Advertisement

Fluorine-18 Labeling of S100 Proteins for Small Animal Positron Emission Tomography

  • Markus Laube
  • Torsten Kniess
  • Christin Neuber
  • Cathleen Haase-Kohn
  • Jens PietzschEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1929)

Abstract

The interaction of S100 proteins (S100s), a multigenic family of Ca2+-binding and Ca2+-modulated proteins, with pattern recognition receptors, e.g., Toll-like receptors (TLRs), the receptor for advanced glycation end products (RAGE), or scavenger receptors (SR), is hypothesized to be of high relevance in the pathogenesis of various diseases. This includes chronic inflammatory conditions, atherosclerosis, cardiomyopathies, neurodegeneration, and progression of cancers. However, data concerning the role of circulating S100s in these pathologies are scarce. One reason for this is the shortage of suitable radiolabeling methods for direct assessment of the metabolic fate of circulating S100s in vivo. We report a radiotracer approach using radiolabeling of recombinant human S100s with the positron emitter fluorine-18 (18F) by conjugation with N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB). The methodological radiochemical part focuses on an optimized and automated synthesis of [18F]SFB comprising HPLC purification to achieve higher chemical purity. The respective radioligands, [18F]fluorobenzoylated S100s ([18F]FB-S100s), were obtained with appropriate radiochemical purities, yields, and effective molar activities. Biological applications comprise cell and tissue binding experiments in vitro, biodistribution and metabolite studies in rodents in vivo/ex vivo, and dynamic positron emission tomography studies using dedicated small animal PET systems. Radiolabeling of S100s with 18F and, particularly, the use of small animal PET provide novel probes to delineate both their metabolic fate and the functional expression of their specific receptors under normal and pathophysiological conditions in rodent models of disease.

Key words

Bolton-Hunter-type reagent In vivo imaging Radiopharmacological characterization 18F-building block Module-assisted radiosynthesis S100 proteins Calcium EF hand 

Notes

Acknowledgments

We apologize to those researchers whose works have not been mentioned due to space restrictions. We are especially grateful to our former colleagues Susan Hoppmann, Ph.D.; Susann Wolf, Ph.D.; and Nadine Herwig (née Tandler), Ph.D., who all received their doctorate in the field of S100 protein research at the Technische Universität Dresden, Faculty of Chemistry and Food Chemistry, Germany, and also to Christoph Tondera, Ph.D., for the dedicated work and many stimulating and fruitful discussions. The authors thank the staff of the cyclotron and GMP radiopharmaceuticals production units for providing [18F]fluoride. The expert technical assistance of Mareike Barth, Catharina Heinig, Regina Herrlich, Uta Lenkeit, Sebastian Meister, Aline Morgenegg, and Andrea Suhr also is greatly acknowledged. Jens Pietzsch is thankful to the Deutsche Forschungsgemeinschaft (DFG) for supporting this work by research grant PI 304/1-1 “Bildgebende In-vivo-Charakterisierung von Rezeptoren für Advanced Glycation End products mittels Kleintier-Positronen-Emissions-Tomographie” and within the Collaborative Research Center Transregio 67 “Functional Biomaterials for Controlling Healing Processes in Bone und Skin—From Material Science to Clinical Application” (CRC/TRR 67/3). This work also is part of the intramural research initiative “Radiation-Induced Vascular Dysfunction (RIVAD).”

References

  1. 1.
    Hermann A, Donato R, Weiger TM, Chazin WJ (2012) S100 calcium binding proteins and ion channels. Front Pharmacol 3:67PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL (2013) Functions of S100 proteins. Curr Mol Med 13(1):24–57PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Marenholz I, Heizmann CW, Fritz G (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 322(4):1111–1122CrossRefGoogle Scholar
  4. 4.
    Pietzsch J, Hoppmann S (2009) Human S100A12: a novel key player in inflammation? Amino Acids 36(3):381–389PubMedCrossRefGoogle Scholar
  5. 5.
    Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C (1997) Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem 272(14):9496–9502PubMedCrossRefGoogle Scholar
  6. 6.
    Davey GE, Murmann P, Heizmann CW (2001) Intracellular Ca2+ and Zn2+ levels regulate the alternative cell density-dependent secretion of S100B in human glioblastoma cells. J Biol Chem 276(33):30819–30826PubMedCrossRefGoogle Scholar
  7. 7.
    Matsunaga H, Ueda H (2006) Evidence for serum-deprivation-induced co-release of FGF-1 and S100A13 from astrocytes. Neurochem Int 49(3):294–303PubMedCrossRefGoogle Scholar
  8. 8.
    Herwig N, Belter B, Wolf S, Haase-Kohn C, Pietzsch J (2016) Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells. J Cell Mol Med 20(5):825–835PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Saho S, Satoh H, Kondo E, Inoue Y, Yamauchi A, Murata H, Kinoshita R, Yamamoto KI, Futami J, Putranto EW, Ruma IM, Sumardika IW, Youyi C, Suzawa K, Yamamoto H, Soh J, Tomida S, Sakaguchi Y, Saito K, Iioka H, Huh NH, Toyooka S, Sakaguchi M (2016) Active secretion of dimerized S100A11 induced by the peroxisome in mesothelioma cells. Cancer Microenviron 9(2–3):93–105PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Tandler N, Mosch B, Pietzsch J (2012) Protein and non-protein biomarkers in melanoma: a critical update. Amino Acids 43(6):2203–2230PubMedCrossRefGoogle Scholar
  11. 11.
    Oesterle A, Bowman MA (2015) S100A12 and the S100/calgranulins: emerging biomarkers for atherosclerosis and possibly therapeutic targets. Arterioscler Thromb Vasc Biol 35(12):2496–2507PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chong ZZ, Changyaleket B, Xu H, Dull RO, Schwartz DE (2016) Identifying S100B as a biomarker and a therapeutic target for brain injury and multiple diseases. Curr Med Chem 23(15):1571–1596CrossRefGoogle Scholar
  13. 13.
    Hoppmann S, Haase C, Richter S, Pietzsch J (2008) Expression, purification and fluorine-18 radiolabeling of recombinant S100 proteins – potential probes for molecular imaging of receptor for advanced glycation endproducts (RAGE) in vivo. Protein Expr Purif 57(2):143–152PubMedCrossRefGoogle Scholar
  14. 14.
    Wolf S, Haase-Kohn C, Lenk J, Hoppmann S, Bergmann R, Steinbach J, Pietzsch J (2011) Expression, purification and fluorine-18 radiolabeling of recombinant S100A4: a potential probe for molecular imaging of receptor for advanced glycation endproducts in vivo? Amino Acids 41(4):809–820PubMedCrossRefGoogle Scholar
  15. 15.
    Hoppmann S, Steinbach J, Pietzsch J (2010) Scavenger receptors are associated with cellular interactions of S100A12 in vitro and in vivo. Int J Biochem Cell Biol 42(5):651–661PubMedCrossRefGoogle Scholar
  16. 16.
    Haase-Kohn C, Wolf S, Lenk J, Pietzsch J (2011) Copper-mediated cross-linking of S100A4, but not of S100A2, results in proinflammatory effects in melanoma cells. Biochem Biophys Res Commun 413(3):494–498PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Pietzsch J, Bergmann R, Rode K, Hultsch C, Pawelke B, Wuest F, van den Hoff J (2004) Fluorine-18 radiolabeling of low-density lipoproteins: a potential approach for characterization and differentiation of metabolism of native and oxidized low-density lipoproteins in vivo. Nucl Med Biol 31(8):1043–1050PubMedCrossRefGoogle Scholar
  18. 18.
    Berndt M, Pietzsch J, Wuest F (2007) Labeling of low-density lipoproteins using the 18F-labeled thiol-reactive reagent N- 6-(4-[18F]fluorobenzylidene)aminooxyhexyl maleimide. Nucl Med Biol 34(1):5PubMedCrossRefGoogle Scholar
  19. 19.
    Wuest F, Kohler L, Berndt M, Pietzsch J (2009) Systematic comparison of two novel, thiol-reactive prosthetic groups for 18F labeling of peptides and proteins with the acylation agent succinimidyl-4-[18F]fluorobenzoate ([18F]SFB). Amino Acids 36(2):283–295PubMedCrossRefGoogle Scholar
  20. 20.
    Vaidyanathan G, Zalutsky MR (1992) Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate. Int J Rad Appl Instrum B 19(3):275–281PubMedCrossRefGoogle Scholar
  21. 21.
    Abad S, Nolis P, Gispert JD, Spengler J, Albericio F, Rojas S, Herance JR (2012) Rapid and high-yielding cysteine labelling of peptides with N-succinimidyl 4-[18F]fluorobenzoate. Chem Commun 48(49):6118–6120CrossRefGoogle Scholar
  22. 22.
    Kuchar M, Pretze M, Kniess T, Jr S, Pietzsch J, Löser R (2012) Site-selective radiolabeling of peptides by 18F-fluorobenzoylation with [18F]SFB in solution and on solid phase: A comparative study. Amino Acids 43(4):1431–1443PubMedCrossRefGoogle Scholar
  23. 23.
    Rojas S, Nolis P, Gispert JD, Spengler J, Albericio F, Herance JR, Abad S (2013) Efficient cysteine labelling of peptides with N-succinimidyl 4-[18F]fluorobenzoate: stability study and in vivo biodistribution in rats by positron emission tomography (PET). RSC Adv 3(21):8028–8036CrossRefGoogle Scholar
  24. 24.
    Matusiak N, Castelli R, Tuin AW, Overkleeft HS, Wisastra R, Dekker FJ, Prly LM, Bischoff RPM, Van Waarde A, Dierckx RAJO, Elsinga PH (2015) A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging. Bioorg Med Chem 23(1):192–202PubMedCrossRefGoogle Scholar
  25. 25.
    Glaser M, Arstad E, Luthra SK, Robins EG (2009) Two-step radiosynthesis of [18F]N-succinimidyl-4-fluorobenzoate ([18F]SFB). J Label Compd Radiopharm 52(8):327–330CrossRefGoogle Scholar
  26. 26.
    Vaidyanathan G, Zalutsky MR (2006) Synthesis of N-succinimidyl 4-[18F]fluorobenzoate, an agent for labeling proteins and peptides with 18F. Nat Protoc 1(4):1655–1661PubMedCrossRefGoogle Scholar
  27. 27.
    Wester HJ, Hamacher K, Stocklin G (1996) A comparative study of N.C.A. fluorine-18 labeling of proteins via acylation and photochemical conjugation. Nucl Med Biol 23(3):365–372PubMedCrossRefGoogle Scholar
  28. 28.
    Scott PJH, Shao X (2010) Fully automated, high yielding production of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB), and its use in microwave-enhanced radiochemical coupling reactions. J Label Compd Radiopharm 53(9):586–591CrossRefGoogle Scholar
  29. 29.
    Tang G, Tang X, Wang X (2010) A facile automated synthesis of N-succinimidyl 4-[18F] fluorobenzoate ([18F]SFB) for 18F-labeled cell-penetrating peptide as PET tracer. J Label Compd Radiopharm 53(8):543–547CrossRefGoogle Scholar
  30. 30.
    Thonon D, Goblet D, Goukens E, Kaisin G, Paris J, Aerts J, Lignon S, Franci X, Hustinx R, Luxen A (2011) Fully automated preparation and conjugation of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) with RGD peptide using a GE FASTlab? synthesizer. Mol Imaging Biol 13(6):1088–1095PubMedCrossRefGoogle Scholar
  31. 31.
    Ackermann U, Yeoh SD, Sachinidis JI, Poniger SS, Scott AM, Tochon-Danguy HJ (2011) A simplified protocol for the automated production of succinimidyl 4-[18F]fluorobenzoate on an IBA Synthera module. J Label Compd Radiopharm 54(10):671–673CrossRefGoogle Scholar
  32. 32.
    Tang G, Zeng W, Yu M, Kabalka G (2008) Facile synthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) for protein labeling. J Label Compd Radiopharm 51(1):68–71CrossRefGoogle Scholar
  33. 33.
    Johnstrom P, Clark JC, Pickard JD, Davenport AP (2008) Automated synthesis of the generic peptide labelling agent N-succinimidyl 4-[(18)F]fluorobenzoate and application to (18)F-label the vasoactive transmitter urotensin-II as a ligand for positron emission tomography. Nucl Med Biol 35(6):725–731PubMedCrossRefGoogle Scholar
  34. 34.
    Bejot R, Elizarov AM, Ball E, Zhang J, Miraghaie R, Kolb HC, Gouverneur V (2011) Batch-mode microfluidic radiosynthesis of N-succinimidyl-4-[18F]fluorobenzoate for protein labelling. J Label Compd Radiopharm 54(3):117–122CrossRefGoogle Scholar
  35. 35.
    Nakanishi H, Saiki H, Saji H, Kimura H, Kawashima H, Tomatsu K, Kuge Y (2012) Method of synthesizing [18F]SFB using microsynthesis technique. EP2404903Google Scholar
  36. 36.
    Kimura H, Yagi Y, Ohneda N, Odajima H, Ono M, Saji H (2014) Development of a resonant-type microwave reactor and its application to the synthesis of positron emission tomography radiopharmaceuticals. J Label Compd Radiopharm 57(12):680–686CrossRefGoogle Scholar
  37. 37.
    Azarian V, Gangloff A, Seimbille Y, Delaloye S, Czernin J, Phelps ME, Silverman DHS (2006) Synthesis and lipsome encapsulation of a novel F-18-conjugate of omega-conotoxin GVIA for the potential imaging of N-type Ca2+ channels in the brain by positron emission tomography. J Label Compd Radiopharm 49(3):269–283CrossRefGoogle Scholar
  38. 38.
    Guenther KJ, Yoganathan S, Garofalo R, Kawabata T, Strack T, Labiris R, Dolovich M, Chirakal R, Valliant JF (2006) Synthesis and in vitro evaluation of 18F- and 19F-labeled insulin: a new radiotracer for PET-based molecular imaging studies. J Med Chem 49(4):1466–1474PubMedCrossRefGoogle Scholar
  39. 39.
    Wüst F, Hultsch C, Bergmann R, Johannsen B, Henle T (2003) Radiolabelling of isopeptide Nε-(γ-glutamyl)-l-lysine by conjugation with N-succinimidyl-4-[18F]fluorobenzoate. Appl Radiat Isot 59(1):43–48PubMedCrossRefGoogle Scholar
  40. 40.
    Taylor NJ, Emer E, Preshlock S, Schedler M, Tredwell M, Verhoog S, Mercier J, Genicot C, Gouverneur V (2017) Derisking the Cu-mediated 18F-fluorination of heterocyclic positron emission tomography radioligands. J Am Chem Soc 139(24):8267–8276PubMedCrossRefGoogle Scholar
  41. 41.
    Mäding P, Füchtner F, Wüst F (2005) Module-assisted synthesis of the bifunctional labelling agent N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB). Appl Radiat Isot 63(3):329–332PubMedCrossRefGoogle Scholar
  42. 42.
    Kapty J, Kniess T, Wuest F, Mercer JR (2011) Radiolabeling of phosphatidylserine-binding peptides with prosthetic groups N-[6-(4-[18F]fluorobenzylidene)aminooxyhexyl]maleimide ([18F]FBAM) and N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB). Appl Radiat Isot 69(9):1218–1225PubMedCrossRefGoogle Scholar
  43. 43.
    Tondera C, Laube M, Pietzsch J (2017) Insights into binding of S100 proteins to scavenger receptors: class B scavenger receptor CD36 binds S100A12 with high affinity. Amino Acids 49:183–191PubMedCrossRefGoogle Scholar
  44. 44.
    Pietzsch J, Bergmann R, Wuest F, Pawelke B, Hultsch C, van den Hoff J (2005) Catabolism of native and oxidized low density lipoproteins: in vivo insights from small animal positron emission tomography studies. Amino Acids 29(4):389–404PubMedCrossRefGoogle Scholar
  45. 45.
    Wolfe RR (1992) Radioactive and stable isotope tracers in biomedicine: principles and practice of kinetic analysis. Wiley-Liss, New York, Wiley-Liss, 471 pGoogle Scholar
