    Article  CAS  PubMed  Google Scholar 

  62. Virtanen H, Silvola JMU, Autio A, et al. Comparison of 68Ga-DOTA-Siglec-9 and 18F-Fluorodeoxyribose-Siglec-9: inflammation imaging and radiation dosimetry. Contrast Media Mol Imaging. 2017;2017:1–10.

    Article  CAS  Google Scholar 

  63. Virtanen H, Autio A, Siitonen R, et al. 68Ga-DOTA-Siglec-9 – a new imaging tool to detect synovitis. Arthritis Res Ther. 2015;17:308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Eichendorff S, Svendsen P, Bender D, Keiding S, Christensen EI, Deleuran B, Moestrup SK. Biodistribution and PET imaging of a novel [68Ga]-anti-CD163-antibody conjugate in rats with collagen-induced arthritis and in controls. Mol Imaging Biol. 2014;17:87–93.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mariza Vorster .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Vorster, M., Sathekge, M. (2022). Gallium Imaging of Infection and Inflammation. In: Harsini, S., Alavi, A., Rezaei, N. (eds) Nuclear Medicine and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-81261-4_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-81261-4_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-81260-7

  • Online ISBN: 978-3-030-81261-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics