Skip to main content
SpringerLink
Log in

Molecular Imaging of Tryptophan Metabolism in Tumors

  • Chapter
Targeting the Broadly Pathogenic Kynurenine Pathway

  • 1026 Accesses

Abstract

Molecular imaging of the kynurenine pathway can be achieved by positron emission tomography (PET) of radiolabeled tryptophan derivatives. While tryptophan is the substrate of protein synthesis, the PET tracer 11C-alpha-methyl-L-tryptophan (AMT) is not incorporated into proteins; rather it is a substrate of indoleamine 2,3-dioxygenase (IDO), the initial and rate-limiting enzyme of the kynurenine pathway. Recent studies of AMT-PET have demonstrated high AMT uptake and accumulation in a variety of WHO grade II–IV gliomas, glioneuronal tumors, and meningiomas. Increased AMT uptake can also readily detect lung cancers and breast cancers. Tracer kinetic analysis of dynamic PET images can differentiate between tryptophan transport and metabolic rates, thus enhancing the clinical utility of AMT-PET. Studies of resected tumor specimens have shown high expression of LAT1, a key transporter of tryptophan, and also IDO and tryptophan 2,3-dioxygenase, in AMT-accumulating tumors. This chapter discusses the mechanisms of high AMT uptake on PET and provides a summary of potential clinical applications, including pretreatment tumor characterization, treatment planning, prognostication, as well as posttreatment tumor detection in various intra- and extracranial tumors.

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
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

Abbreviations

AHR:

Aryl hydrocarbon receptor

AMT:

11C-alpha-methyl-L-tryptophan

DNET:

Dysembryoplastic neuroepithelial tumor

FDOPA:

18F-fluoro-L-dihydroxy-phenylalanine

FEHTP:

5-(2-18F-fluoroethoxy)-L-tryptophan

FET:

18F-fluoroethyl-tyrosine

GTV:

Gross tumor volume

HR-GTV:

High-risk gross tumor volume

IDO:

Indoleamine 2,3-dioxygenase

LAT1:

L-type amino acid transporter 1

MET:

L-[methyl-11C]methionine

NSCLC:

Non-small cell lung cancer

PET:

Positron emission tomography

SUV:

Standardized uptake value

TDO:

Tryptophan 2,3-dioxygenase

TPH1:

Tryptophan hydroxylase 1

VD:

Volume of distribution

References

  1. Hubner KF, Andrews GA, Buonocore E, Hayes RL, Washburn LC, Collmann IR, et al. Carbon-11-labeled amino acids for the rectilinear and positron tomographic imaging of the human pancreas. J Nucl Med. 1979;20(6):507–13.

    CAS  PubMed  Google Scholar 

  2. Hubner KF, Purvis JT, Mahaley Jr SM, Robertson JT, Rogers S, Gibbs WD, et al. Brain tumor imaging by positron emission computed tomography using 11C-labeled amino acids. J Comput Assist Tomogr. 1982;6(3):544–50.

    Article  CAS  PubMed  Google Scholar 

  3. Nikolaou A, Thomas D, Kampanellou C, Alexandraki K, Andersson LG, Sundin A, et al. The value of 11C-5-hydroxy-tryptophan positron emission tomography in neuroendocrine tumor diagnosis and management: experience from one center. J Endocrinol Invest. 2010;33(11):794–9.

    Article  CAS  PubMed  Google Scholar 

  4. Kramer SD, Mu L, Muller A, Keller C, Kuznetsova OF, Schweinsberg C, et al. 5-(2-18F-fluoroethoxy)-L-tryptophan as a substrate of system L transport for tumor imaging by PET. J Nucl Med. 2012;53(3):434–42.

    Article  CAS  PubMed  Google Scholar 

  5. Chiotellis A, Mu L, Muller A, Selivanova SV, Keller C, Schibli R, et al. Synthesis and biological evaluation of (1)(8)F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging. Eur J Med Chem. 2013;70:768–80.

    Article  CAS  PubMed  Google Scholar 

  6. Diksic M, Nagahiro S, Sourkes TL, Yamamoto YL. A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model. J Cereb Blood Flow Metab. 1990;10(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  7. Diksic M, Nagahiro S, Chaly T, Sourkes TL, Yamamoto YL, Feindel W. Serotonin synthesis rate measured in living dog brain by positron emission tomography. J Neurochem. 1991;56(1):153–62.

    Article  CAS  PubMed  Google Scholar 

  8. Diksic M, Tohyama Y, Takada A. Brain net unidirectional uptake of alpha-[14c]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp. Neurochem Res. 2000;25(12):1537–46.

    Article  CAS  PubMed  Google Scholar 

  9. Muzik O, Chugani DC, Chakraborty P, Mangner T, Chugani HT. Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J Cereb Blood Flow Metab. 1997;17(6):659–69.

    Article  CAS  PubMed  Google Scholar 

  10. Diksic M, Young SN. Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan. J Neurochem. 2001;78(6):1185–200.

    Article  CAS  PubMed  Google Scholar 

  11. Frey BN, Skelin I, Sakai Y, Nishikawa M, Diksic M. Gender differences in alpha-[(11)C]MTrp brain trapping, an index of serotonin synthesis, in medication-free individuals with major depressive disorder: a positron emission tomography study. Psychiatry Res. 2010;183(2):157–66.

    Article  CAS  PubMed  Google Scholar 

  12. Chugani DC, Chugani HT, Muzik O, Shah JR, Shah AK, Canady A, et al. Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann Neurol. 1998;44(6):858–66.

    Article  CAS  PubMed  Google Scholar 

  13. Juhasz C, Chugani DC, Muzik O, Shah A, Asano E, Mangner TJ, et al. Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology. 2003;60(6):960–8.

    Article  CAS  PubMed  Google Scholar 

  14. Juhasz C, Chugani DC, Padhye UN, Muzik O, Shah A, Asano E, et al. Evaluation with alpha-[11C]methyl-L-tryptophan positron emission tomography for reoperation after failed epilepsy surgery. Epilepsia. 2004;45(2):124–30.

    Article  PubMed  Google Scholar 

  15. Chugani HT, Luat AF, Kumar A, Govindan R, Pawlik K, Asano E. alpha-[11C]-methyl-L-tryptophan—PET in 191 patients with tuberous sclerosis complex. Neurology. 2013;81(7):674–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269–74.

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Imai H, Kaira K, Oriuchi N, Shimizu K, Tominaga H, Yanagitani N, et al. Inhibition of L-type amino acid transporter 1 has antitumor activity in non-small cell lung cancer. Anticancer Res. 2010;30(12):4819–28.

    CAS  PubMed  Google Scholar 

  19. Zitron IM, Kamson DO, Kiousis S, Juhasz C, Mittal S. In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1. Cancer Biol Ther. 2013;14(4):333–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Nduom EK, Yang C, Merrill MJ, Zhuang Z, Lonser RR. Characterization of the blood–brain barrier of metastatic and primary malignant neoplasms. J Neurosurg. 2013;119(2):427–33.

    Article  PubMed  Google Scholar 

  21. McConathy J, Martarello L, Malveaux EJ, Camp VM, Simpson NE, Simpson CP, et al. Radiolabeled amino acids for tumor imaging with PET: radiosynthesis and biological evaluation of 2-amino-3-[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid. J Med Chem. 2002;45(11):2240–9.

    Article  CAS  PubMed  Google Scholar 

  22. Baek S, Choi CM, Ahn SH, Lee JW, Gong G, Ryu JS, et al. Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging xC- transporter using positron emission tomography in patients with non-small cell lung or breast cancer. Clin Cancer Res. 2012;18(19):5427–37.

    Article  CAS  PubMed  Google Scholar 

  23. Huang C, McConathy J. Radiolabeled amino acids for oncologic imaging. J Nucl Med. 2013;54(7):1007–10.

    Article  CAS  PubMed  Google Scholar 

  24. del Amo EM, Urtti A, Yliperttula M. Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2. Eur J Pharm Sci. 2008;35(3):161–74.

    Article  PubMed  Google Scholar 

  25. Wiriyasermkul P, Nagamori S, Tominaga H, Oriuchi N, Kaira K, Nakao H, et al. Transport of 3-fluoro-L-alpha-methyl-tyrosine by tumor-upregulated L-type amino acid transporter 1: a cause of the tumor uptake in PET. J Nucl Med. 2012;53(8):1253–61.

    Article  CAS  PubMed  Google Scholar 

  26. Juhasz C, Dwivedi S, Kamson DO, Michelhaugh SK, Mittal S. Comparison of amino acid positron emission tomographic radiotracers for molecular imaging of primary and metastatic brain tumors. Mol Imaging. 2014;13.

    Google Scholar 

  27. Chugani DC, Muzik O. Alpha[C-11]methyl-L-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism. J Cereb Blood Flow Metab. 2000;20(1):2–9.

    Article  CAS  PubMed  Google Scholar 

  28. Hayaishi O. Properties and function of indoleamine 2,3-dioxygenase. J Biochem. 1976;79(4):13P–21P.

    CAS  PubMed  Google Scholar 

  29. Shimizu T, Nomiyama S, Hirata F, Hayaishi O. Indoleamine 2,3-dioxygenase. Purification and some properties. J Biol Chem. 1978;253(13):4700–6.

    CAS  PubMed  Google Scholar 

  30. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203.

    Article  CAS  PubMed  Google Scholar 

  31. Chung KT, Gadupudi GS. Possible roles of excess tryptophan metabolites in cancer. Environ Mol Mutagen. 2011;52(2):81–104.

    Article  CAS  PubMed  Google Scholar 

  32. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185(6):3190–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Batista CE, Juhasz C, Muzik O, Kupsky WJ, Barger G, Chugani HT, et al. Imaging correlates of differential expression of indoleamine 2,3-dioxygenase in human brain tumors. Mol Imaging Biol. 2009;11(6):460–6.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Alkonyi B, Mittal S, Zitron I, Chugani DC, Kupsky WJ, Muzik O, et al. Increased tryptophan transport in epileptogenic dysembryoplastic neuroepithelial tumors. J Neurooncol. 2012;107(2):365–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Bosnyák E, Kamson DO, Guastella AR, Varadarajan K, Robinette NL, Kupsky WJ, et al. Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas. Neuro Oncol. 2015. doi:10.1093/neuonc/nov098.

    PubMed  Google Scholar 

  36. Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frederick R, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci USA. 2012;109(7):2497–502.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010;115(17):3520–30.

    Article  CAS  PubMed  Google Scholar 

  38. Juhasz C, Chugani DC, Muzik O, Wu D, Sloan AE, Barger G, et al. In vivo uptake and metabolism of alpha-[11C]methyl-L-tryptophan in human brain tumors. J Cereb Blood Flow Metab. 2006;26(3):345–57.

    Article  CAS  PubMed  Google Scholar 

  39. Juhasz C, Muzik O, Chugani DC, Chugani HT, Sood S, Chakraborty PK, et al. Differential kinetics of alpha-[11C]methyl-L-tryptophan on PET in low-grade brain tumors. J Neurooncol. 2011;102(3):409–15.

    Google Scholar 

  40. Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  41. Shinozaki N, Uchino Y, Yoshikawa K, Matsutani T, Hasegawa A, Saeki N, et al. Discrimination between low-grade oligodendrogliomas and diffuse astrocytoma with the aid of 11C-methionine positron emission tomography. J Neurosurg. 2011;114(6):1640–7.

    Article  PubMed  Google Scholar 

  42. Kamson DO, Mittal S, Buth A, Muzik O, Kupsky WJ, Robinette NL, et al. Differentiation of glioblastomas from metastatic brain tumors by tryptophan uptake and kinetic analysis: a positron emission tomographic study with magnetic resonance imaging comparison. Mol Imaging. 2013;12(5):327–37.

    PubMed Central  PubMed  Google Scholar 

  43. Juhasz C, Chugani DC, Barger GR, Kupsky WJ, Chakraborty PK, Muzik O, et al. Quantitative PET imaging of tryptophan accumulation in gliomas and remote cortex: correlation with tumor proliferative activity. Clin Nucl Med. 2012;37(9):838–42.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Kamson DO, Juhasz C, Buth A, Kupsky WJ, Barger GR, Chakraborty PK, et al. Tryptophan PET in pretreatment delineation of newly-diagnosed gliomas: MRI and histopathologic correlates. J Neurooncol. 2013;112(1):121–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Alkonyi B, Barger GR, Mittal S, Muzik O, Chugani DC, Bahl G, et al. Accurate differentiation of recurrent gliomas from radiation injury by kinetic analysis of alpha-11C-methyl-L-tryptophan PET. J Nucl Med. 2012;53(7):1058–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Popperl G, Kreth FW, Mehrkens JH, Herms J, Seelos K, Koch W, et al. FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. Eur J Nucl Med Mol Imaging. 2007;34(12):1933–42.

    Article  PubMed  Google Scholar 

  47. Terakawa Y, Tsuyuguchi N, Iwai Y, Yamanaka K, Higashiyama S, Takami T, et al. Diagnostic accuracy of 11C-methionine PET for differentiation of recurrent brain tumors from radiation necrosis after radiotherapy. J Nucl Med. 2008;49(5):694–9.

    Article  PubMed  Google Scholar 

  48. Kamson DO, Mittal S, Robinette NL, Muzik O, Kupsky WJ, Barger GR, et al. Increased tryptophan uptake on PET has strong independent prognostic value in patients with a previously treated high-grade glioma. Neuro Oncol. 2014;16(10):1373–83.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Kamson DO, Lee TJ, Varadarajan K, Robinette NL, Muzik O, Chakraborty PK, et al. Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma. J Nucl Med. 2014;55(10):1605–10.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Peng F, Juhasz C, Bhambhani K, Wu D, Chugani DC, Chugani HT. Assessment of progression and treatment response of optic pathway glioma with positron emission tomography using alpha-[(11)C]methyl-L-tryptophan. Mol Imaging Biol. 2007;9(3):106–9.

    Article  PubMed  Google Scholar 

  51. Christensen M, Kamson DO, Snyder M, Kim H, Robinette N, Mittal S, et al. Tryptophan PET-defined gross tumor volume offers better coverage of initial progression than standard MRI-based planning in glioblastoma patients. J Radiat Oncol. 2014;3(2):131–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Juhasz C, Muzik O, Lu X, Jahania MS, Soubani AO, Khalaf M, et al. Quantification of tryptophan transport and metabolism in lung tumors using PET. J Nucl Med. 2009;50(3):356–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Astigiano S, Morandi B, Costa R, Mastracci L, D’Agostino A, Ratto GB, et al. Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer. Neoplasia. 2005;7(4):390–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Karanikas V, Zamanakou M, Kerenidi T, Dahabreh J, Hevas A, Nakou M, et al. Indoleamine 2,3-dioxygenase (IDO) expression in lung cancer. Cancer Biol Ther. 2007;6(8):1258–62.

    Article  CAS  PubMed  Google Scholar 

  55. Juhasz C, Nahleh Z, Zitron I, Chugani DC, Janabi MZ, Bandyopadhyay S, et al. Tryptophan metabolism in breast cancers: molecular imaging and immunohistochemistry studies. Nucl Med Biol. 2012;39(7):926–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Sakurai K, Amano S, Enomoto K, Kashio M, Saito Y, Sakamoto A, et al. Study of indoleamine 2,3-dioxygenase expression in patients with breast cancer. Gan To Kagaku Ryoho. 2005;32(11):1546–9.

    CAS  PubMed  Google Scholar 

  57. Pai VP, Marshall AM, Hernandez LL, Buckley AR, Horseman ND. Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival. Breast Cancer Res. 2009;11(6):R81.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Lyon DE, Walter JM, Starkweather AR, Schubert CM, McCain NL. Tryptophan degradation in women with breast cancer: a pilot study. BMC Res Notes. 2011;4:156.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Kaper T, Looger LL, Takanaga H, Platten M, Steinman L, Frommer WB. Nanosensor detection of an immunoregulatory tryptophan influx/kynurenine efflux cycle. PLoS Biol. 2007;5(10), e257.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Serbecic N, Lahdou I, Scheuerle A, Hoftberger R, Aboul-Enein F. Function of the tryptophan metabolite, L-kynurenine, in human corneal endothelial cells. Mol Vis. 2009;15:1312–24.

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

    Csaba Juhász M.D.,Ph.D.

  2. Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA

    Csaba Juhász M.D.,Ph.D.

  3. Karmanos Cancer Institute, Detroit, MI, USA

    Csaba Juhász M.D.,Ph.D. & Sandeep Mittal M.D.,F.R.C.S.C.,F.A.C.S.

  4. Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

    Sandeep Mittal M.D.,F.R.C.S.C.,F.A.C.S.

  5. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

    Sandeep Mittal M.D.,F.R.C.S.C.,F.A.C.S.

Authors
  1. Csaba Juhász M.D.,Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandeep Mittal M.D.,F.R.C.S.C.,F.A.C.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Csaba Juhász M.D.,Ph.D. .

Editor information

Editors and Affiliations

  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Juhász, C., Mittal, S. (2015). Molecular Imaging of Tryptophan Metabolism in Tumors. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_28

Download citation

Publish with us

Policies and ethics

Search

Navigation