  46. 46.
    Bergmann R, Pietzsch J (2005) Small animal positron emission tomography in food sciences. Amino Acids 29(4):355–376PubMedCrossRefGoogle Scholar
  47. 47.
    van den Hoff J (2005) Principles of quantitative positron emission tomography. Amino Acids 29(4):341–353PubMedCrossRefGoogle Scholar
  48. 48.
    Perera C, McNeil HP, Geczy CL (2010) S100 Calgranulins in inflammatory arthritis. Immunol Cell Biol 88(1):41–49PubMedCrossRefGoogle Scholar
  49. 49.
    van de Logt F, Day AS (2013) S100A12: a noninvasive marker of inflammation in inflammatory bowel disease. J Dig Dis 14(2):62–67PubMedCrossRefGoogle Scholar
  50. 50.
    Nazari A, Khorramdelazad H, Hassanshahi G, Day AS, Sardoo AM, Fard ET, Abedinzadeh M, Nadimi AE (2017) S100A12 in renal and cardiovascular diseases. Life Sci 191:253–258PubMedCrossRefGoogle Scholar
  51. 51.
    Farokhzadian J, Mangolian Shahrbabaki P, Bagheri V (2017) S100A12-CD36 axis: a novel player in the pathogenesis of atherosclerosis? Cytokine 6(17):3021–3029Google Scholar
  52. 52.
    Lindholm B (2015) Serum S100A12: a risk marker or risk factor of vascular calcification in chronic kidney disease. Am J Nephrol 42(1):1–3PubMedCrossRefGoogle Scholar
  53. 53.
    Isoyama N, Machowska A, Qureshi AR, Yamamoto T, Anderstam B, Heimburger O, Barany P, Stenvinkel P, Lindholm B (2016) Elevated circulating s100a12 associates with vascular disease and worse clinical outcome in peritoneal dialysis patients. Perit Dial Int 36(3):269–276PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Yang X, Okamura DM, Lu X, Chen Y, Moorhead J, Varghese Z, Ruan XZ (2017) CD36 in chronic kidney disease: novel insights and therapeutic opportunities. Nat Rev Nephrol 13(12):769–781PubMedCrossRefGoogle Scholar
  55. 55.
    Kiryushko D, Novitskaya V, Soroka V, Klingelhofer J, Lukanidin E, Berezin V, Bock E (2006) Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein. Mol Cell Biol 26(9):3625–3638PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Semov A, Moreno MJ, Onichtchenko A, Abulrob A, Ball M, Ekiel I, Pietrzynski G, Stanimirovic D, Alakhov V (2005) Metastasis-associated protein S100A4 induces angiogenesis through interaction with annexin II and accelerated plasmin formation. J Biol Chem 280(21):20833–20841PubMedCrossRefGoogle Scholar
  57. 57.
    Haase-Kohn C, Wolf S, Herwig N, Mosch B, Pietzsch J (2014) Metastatic potential of B16-F10 melanoma cells is enhanced by extracellular S100A4 derived from RAW264.7 macrophages. Biochem Biophys Res Commun 446(1):143–148PubMedCrossRefGoogle Scholar
  58. 58.
    Herwig N, Belter B, Pietzsch J (2016) Extracellular S100A4 affects endothelial cell integrity and stimulates transmigration of A375 melanoma cells. Biochem Biophys Res Commun 477(4):963–969PubMedCrossRefGoogle Scholar
  59. 59.
    Syed DN, Aljohani A, Waseem D, Mukhtar H (2018) Ousting RAGE in melanoma: a viable therapeutic target? Semin Cancer Biol 49:20–28PubMedCrossRefGoogle Scholar
  60. 60.
    Kircher DA, Silvis MR, Cho JH, Holmen SL (2016) Melanoma brain metastasis: mechanisms, models, and medicine. Int J Mol Sci 17(9):1468PubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Markus Laube
    • 1
  • Torsten Kniess
    • 2
  • Christin Neuber
    • 1
  • Cathleen Haase-Kohn
    • 1
  • Jens Pietzsch
    • 1
    • 3
    Email author
  1. 1.Department of Radiopharmaceutical and Chemical BiologyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer ResearchDresdenGermany
  2. 2.Department of GMP Radiopharmaceuticals ProductionHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer ResearchDresdenGermany
  3. 3.Faculty of Chemistry and Food ChemistryTechnische Universität DresdenDresdenGermany

Personalised recommendations