Journal of Neuro-Oncology

, Volume 102, Issue 3, pp 409–415 | Cite as

Differential kinetics of α-[11C]methyl-l-tryptophan on PET in low-grade brain tumors

  • Csaba Juhász
  • Otto Muzik
  • Diane C. Chugani
  • Harry T. Chugani
  • Sandeep Sood
  • Pulak K. Chakraborty
  • Geoffrey R. Barger
  • Sandeep Mittal
Clinical Study – Patient Study


Increased tryptophan metabolism via the kynurenine pathway is a major mechanism of tumor immuno-resistance. α-[11C]Methyl-l-tryptophan (AMT) is a positron emission tomography (PET) tracer for tryptophan catabolism, and increased AMT uptake has been demonstrated in brain tumors. In this study we evaluated the use of AMT PET for detection of low-grade gliomas and glioneuronal tumors, and determined if kinetic parameters of AMT uptake can differentiate among tumor types. AMT PET images were obtained in 23 patients with newly diagnosed low-grade brain tumors (WHO grade II gliomas and WHO grade I dysembryoplastic neuroepithelial tumors [DNETs]). Kinetic variables, including the unidirectional uptake rate (K-complex) and volume of distribution (VD; which characterizes tracer transport), were measured using a graphical approach from tumor dynamic PET and blood-input data, and metabolic rates (\( k^{\prime}_{3} \)) were also calculated. These values as well as tumor/cortex ratios were compared across tumor types. AMT PET showed increased tumor/cortex K-complex (n = 16) and/or VD ratios (n = 15) in 21/23 patients (91%), including 11/13 tumors with no gadolinium enhancement on MRI. No increases in AMT were seen in an oligodendroglioma and a DNET. Astrocytomas and oligoastrocytomas showed higher \( k^{\prime}_{3} \) tumor/cortex ratios (1.66 ± 0.46) than oligodendrogliomas (0.96 ± 0.21; P = 0.001) and DNETs (0.75 ± 0.39; P < 0.001). These results demonstrate that AMT PET identifies most low-grade gliomas and DNETs by high uptake, even if these tumors are not contrast-enhancing on MRI. Kinetic analysis of AMT uptake shows significantly higher tumor/cortex tryptophan metabolic ratios in astrocytomas and oligoastrocytomas in comparison with oligodendrogliomas and DNETs.


Gliomas Astrocytoma Low-grade Positron emission tomography Tryptophan Metabolism 



The study was supported by a grant from the National Cancer Institute (#CA123451, to C. Juhász). The authors thank Cathie Germain, MA, Angela Wigeluk, CNMT, Carole Clapko, CNMT, Galina Rabkin, CNMT, Melissa Burkett, CNMT, Andrew Mosqueda, CNMT, Anna DeBoard, RN, Jane Cornett, RN, and Mei-li Lee, MS, for their assistance in patient recruitment and preparation, as well as performing the PET studies.


