Skip to main content
SpringerLink
Log in

L-[5-11C]-Glutamine and Metabolic Imaging in Cancer Cells

  • Chapter
  • First Online:
Glutamine in Clinical Nutrition

Part of the book series: Nutrition and Health ((NH))

  • 1710 Accesses

Abstract

It is well-established now that position emission tomography (PET) with 2-[18F]fluoro-2-deoxy-glucose (FDG) is a common imaging procedure for mapping cellular glucose metabolism. The uptake of FDG in tumors with higher rates of glycolysis leads to high signal to noise ratios. Despite the tremendous promise of using FDG-PET to detect and monitor tumor metabolism, many indolent tumors are FDG-negative; the tumors may have switched their energy source from glucose to glutamine, thus escaping detection. Glutamine is the most abundant amino acid in the human body. It was recognized early (1960) that glutamine plays an important role in tumor growth and proliferation. We report herein two radiolabeled glutamines, namely L-[5-11C]-glutamine and [18F](2S,4R)4-fluoro-glutamine. These two radioactive glutamines might be useful to map glutamine metabolism in vivo in tumor tissue. We recently developed an efficient method to make L-[5-11C]-glutamine and we could show that L-[5-11C]-glutamine is taken into tumor cells (9L and SF188) and incorporated into protein. Small animal imaging studies on F344 rats bearing 9L xenographed tumors confirmed uptake of the tracer into tumor. But with a short half-life of only 20 minutes, it requires a cyclotron nearby and thus hindering its widespread application. We therefore developed a [18F] fluorinated version (half life of 18F is 110 min)of glutamine, namely [18F](2S,4R)4-fluoro-glutamine. This tracer can be produced and distributed centralized, making it more suitable for clinical use. [18F](2S,4R)4-fluoro-glutamine displayed high cell uptake in 9L and SF188 (derived from human glioblastoma) cell lines and is incorporated into tumor protein. It appears that the transport mechanism may be predominantly through system ASC and may prefer its subtype ASCT2. Small animal imaging studies in F344 rats bearing 9L xenographed tumors, showed rapid uptake into tumor (maximum was reached at 20 min post injection) and the uptake remained constant during the imaging study. The in vivo imaging studies may provide an interesting tool for measuring glutamine metabolism and monitor changes of tumor metabolism.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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. Rajagopalan KN, Deberardinis RJ. Role of glutamine in cancer: therapeutic and imaging implications. J Nucl Med. 2011;52(7):1005–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Erickson J, Cerione R. Glutaminase: A hot spot for regulation of cancer cell metabolism? Oncotarget. 2010;1(8):734–40.

    PubMed Central  PubMed  Google Scholar 

  3. McGivan JD, Bungard CI. The transport of glutamine into mammalian cells. Front Biosci. 2007;12:874–82.

    Article  CAS  PubMed  Google Scholar 

  4. Plathow C, Weber WA. Tumor cell metabolism imaging. J Nucl Med. 2008;49 Suppl 2:43S–63.

    Article  CAS  PubMed  Google Scholar 

  5. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.

    Article  CAS  PubMed  Google Scholar 

  6. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11(5):325–37.

    Article  CAS  PubMed  Google Scholar 

  7. Mattaini KR, Vander Heiden MG. Cancer. Glycosylation to adapt to stress. Science. 2012;337(6097):925–6.

    Article  PubMed  Google Scholar 

  8. Metallo CM, Vander Heiden MG. Understanding metabolic regulation and its influence on cell physiology. Mol Cell. 2013;49(3):388–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Vander Heiden M, Cantley L, Thompson C. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Ong LC, Jin Y, Song IC, Yu S, Zhang K, Chow PK. 2-[18F]-2-Deoxy-D-Glucose (FDG) Uptake in Human Tumor Cells Is Related to the Expression of GLUT-1 and Hexokinase II. Acta Radiologica. 2008;31:1–10.

    Google Scholar 

  11. Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 2008;49 Suppl 2:24S–42.

    Article  CAS  PubMed  Google Scholar 

  12. Gambhir SS. Molecular imaging of cancer: from molecules to humans. Introduction. J Nucl Med. 2008;49 Suppl 2:S1–4.

    Article  Google Scholar 

  13. Buerkle A, Weber WA. Imaging of tumor glucose utilization with positron emission tomography. Cancer Metastasis Rev. 2008;27(4):545–54.

    Article  PubMed  Google Scholar 

  14. van Baardwijk A, Dooms C, van Suylen RJ, et al. The maximum uptake of (18)F-deoxyglucose on positron emission tomography scan correlates with survival, hypoxia inducible factor-1alpha and GLUT-1 in non-small cell lung cancer. Eur J Cancer. 2007;43(9):1392–8.

