Top

Molecular Imaging and Biology

Published in:

01-06-2018 | Research Article

A Non-Peptidic S100A9 Specific Ligand for Optical Imaging of Phagocyte Activity In Vivo

Authors: Tom Völler, Andreas Faust, Johannes Roth, Michael Schäfers, Thomas Vogl, Sven Hermann

Published in: Molecular Imaging and Biology | Issue 3/2018

Abstract

Purpose

Non-invasive assessment of inflammatory activity in the course of various diseases is a largely unmet clinical challenge. An early feature of inflammation is local secretion of the alarmin S100A8/A9 by activated phagocytes. We here evaluate a novel S100A9-targeted small molecule tracer Cy5.5-CES271 for in vivo optical imaging of inflammatory activity in exemplary disease models.

Procedures

Dynamics of Cy5.5-CES271 was characterized in a model of irritant contact dermatitis by sequential fluorescence reflectance imaging (FRI) up to 24 h postinjection (p.i.). Specificity of Cy5.5-CES271 binding to S100A9 in vivo was examined by blocking studies and by employing S100A9^−/− mice. Finally, S100A9 secretion in acute lung inflammation was assessed by Cy5.5-CES271 and FRI of explanted lungs.

Results

In ear inflammation, we were able to non-invasively follow the time course of S100A9 expression using Cy5.5-CES271 and FRI over 24 h p.i. (peak activity at 3 h p.i.). Specificity of imaging could be shown by a significant signal reduction after predosing and using S100A9^−/− mice. In acute lung injury, local and systemic S100A8/A9 levels increased over time and correlated significantly with FRI signal levels in explanted lungs.

Conclusions

Cy5.5-CES271 shows significant accumulation in models of inflammatory diseases and specific binding to S100A9 in vivo. This study, for the first time, demonstrates the potential of a small molecule non-peptidic tracer enabling imaging of S100A9 as a marker of local phagocyte activity in inflammatory scenarios suggesting this compound class for translational attempts.

Vaidyanathan S, Patel CN, Scarsbrook AF, Chowdhury FU (2015) FDG PET/CT in infection and inflammation—current and emerging clinical applications. Clin Radiol 70(7):787–800. https://doi.org/10.1016/j.crad.2015.03.010 CrossRefPubMed

Hammoud DA (2016) Molecular imaging of inflammation: current status. J Nucl Med 57(8):1161–1165. https://doi.org/10.2967/jnumed.115.161182 CrossRefPubMedPubMedCentral

Gorla R, Erbel R, Kuehl H, Kahlert P, Tsagakis K, Jakob H, Mahabadi AA, Schlosser T, Bockisch A, Eggebrecht H, Bossone E, Jánosi RA (2015) Prognostic value of ¹⁸F-fluorodeoxyglucose PET-CT imaging in acute aortic syndromes: comparison with serological biomarkers of inflammation. Int J Cardiovasc Imaging 31(8):1677–1685. https://doi.org/10.1007/s10554-015-0725-8 CrossRefPubMed

Palestro CJ, Love C, Bhargava KK (2009) Labeled leukocyte imaging: current status and future directions. Q J Nucl Med Mol Imaging 53(1):105–123PubMed

Van De Wiele C, Sathekge M, Maes A (2014) Targeting monocytes and macrophages by means of SPECT and PET. Q J Nucl Med Mol Imaging 58:269–275

Rennen HJJM, Boerman OC, Oyen WJG, Corstens FHM (2014) Imaging infection/inflammation in the new millennium. Eur J Nucl Med 28:241–252CrossRef

Love C, Tronco GG, Palestro CJ (2006) Imaging of infection and inflammation with 99mTc-Fanolesomab. Q J Nucl Med Mol Imaging 50(2):113–120PubMed

Palestro CJ (2007) In vivo leukocyte labeling: the quest continues. J Nucl Med 48(3):332–334PubMed

Weissleder R, Nahrendorf M, Pittet MJ (2014) Imaging macrophages with nanoparticles. Nat Mater 13(2):125–138. https://doi.org/10.1038/nmat3780 CrossRefPubMed

10.

Rashidian M, Keliher EJ, Bilate AM, Duarte JN, Wojtkiewicz GR, Jacobsen JT, Cragnolini J, Swee LK, Victora GD, Weissleder R, Ploegh HL (2015) Noninvasive imaging of immune responses. Proc Nat Acad Sc USA 112(19):6146–6151. https://doi.org/10.1073/pnas.1502609112 CrossRef

11.

Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435. https://doi.org/10.1038/nature07201 CrossRefPubMed

12.

Chan JK, Roth J, Oppenheim JJ, Tracey KJ, Vogl T, Feldmann M, Horwood N, Nanchahal J (2012) Alarmins: awaiting a clinical response. J Clin Invest 122(8):2711–2719. https://doi.org/10.1172/JCI62423 CrossRefPubMedPubMedCentral

13.

Harris HE, Andersson U, Pisetsky DS (2012) HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol 8(4):195–202. https://doi.org/10.1038/nrrheum.2011.222 CrossRefPubMed

14.

Rock KL, Latz E, Ontiveros F, Kono H (2010) The sterile inflammatory response. Ann Rev Immunol 28(1):321–342. https://doi.org/10.1146/annurev-immunol-030409-101311 CrossRef

15.

Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MAD, Nacken W, Foell D, van der Poll T, Sorg C, Roth J (2007) Mrp8 and Mrp14 are endogenous activators of toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nature Med 13(9):1042–1049. https://doi.org/10.1038/nm1638 CrossRefPubMed

16.

Frosch M, Strey A, Vogl T, Wulffraat NM, Kuis W, Sunderkötter C, Harms E, Sorg C, Roth J (2000) Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis. Arthritis Rheumatol 43(3):628–637. https://doi.org/10.1002/1529-0131(200003)43:3<628::AID-ANR20>3.0.CO;2-X CrossRef

17.

Frosch M, Vogl T, Seeliger S, Wulffraat N, Kuis W, Viemann D, Foell D, Sorg C, Sunderkötter C, Roth J (2003) Expression of myeloid-related proteins 8 and 14 in systemic-onset juvenile rheumatoid arthritis. Arthritis Rheumatol 48(9):2622–2626. https://doi.org/10.1002/art.11177 CrossRef

18.

Petersen B, Wolf M, Austermann J, van Lent P, Foell D, Ahlmann M, Kupas V, Loser K, Sorg C, Roth J, Vogl T (2013) The alarmin Mrp8/14 as regulator of the adaptive immune response during allergic contact dermatitis. EMBO J 32(1):100–111. https://doi.org/10.1038/emboj.2012.309 CrossRefPubMed

19.

Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, Stanevicha V, Mihaylova D, Ferriani V, Tsakalidou FK, Foeldvari I, Cuttica R, Gonzalez B, Ravelli A, Khubchandani R, Oliveira S, Armbrust W, Garay S, Vojinovic J, Norambuena X, Gamir ML, García-Consuegra J, Lepore L, Susic G, Corona F, Dolezalova P, Pistorio A, Martini A, Ruperto N, Roth J, Paediatric Rheumatology International Trials Organization (PRINTO) (2010) Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. J Am Med Assoc 303(13):1266–1273. https://doi.org/10.1001/jama.2010.375 CrossRef

20.

Henderson P, Anderson NH, Wilson DC (2014) The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 109(5):637–645. https://doi.org/10.1038/ajg.2013.131 CrossRefPubMed

21.

Gerss J, Roth J, Holzinger D, Ruperto N, Wittkowski H, Frosch M, Wulffraat N, Wedderburn L, Stanevicha V, Mihaylova D, Harjacek M, Len C, Toppino C, Masi M, Minden K, Saurenmann T, Uziel Y, Vesely R, Apaz MT, Kuester RM, Elorduy MJR, Burgos-Vargas R, Ioseliani M, Magni-Manzoni S, Unsal E, Anton J, Balogh Z, Hagelberg S, Mazur-Zielinska H, Tauber T, Martini A, Foell D, for the Paediatric Rheumatology International Trials Organization (PRINTO) (2012) Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study. Ann Rheum Dis 71(12):1991–1997. https://doi.org/10.1136/annrheumdis-2012-201329 CrossRefPubMed

22.

von Roon AC, Karamountzos L, Purkayastha S, Reese GE, Darzi AW, Teare JP, Paraskeva P, Tekkis PP (2007) Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol 102(4):803–813. https://doi.org/10.1111/j.1572-0241.2007.01126.x CrossRef

23.

Pruenster M, Vogl T, Roth J, Sperandio M (2016) S100A8/A9: from basic science to clinical application. Pharmacol Therap 167:120–131. https://doi.org/10.1016/j.pharmthera.2016.07.015 CrossRef

24.

Vogl T, Eisenblatter M, Voller T et al (2014) Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity. Nat Commun 5:4593. https://doi.org/10.1038/ncomms5593 CrossRefPubMedPubMedCentral

25.

Becker A, Hokamp NG, Zenker S, Flores-Borja F, Barzcyk K, Varga G, Roth J, Geyer C, Heindel W, Bremer C, Vogl T, Eisenblaetter M (2015) Optical in vivo imaging of the alarmin S100A9 in tumor lesions allows for estimation of the individual malignant potential by evaluation of tumor-host cell interaction. J Nucl Med 56(3):450–456. https://doi.org/10.2967/jnumed.114.146688 CrossRefPubMed

26.

Bjork P, Bjork A, Vogl T et al (2009) Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol e97:7

27.

Ichikawa T, Lamb JC, Christensson PI, Hartley-Asp B, Isaacs JT (1992) The antitumor effects of the quinoline-3-carboxamide linomide on Dunning R-3327 rat prostatic cancers. Cancer Res 52(11):3022–3028PubMed

28.

Faust A, Voller T, Busch F et al (2015) Development and evaluation of a non-peptidic ligand for the molecular imaging of inflammatory processes using S100A9 (MRP14) as a novel target. Chem Commun (Camb) 51(86):15637–15640. https://doi.org/10.1039/C5CC07019H CrossRef

29.

Achouiti A, Vogl T, Urban CF et al (2012) Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis. PLoS Pathog 8:e1002987CrossRefPubMedPubMedCentral

30.

Manitz MP, Horst B, Seeliger S, Strey A, Skryabin BV, Gunzer M, Frings W, Schonlau F, Roth J, Sorg C, Nacken W (2003) Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol Cell Biol 23(3):1034–1043. https://doi.org/10.1128/MCB.23.3.1034-1043.2003 CrossRefPubMedPubMedCentral

31.

Hobbs JA, May R, Tanousis K et al (2003) Myeloid cell function in MRP-14 (S100A9) null mice. Mol Cell Biol 23(7):2564–2576. https://doi.org/10.1128/MCB.23.7.2564-2576.2003 CrossRefPubMedPubMedCentral

32.

van Zoelen MA, Vogl T, Foell D et al (2009) Expression and role of myeloid-related protein-14 in clinical and experimental sepsis. Am J Resp Crit Care 180(11):1098–1106. https://doi.org/10.1164/rccm.200810-1552OC CrossRef

33.

Gopal R, Monin L, Torres D et al (2013) S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Resp Crit Care 188:1137–1146CrossRef

34.

Ehrchen JM, Sunderkotter C, Foell D, Vogl T, Roth J (2009) The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 86(3):557–566. https://doi.org/10.1189/jlb.1008647 CrossRefPubMed

35.

Achouiti A, Vogl T, Endeman H, Mortensen BL, Laterre PF, Wittebole X, van Zoelen MAD, Zhang Y, Hoogerwerf JJ, Florquin S, Schultz MJ, Grutters JC, Biesma DH, Roth J, Skaar EP, van ’t Veer C, de Vos AF, van der Poll T (2014) Myeloid-related protein-8/14 facilitates bacterial growth during pneumococcal pneumonia. Thorax 69(11):1034–1042. https://doi.org/10.1136/thoraxjnl-2014-205668 CrossRefPubMed

36.

Weissleder R, Ntziachristos V (2003) Shedding light onto live molecular targets. Nature Med 9(1):123–128. https://doi.org/10.1038/nm0103-123 CrossRefPubMed

37.

Glimm AM, Werner SG, Burmester GR, Backhaus M, Ohrndorf S (2016) Analysis of distribution and severity of inflammation in patients with osteoarthitis compared to rheumatoid arthritis by ICG-enhanced fluorescence optical imaging and musculoskeletal ultrasound: a pilot study. Ann Rheumat Dis 75(3):566–570. https://doi.org/10.1136/annrheumdis-2015-207345 CrossRefPubMed

38.

Werner SG, Langer HE, Ohrndorf S, Bahner M, Schott P, Schwenke C, Schirner M, Bastian H, Lind-Albrecht G, Kurtz B, Burmester GR, Backhaus M (2012) Inflammation assessment in patients with arthritis using a novel in vivo fluorescence optical imaging technology. Ann Rheumat Dis 71(4):504–510. https://doi.org/10.1136/annrheumdis-2010-148288 CrossRefPubMed

39.

Bengtsson AA, Sturfelt G, Lood C et al (2012) Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus. Arthritis Rheumatol 64:1579–1588CrossRef

40.

Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj KW, Sharrack B, Filippi M (2008) Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 371(9630):2085–2092. https://doi.org/10.1016/S0140-6736(08)60918-6 CrossRefPubMed

Title: A Non-Peptidic S100A9 Specific Ligand for Optical Imaging of Phagocyte Activity In Vivo
Authors: Tom Völler
Andreas Faust
Johannes Roth
Michael Schäfers
Thomas Vogl
Sven Hermann
Publication date: 01-06-2018
Publisher: Springer International Publishing
Published in: Molecular Imaging and Biology / Issue 3/2018
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-017-1148-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A Non-Peptidic S100A9 Specific Ligand for Optical Imaging of Phagocyte Activity In Vivo

Abstract

Purpose

Procedures

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2018

Translating Molecular Imaging of the Vulnerable Plaque—a Vulnerable Project?

Nanostructured Lipid Carrier Co-loaded with Doxorubicin and Docosahexaenoic Acid as a Theranostic Agent: Evaluation of Biodistribution and Antitumor Activity in Experimental Model

Assessing Glomerular Filtration in Small Animals Using [68Ga]DTPA and [68Ga]EDTA with PET Imaging

MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding

Correction to: LyP-1 Conjugated Nanoparticles for Magnetic Resonance Imaging of Triple Negative Breast Cancer

Applying Amide Proton Transfer MR Imaging to Hybrid Brain PET/MR: Concordance with Gadolinium Enhancement and Added Value to [18F]FDG PET