  1. 1.
    Diksic M, Nagahiro S, Sourkes TL, Yamamoto YL (1990) A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model. J Cereb Blood Flow Metab 10:1–12PubMedCrossRefGoogle Scholar
  2. 2.
    Muzik O, Chugani DC, Chakraborty P, Mangner T, Chugani HT (1997) Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J Cereb Blood Flow Metab 17:659–669PubMedCrossRefGoogle Scholar
  3. 3.
    Chugani DC, Muzik O (2000) Alpha[C-11]methyl-l-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism. J Cereb Blood Flow Metab 20:2–9PubMedCrossRefGoogle Scholar
  4. 4.
    Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154PubMedCrossRefGoogle Scholar
  5. 5.
    Batista CEA, Juhász C, Muzik O, Kupsky WJ, Barger G, Chugani HT, Chugani HT, Mittal S, Sood S, Chakraborty PK, Chugani DC (2009) Imaging correlates of differential expression of indoleamine 2,3-dioxygenase in human brain tumors. Mol Imaging Biol 11:460–466PubMedCrossRefGoogle Scholar
  6. 6.
    Chen W (2007) Clinical applications of PET in brain tumors. J Nucl Med 48:1468–1481PubMedCrossRefGoogle Scholar
  7. 7.
    Mittal S, Szlaczky MC, Barger GR (2008) Low-grade gliomas in adults. Curr Treat Options Neurol 10:271–284PubMedCrossRefGoogle Scholar
  8. 8.
    Juhász C, Chugani DC, Muzik O et al (2006) In vivo uptake and metabolism of alpha-[11C]methyl-l-tryptophan in human brain tumors. J Cereb Blood Flow Metab 26:345–357PubMedCrossRefGoogle Scholar
  9. 9.
    Atkinson M, Juhász C, Shah J, Guo X, Kupsky W, Fuerst D, Johnson R, Watson C (2008) Paradoxical imaging findings in cerebral gliomas. J Neurol Sci 269:180–183PubMedCrossRefGoogle Scholar
  10. 10.
    Chugani DC, Muzik O, Chakraborty P, Mangner T, Chugani HT (1998) Human brain serotonin synthesis capacity measured in vivo with alpha-[C-11]methyl-l-tryptophan. Synapse 28:33–43PubMedCrossRefGoogle Scholar
  11. 11.
    Muzik O, Behrendt DB, Mangner TJ, Chugani HT (1994) Design of a pediatric protocol for quantitative brain FDG studies with PET not requiring invasive blood sampling. J Nucl Med 35:104 [abstract]Google Scholar
  12. 12.
    Suhonen-Pulvi H, Ruotsalainen U, Kinnala A, Bergman J, Haaparanta M, Teräs M, Mäkelä P, Solin O, Wegelius U (1995) FDG-PET in early infancy: simplified quantification methods to measure cerebral glucose utilization. J Nucl Med 36:1249–1254Google Scholar
  13. 13.
    Gjedde A (1981) High- and low-affinity transport of d-glucose from blood to brain. J Neurochem 36:1463–1471PubMedCrossRefGoogle Scholar
  14. 14.
    Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7PubMedCrossRefGoogle Scholar
  15. 15.
    Juhász C, Chugani DC, Muzik O, Shah A, Asano E, Mangner T, Chakraborty PK, Sood S, Chugani HT (2003) Alpha-methyl-l-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 60:960–968PubMedGoogle Scholar
  16. 16.
    Pollack IF (1994) Brain tumors in children. N Engl J Med 331:1500–1507PubMedCrossRefGoogle Scholar
  17. 17.
    Schomas DA, Laack NN, Rao RD, Meyer FB, Shaw EG, O’Neill BP, Giannini C, Brown PD (2009) Intracranial low-grade gliomas in adults: 30-year experience with long-term follow-up at Mayo Clinic. Neuro-Oncology 11:437–445PubMedCrossRefGoogle Scholar
  18. 18.
    Vertosick FT Jr, Selker RG, Arena VC (1991) Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography. Neurosurgery 28:496–501PubMedCrossRefGoogle Scholar
  19. 19.
    McCormack BM, Miller DC, Budzilovich GN, Voorhees GJ, Ransohoff J (1992) Treatment and survival of low-grade astrocytoma in adults—1977–1988. Neurosurgery 31:636–642PubMedCrossRefGoogle Scholar
  20. 20.
    Mason WP, Krol GS, DeAngelis LM (1996) Low-grade oligodendroglioma responds to chemotherapy. Neurology 46:203–207PubMedGoogle Scholar
  21. 21.
    Olson JD, Riedel E, DeAngelis LM (2000) Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology 54:1442–1448PubMedGoogle Scholar
  22. 22.
    Kitange GJ, Smith JS, Jenkins RB (2001) Genetic alterations and chemotherapeutic response in human diffuse gliomas. Expert Rev Anticancer Ther 1:595–605PubMedCrossRefGoogle Scholar
  23. 23.
    Tozer DJ, Jäger HR, Danchaivijitr N, Benton CE, Tofts PS, Rees JH, Waldman AD (2007) Apparent diffusion coefficient histograms may predict low-grade glioma subtype. NMR Biomed 20:49–57PubMedCrossRefGoogle Scholar
  24. 24.
    Khayal IS, McKnight TR, McGue C, Vandenberg S, Lamborn KR, Chang SM, Cha S, Nelson SJ (2009) Apparent diffusion coefficient and fractional anisotropy of newly diagnosed grade II gliomas. NMR Biomed 22:449–455PubMedCrossRefGoogle Scholar
  25. 25.
    Khayal IS, Nelson SJ (2009) Characterization of low-grade gliomas using RGB color maps derived from ADC histograms. J Magn Reson Imaging 30:209–213PubMedCrossRefGoogle Scholar
  26. 26.
    Galldiks N, Kracht LW, Berthold F, Miletic H, Klein JC, Herholz K, Jacobs AH, Heiss WD (2010) [11C]-l-Methionine positron emission tomography in the management of children and young adults with brain tumors. J Neurooncol 96:231–239PubMedCrossRefGoogle Scholar
  27. 27.
    Hatakeyama T, Kawai N, Nishiyama Y, Yamamoto Y, Sasakawa Y, Ichikawa T, Tamiya T (2008) 11C-Methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma. Eur J Nucl Med Mol Imaging 35:2009–2017PubMedCrossRefGoogle Scholar
  28. 28.
    Kato T, Shinoda J, Nakayama N, Miwa K, Okumura A, Yano H, Yoshimura S, Maruyama T, Muragaki Y, Iwama T (2008) Metabolic assessment of gliomas using 11C-methionine, [18F] fluorodeoxyglucose, and 11C-choline positron-emission tomography. AJNR Am J Neuroradiol 29:1176–1182PubMedCrossRefGoogle Scholar
  29. 29.
    Kato T, Shinoda J, Oka N, Miwa K, Nakayama N, Yano H, Maruyama T, Muragaki Y, Iwama T (2008) Analysis of 11C-methionine uptake in low-grade gliomas and correlation with proliferative activity. AJNR Am J Neuroradiol 29:1867–1871PubMedCrossRefGoogle Scholar
  30. 30.
    Maehara T, Nariai T, Arai N, Kawai K, Shimizu H, Ishii K, Ishiwata K, Ohno K (2004) Usefulness of [11C]methionine PET in the diagnosis of dysembryoplastic neuroepithelial tumor with temporal lobe epilepsy. Epilepsia 45:41–45PubMedCrossRefGoogle Scholar
  31. 31.
    Rosenberg DS, Demarquay G, Jouvet A, Le Bars D, Streichenberger N, Sindou M, Kopp N, Mauguière F, Ryvlin P (2005) [11C]-Methionine PET: dysembryoplastic neuroepithelial tumours compared with other epileptogenic brain neoplasms. J Neurol Neurosurg Psychiatry 76:1686–1692PubMedCrossRefGoogle Scholar
  32. 32.
    Okubo S, Zhen HN, Kawai N, Nishiyama Y, Haba R, Tamiya T (2010) Correlation of l-methyl-11C-methionine (MET) uptake with l-type amino acid transporter 1 in human gliomas. J Neurooncol. doi: 10.1007/s11060-010-0117-9
  33. 33.
    Astigiano S, Morandi B, Costa R, Mastracci L, D’Agostino A, Ratto GB, Melioli G, Frumento G (2005) Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer. Neoplasia 7:390–396PubMedCrossRefGoogle Scholar
  34. 34.
    Okamoto A, Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y, Ishii N, Yanaihara N, Yamada K, Takikawa O, Kawaguchi R, Isonishi S, Tanaka T, Urashima M (2005) Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res 11:6030–6039PubMedCrossRefGoogle Scholar
  35. 35.
    Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Göbel G, Margreiter R, Königsrainer A, Fuchs D, Amberger A (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12:1144–1151PubMedCrossRefGoogle Scholar
  36. 36.
    Liu X, Newton RC, Friedman SM, Scherle PA (2009) Indoleamine 2,3-dioxygenase, an emerging target for anti-cancer therapy. Curr Cancer Drug Targets 9:938–952PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Csaba Juhász
    • 1
    • 2
    • 3
    • 6
  • Otto Muzik
    • 1
    • 2
    • 3
    • 4
  • Diane C. Chugani
    • 1
    • 2
    • 4
  • Harry T. Chugani
    • 1
    • 2
    • 3
  • Sandeep Sood
    • 2
    • 5
  • Pulak K. Chakraborty
    • 1
    • 4
  • Geoffrey R. Barger
    • 3
    • 6
  • Sandeep Mittal
    • 5
    • 6
  1. 1.PET Center, Children’s Hospital of MichiganWayne State University School of MedicineDetroitUSA
  2. 2.Carman and Ann Adams Department of PediatricsWayne State University School of MedicineDetroitUSA
  3. 3.Department of NeurologyWayne State University School of MedicineDetroitUSA
  4. 4.Department of RadiologyWayne State University School of MedicineDetroitUSA
  5. 5.Department of NeurosurgeryWayne State University School of MedicineDetroitUSA
  6. 6.The Barbara Ann Karmanos Cancer InstituteDetroitUSA

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