    Article  PubMed  Google Scholar 

  15. Busk M, Horsman MR, Kristjansen PE, van der Kogel AJ, Bussink J, Overgaard J. Aerobic glycolysis in cancers: implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia. Int J Cancer. 2008;122(12):2726–34.

    Article  CAS  PubMed  Google Scholar 

  16. Kaelin Jr WG, Thompson CB. Q&A: Cancer: clues from cell metabolism. Nature. 2010;465(7298):562–4.

    Article  CAS  PubMed  Google Scholar 

  17. Wise DR, Ward PS, Shay JE, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011;108(49):19611–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Daye D, Wellen KE. Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. 2012;23(4):362–9.

    Article  CAS  PubMed  Google Scholar 

  19. Dang CV, Hamaker M, Sun P, Le A, Gao P. Therapeutic targeting of cancer cell metabolism. J Mol Med. 2011;89(3):205–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Dang CV. Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? Cell Cycle. 2010;9(19):3884–6.

    Article  CAS  PubMed  Google Scholar 

  21. Kvamme E, Svenneby G. Effect of anaerobiosis and addition of keto acids on glutamine utilization by Ehrlich ascites-tumor cells. Biochim Biophys Acta. 1960;42:187–8.

    Article  CAS  PubMed  Google Scholar 

  22. Eagle H. The specific amino acid requirements of a human carcinoma cell (Stain HeLa) in tissue culture. J Exp Med. 1955;102(1):37–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Yang C, Sudderth J, Dang T, Bachoo RM, McDonald JG, DeBerardinis RJ. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 2009;69(20):7986–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Wise D, DeBerardinis R, Mancuso A, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A. 2008;105(48):18782–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. DeBerardinis RJ, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A. 2007;104(49):19345–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7(1):11–20.

    Article  CAS  PubMed  Google Scholar 

  27. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18(1):54–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. DeBerardinis R, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29(3):313–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Nicklin P, Bergman P, Zhang B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009;136(3):521–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Klasner BD, Krause BJ, Beer AJ, Drzezga A. PET imaging of gliomas using novel tracers: a sleeping beauty waiting to be kissed. Expert Rev Anticancer Ther. 2010;10(5):609–13.

    Article  PubMed  Google Scholar 

  31. Robey IF, Stephen RM, Brown KS, Baggett BK, Gatenby RA, Gillies RJ. Regulation of the Warburg effect in early-passage breast cancer cells. Neoplasia. 2008;10(8):745–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Conlon KC, Bading JR, DiResta GR, Corbally MT, Gelbard AS, Brennan MF. Validation of transport measurements in skeletal muscle with N-13 amino acids using a rabbit isolated hindlimb model. Life Sci. 1989;44(13):847–59.

    Article  CAS  PubMed  Google Scholar 

  33. Gelbard AS, Christie TR, Clarke LP, Laughlin JS. Imaging of spontaneous canine tumours with ammonia and L-glutamine labeled with N-13. J Nucl Med. 1977;18(7):718–23.

    CAS  PubMed  Google Scholar 

  34. Qu W, Oya S, Lieberman BP, et al. Preparation and Characterization of L-[5-11C]-Glutamine for Metabolic Imaging of Tumors. J Nucl Med. 2012;53:98–105.

    Article  CAS  PubMed  Google Scholar 

  35. Iwata R, Ido T, Takahashi T, Nakanishi H, Iida S. Optimization of [11C]HCN production and no-carrier-added [1-11C]amino acid synthesis. Int J Rad Appl Instrum A. 1987;38(2):97–102.

    Article  CAS  PubMed  Google Scholar 

  36. Antoni G, Omura H, Ikemoto M, Moulder R, Watanabe Y, Langstrom B. Enzyme catalyzed synthesis of L-[4-11C]aspartate and L-[5-11C]glutamate. J Labelled Compd Rad. 2001;44(4):287–94.

    Article  CAS  Google Scholar 

  37. Lieberman BP, Ploessl K, Wang L, et al. PET imaging of glutaminolysis in tumors by 18F-(2S,4R)4-fluoroglutamine. J Nucl Med. 2011;52:1947–55.

    Article  CAS  PubMed  Google Scholar 

  38. Qu W, Zha Z, Ploessl K, et al. Synthesis of optically pure 4-fluoro-glutamines as potential metabolic imaging agents for tumors. J Am Chem Soc. 2011;133(4):1122–33.

