18 F-AzaFol for Detection of Folate Receptor-β Positive Macrophages in Experimental Interstitial Lung Disease-A Proof-of-Concept Study.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Lausanne : Frontiers Research Foundation]
    • Subject Terms:
      Fluorine Radioisotopes*/chemistry ; Fluorine Radioisotopes*/pharmacology ; Folic Acid*/analogs & derivatives ; Folic Acid*/chemistry ; Folic Acid*/pharmacology ; Lung Diseases, Interstitial*/chemically induced ; Lung Diseases, Interstitial*/diagnostic imaging ; Lung Diseases, Interstitial*/immunology ; Positron Emission Tomography Computed Tomography* ; Radiopharmaceuticals*/chemistry ; Radiopharmaceuticals*/pharmacology; Folate Receptor 2/*immunology ; Macrophages/*immunology; Animals ; Bleomycin/adverse effects ; Bleomycin/pharmacology ; Female ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/immunology ; Humans ; Mice ; Proof of Concept Study
    • Abstract:
      Background: Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-β is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of 18 F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD. Methods: The pulmonary expression of folate receptor-β was analyzed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the 18 F-based folate radiotracer 18 F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies. Results: Folate receptor-β expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodeling. A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it also correlated with disease extent. In the mouse model of BLM-induced ILD, pulmonary accumulation of 18 F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-β positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated vs. control animals (0.31 ± 0.06% % injected activity/lung; p < 0.01). Conclusion: Our preclinical proof-of-concept study demonstrated the potential of 18 F-AzaFol as a novel imaging tool for the visualization of macrophage-driven fibrotic lung diseases.
      (Copyright © 2019 Schniering, Benešová, Brunner, Haller, Cohrs, Frauenfelder, Vrugt, Feghali-Bostwick, Schibli, Distler, Müller and Maurer.)
    • References:
      Genome Med. 2017 Mar 23;9(1):27. (PMID: 28330499)
      Eur J Nucl Med Mol Imaging. 2012 Mar;39(3):521-8. (PMID: 22258710)
      Respir Med. 2017 Oct;131:49-57. (PMID: 28947042)
      Nat Immunol. 2019 Feb;20(2):163-172. (PMID: 30643263)
      Nature. 2007 Nov 1;450(7166):110-4. (PMID: 17934446)
      Clin Chest Med. 2019 Sep;40(3):561-572. (PMID: 31376891)
      Curr Rheumatol Rev. 2017;13(3):206-218. (PMID: 28675998)
      Lab Invest. 2018 Jan;98(1):141-149. (PMID: 29035378)
      J Clin Pathol. 1988 Apr;41(4):467-70. (PMID: 3366935)
      Mol Pharm. 2015 Oct 5;12(10):3547-55. (PMID: 26333010)
      Osteoarthritis Cartilage. 2016 Sep;24(9):1613-21. (PMID: 27084348)
      Mol Syst Biol. 2015 Jul 14;11(7):819. (PMID: 26174933)
      J Nucl Med. 2016 Dec;57(12):1899-1904. (PMID: 27339874)
      Arch Biochem Biophys. 1961 Apr;93:85-94. (PMID: 13786178)
      Mod Rheumatol. 2014 Sep;24(5):816-22. (PMID: 24498991)
      Cell Immunol. 2018 Aug;330:168-174. (PMID: 29397903)
      J Nucl Med. 2017 Jan;58(1):138-143. (PMID: 27469361)
      Trends Pharmacol Sci. 2006 Aug;27(8):402-9. (PMID: 16822554)
      Ann Rheum Dis. 2019 Feb;78(2):218-227. (PMID: 30448769)
      Arthritis Res Ther. 2018 Aug 16;20(1):183. (PMID: 30115119)
      Eur Respir J. 2007 Nov;30(5):835-9. (PMID: 17978154)
      J Cereb Blood Flow Metab. 2010 Sep;30(9):1608-18. (PMID: 20424634)
      Curr Opin Chem Biol. 2009 Jun;13(3):256-62. (PMID: 19419901)
      Lancet Respir Med. 2015 Jun;3(6):483-96. (PMID: 25975761)
      Respir Res. 2019 Jan 15;20(1):10. (PMID: 30646908)
      J Nucl Med. 2014 Dec;55(12):1945-51. (PMID: 25359878)
      Autoimmun Rev. 2017 Jan;16(1):48-54. (PMID: 27682894)
      Ann Rheum Dis. 2019 Apr;78(4):577-578. (PMID: 30337426)
      Contrast Media Mol Imaging. 2017 Sep 25;2017:6592139. (PMID: 29114179)
      Curr Rheumatol Rep. 2017 Nov 9;19(12):79. (PMID: 29119259)
      Sci Rep. 2017 Oct 16;7(1):13281. (PMID: 29038604)
      Respir Med. 2013 Sep;107(9):1444-52. (PMID: 23831213)
      Ann Rheum Dis. 2018 Feb;77(2):212-220. (PMID: 29066464)
      Am J Respir Cell Mol Biol. 2015 Jul;53(1):50-9. (PMID: 25375039)
      Arthritis Rheum. 2011 Jul;63(7):1898-907. (PMID: 21437875)
      Sci Rep. 2016 Jan 22;6:19755. (PMID: 26797565)
      Bioconjug Chem. 2013 Feb 20;24(2):205-14. (PMID: 23273015)
      Eur J Nucl Med Mol Imaging. 2014 Feb;41(2):337-42. (PMID: 23942907)
      Am J Respir Crit Care Med. 2019 Nov 15;200(10):1258-1266. (PMID: 31310156)
      Mol Pharm. 2018 Nov 5;15(11):4995-5004. (PMID: 30265552)
      Arthritis Care Res (Hoboken). 2015 Jan;67(1):4-11. (PMID: 25048539)
      J Nucl Med. 2010 May;51(5):768-74. (PMID: 20395331)
      Am J Respir Cell Mol Biol. 2014 Jan;50(1):212-22. (PMID: 24003988)
      Respir Med. 2004 Jun;98(6):567-73. (PMID: 15191043)
      Rheumatology (Oxford). 2018 Feb 1;57(2):255-262. (PMID: 28379478)
      Ann Am Thorac Soc. 2014 Oct;11(8):1176-85. (PMID: 25165873)
      Sci Rep. 2018 Jun 26;8(1):9720. (PMID: 29946129)
      Chest. 2009 Nov;136(5):1333-1340. (PMID: 19892673)
      J Nucl Med. 2004 May;45(5):857-66. (PMID: 15136637)
      Semin Nucl Med. 2009 Mar;39(2):124-45. (PMID: 19187805)
      Leukemia. 2016 Jun;30(6):1355-64. (PMID: 26898190)
      J Nucl Med. 2015 Jan;56(1):127-32. (PMID: 25537989)
      Arthritis Rheum. 2011 Mar;63(3):783-94. (PMID: 21360508)
      Dis Model Mech. 2016 Jan;9(1):91-8. (PMID: 26563390)
      J Nucl Med. 2011 Jan;52(1):24-32. (PMID: 21149489)
      Curr Opin Rheumatol. 2016 May;28(3):236-45. (PMID: 27027811)
      Contrast Media Mol Imaging. 2018 Feb 21;2018:8092781. (PMID: 29681783)
      Ann Rheum Dis. 2017 Nov;76(11):1941-1948. (PMID: 28814429)
      Am J Respir Crit Care Med. 2010 Feb 1;181(3):254-63. (PMID: 19850947)
      Arthritis Res Ther. 2011 Apr 08;13(2):R59. (PMID: 21477314)
      PLoS Comput Biol. 2015 Jan 08;11(1):e1004005. (PMID: 25569146)
      N Engl J Med. 2019 Jun 27;380(26):2518-2528. (PMID: 31112379)
      Nat Rev Rheumatol. 2014 Dec;10(12):728-39. (PMID: 25266451)
      Eur J Nucl Med Mol Imaging. 2018 May;45(5):806-815. (PMID: 29335764)
      J Nucl Med. 2019 Jan;60(1):135-141. (PMID: 30042162)
      PLoS One. 2018 Mar 16;13(3):e0193057. (PMID: 29547661)
      Am J Respir Cell Mol Biol. 2013 Oct;49(4):503-10. (PMID: 23672262)
      PLoS One. 2015 Jan 15;10(1):e0116775. (PMID: 25590613)
      Rheumatology (Oxford). 2019 Apr 1;58(4):567-579. (PMID: 29893938)
      Curr Radiopharm. 2017;10(2):85-92. (PMID: 28530533)
      J Nucl Med. 2017 Feb;58(2):201-207. (PMID: 28082432)
      Mol Imaging. 2014;13:null. (PMID: 24757762)
      Chest. 2005 Jan;127(1):266-74. (PMID: 15653994)
      Respir Res. 2017 Apr 27;18(1):74. (PMID: 28449678)
      Sci Transl Med. 2017 Apr 5;9(384):. (PMID: 28381537)
      Adv Drug Deliv Rev. 2004 Apr 29;56(8):1205-17. (PMID: 15094216)
      Nat Med. 2016 Feb;22(2):154-62. (PMID: 26779814)
      Thorax. 2015 Dec;70(12):1189-96. (PMID: 26286722)
      Clin Exp Immunol. 2010 Aug;161(2):348-56. (PMID: 20550546)
      Nat Rev Immunol. 2004 Aug;4(8):583-94. (PMID: 15286725)
      J Cereb Blood Flow Metab. 2012 Jan;32(1):1-5. (PMID: 22008728)
      J Clin Biochem Nutr. 2018 Jul;63(1):58-65. (PMID: 30087545)
      Biochem Pharmacol. 1993 Aug 3;46(3):551-4. (PMID: 8394087)
      Arthritis Rheumatol. 2014 Mar;66(3):714-25. (PMID: 24574232)
      Blood. 2009 Jan 8;113(2):438-46. (PMID: 18952896)
      Trends Mol Med. 2016 Apr;22(4):303-316. (PMID: 26979628)
      J Nucl Med. 2009 Apr;50(4):538-45. (PMID: 19289428)
      J Dermatol. 2019 Mar;46(3):213-218. (PMID: 30614031)
    • Grant Information:
      P30 AR061271 United States AR NIAMS NIH HHS
    • Contributed Indexing:
      Keywords: animal model of lung fibrosis; folate receptor; folate-based 18F-PET tracer; imaging biomarkers; inflammation; interstitial lung disease; macrophages; positron emission tomography
    • Accession Number:
      0 (FOLR2 protein, human)
      0 (Fluorine Radioisotopes)
      0 (Folate Receptor 2)
      0 (Folr2 protein, mouse)
      0 (Radiopharmaceuticals)
      11056-06-7 (Bleomycin)
      935E97BOY8 (Folic Acid)
      GZ5I74KB8G (Fluorine-18)
    • Publication Date:
      Date Created: 20191212 Date Completed: 20201106 Latest Revision: 20240422
    • Publication Date:
      20240422
    • Accession Number:
      PMC6883947
    • Accession Number:
      10.3389/fimmu.2019.02724
    • Accession Number:
      31824505