    Article  CAS  PubMed  Google Scholar 

  39. Yu W, Williams L, Camp V, Olson J, Goodman M. Synthesis and biological evaluation of anti-1-amino-2-[18F]fluoro-cyclobutyl-1-carboxylic acid (anti-2-[18F]FACBC) in rat 9 L gliosarcoma. Bioorg Med Chem Lett. 2010;20(7):2140–3.

    Article  CAS  PubMed  Google Scholar 

  40. Martarello L, McConathy J, Camp VM, et al. Synthesis of syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC), potential PET ligands for tumor detection. J Med Chem. 2002;45(11):2250–9.

    Article  CAS  PubMed  Google Scholar 

  41. Schuster DM, Savir-Baruch B, Nieh PT, et al. Detection of recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/CT and 111In-capromab pendetide SPECT/CT. Radiology. 2011;259(3):852–61.

    Article  PubMed Central  PubMed  Google Scholar 

  42. McConathy J, Goodman MM. Non-natural amino acids for tumor imaging using positron emission tomography and single photon emission computed tomography. Cancer Metastasis Rev. 2008;27(4):555–73.

    Article  PubMed  Google Scholar 

  43. Wasa M, Wang HS, Okada A. Characterization of L-glutamine transport by a human neuroblastoma cell line. Am J Physiol Cell Physiol. 2002;282(6):C1246–53.

    Article  CAS  PubMed  Google Scholar 

  44. Hatanaka T, Nakanishi T, Huang W, et al. Na+- and Cl– -coupled active transport of nitric oxide synthase inhibitors via amino acid transport system B(0,+). J Clin Invest. 2001;107(8):1035–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Bodoy S, Martin L, Zorzano A, Palacin M, Estevez R, Bertran J. Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem. 2005;280(12):12002–11.

    Article  CAS  PubMed  Google Scholar 

  46. Kekuda R, Prasad PD, Fei YJ, et al. Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter Bo from a human placental choriocarcinoma cell line. J Biol Chem. 1996;271(31):18657–61.

    Article  CAS  PubMed  Google Scholar 

  47. Fuchs BC, Bode BP. Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Semin Cancer Biol. 2005;15(4):254–66.

    Article  CAS  PubMed  Google Scholar 

  48. Okudaira H, Shikano N, Nishii R, et al. Putative Transport Mechanism and Intracellular Fate of Trans-1-Amino-3-18F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer. J Nucl Med. 2011;52(5):822–9.

    Article  CAS  PubMed  Google Scholar 

  49. Esslinger CS, Cybulski KA, Rhoderick JF. N-gamma-aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site. Bioorg Med Chem. 2005;13(4):1111–8.

    Article  CAS  PubMed  Google Scholar 

  50. Lee TS, Ahn SH, Moon BS, et al. Comparison of 18F-FDG, 18F-FET and 18F-FLT for differentiation between tumor and inflammation in rats. Nucl Med Biol. 2009;36(6):681–6.

    Article  CAS  PubMed  Google Scholar 

  51. Yu W, Williams L, Camp V, Malveaux E, Olson J, Goodman M. Stereoselective synthesis and biological evaluation of syn-1-amino-3-[18F]fluorocyclobutyl-1-carboxylic acid as a potential positron emission tomography brain tumor imaging agent. Bioorg Med Chem. 2009;17(5):1982–90.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

 This work was supported in part by grants from Stand-Up 2 Cancer (SU2C), PA Health, and NIH CA-0164490.

Author information

Authors and Affiliations

  1. Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Karl Ploessl Ph.D., Brian P. Lieberman, Seok Rye Choi Ph.D., Lin Zhu Ph.D. & Hank F. Kung Ph.D.

  2. College of Chemistry, Beijing Normal University, Beijing, China

    Lin Zhu Ph.D.

Authors
  1. Karl Ploessl Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian P. Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seok Rye Choi Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Zhu Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hank F. Kung Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karl Ploessl Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Intensive Care, Barnet and Chase Farm Hospitals, London, United Kingdom

    Rajkumar Rajendram

  2. Department of Nutrition and Dietetics, Diabetes and Nutritional Sciences, School of Medicine, King’s College London, London, United Kingdom

    Victor R. Preedy

  3. Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Ploessl, K., Lieberman, B.P., Choi, S.R., Zhu, L., Kung, H.F. (2015). L-[5-11C]-Glutamine and Metabolic Imaging in Cancer Cells. In: Rajendram, R., Preedy, V., Patel, V. (eds) Glutamine in Clinical Nutrition. Nutrition and Health. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1932-1_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-1932-1_9

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-1931-4

  • Online ISBN: 978-1-4939-1932-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation