Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review

  • Flóra John
  • Otto Muzik
  • Sandeep Mittal
  • Csaba JuhászEmail author
Review Article


Due to its metabolism via the serotonin and kynurenine pathways, tryptophan plays a key role in multiple disease processes including cancer. Imaging tryptophan uptake and metabolism in vivo can be achieved with tryptophan derivative positron emission tomography (PET) radiotracers. While human studies with such tracers have been confined to C-11-labeled compounds, preclinical development of F-18-labeled tryptophan-based radiotracers has surged in recent years. We performed a systematic review of studies reporting on such F-18-labeled tryptophan tracers to summarize and compare their biological characteristics and their potential for tumor imaging, with a particular focus on key enzymes of the kynurenine pathway (indoleamine 2,3-dioxygenase [IDO] and tryptophan 2,3-dioxygenase [TDO]), which play an important role in tumoral immune resistance. From a PubMed search, English language articles including data on the preparation and radiochemical and/or biological characteristics of F-18-labeled tryptophan derivative radiotracers were reviewed. A total of 19 original papers included data on 15 unique radiotracers, the majority of which were synthesized with an adequate radiochemical yield. Automated synthesis was reported for 1-(2-[18F]fluoroethyl)-L-tryptophan, the most extensively evaluated tracer thus far. Biodistribution studies showed high uptake in the pancreas, while the L-type amino acid transporter was the dominant transport mechanism for most of the reviewed tracers. Tracers tested for tumor uptake showed accumulation in tumor cell lines in vitro and in xenografts in vivo, often with favorable tumor-to-background uptake ratios in comparison with clinically used F-18-labeled radiotracers. Five tracers showed promise for imaging IDO activity, including 1-(2-[18F]fluoroethyl)-L-tryptophan and a F-18-labeled analog of alpha-[11C]methyl-L-tryptophan tested clinically in previous studies. Two radiotracers were metabolized by TDO but showed defluorination in vivo. In summary, most F-18-labeled tryptophan derivative PET tracers share common transport mechanisms and biodistribution characteristics. Several reported tracers could be candidates for further testing and validation toward PET imaging applications in a variety of human diseases.

Key Words

Fluorine-18-labeled compounds Radioactive tracer Tryptophan metabolism Kynurenine pathway Indoleamine 2,3-dioxygenase PET Molecular imaging 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Peters JC (1991) Tryptophan nutrition and metabolism: an overview. Adv Exp Med Biol 294:345–358CrossRefGoogle Scholar
  2. 2.
    Carhart-Harris RL, Nutt DJ (2017) Serotonin and brain function: a tale of two receptors. J Psychopharmacol 31:1091–1120CrossRefGoogle Scholar
  3. 3.
    Popova NK, Naumenko VS (2019) Neuronal and behavioral plasticity: the role of serotonin and BDNF systems tandem. Expert Opin Ther Targets 23:227–239CrossRefGoogle Scholar
  4. 4.
    Kennedy PJ, Cryan JF, Dinan TG, Clarke G (2017) Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 112:399–412CrossRefGoogle Scholar
  5. 5.
    Schwarcz R, Stone TW (2017) The kynurenine pathway and the brain: challenges, controversies and promises. Neuropharmacology 112:237–247CrossRefGoogle Scholar
  6. 6.
    Oxenkrug G (2013) Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol 48:294–301CrossRefGoogle Scholar
  7. 7.
    Michelhaugh SK, Guastella AR, Mittal S (2015) Overview of the kynurenine pathway of tryptophan metabolism. In: Mittal S (ed) Targeting the broadly pathogenic kynurenine pathway. Springer International Publishing, Switzerland, pp 3–9CrossRefGoogle Scholar
  8. 8.
    Muzik O, Burghardt P, Yi Z, Kumar A, Seyoum B (2017) Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway. Biochem Biophys Res Commun 488:29–32CrossRefGoogle Scholar
  9. 9.
    Lovelace MD, Varney B, Sundaram G, Lennon MJ, Lim CK, Jacobs K, Guillemin GJ, Brew BJ (2017) Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology 112:373–388CrossRefGoogle Scholar
  10. 10.
    Savitz J (2017) Role of kynurenine metabolism pathway activation in major depressive disorders. Curr Top Behav Neurosci 31:249–267CrossRefGoogle Scholar
  11. 11.
    Platten M, Nollen EAA, Rohrig UF et al (2019) Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov 18:379–401CrossRefGoogle Scholar
  12. 12.
    Uyttenhove C, Pilotte L, Theate I et al (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274CrossRefGoogle Scholar
  13. 13.
    Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154CrossRefGoogle Scholar
  14. 14.
    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203CrossRefGoogle Scholar
  15. 15.
    Collin M (2016) Immune checkpoint inhibitors: a patent review (2010-2015). Expert Opin Ther Pat 26:555–564CrossRefGoogle Scholar
  16. 16.
    Prendergast GC, Malachowski WP, DuHadaway JB, Muller AJ (2017) Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res 77:6795–6811CrossRefGoogle Scholar
  17. 17.
    Muller AJ, Manfredi MG, Zakharia Y, Prendergast GC (2019) Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Semin Immunopathol 41:41–48CrossRefGoogle Scholar
  18. 18.
    Busch H, Davis JR, Honig GR et al (1959) The uptake of a variety of amino acids into nuclear proteins of tumors and other tissues. Cancer Res 19:1030–1039Google Scholar
  19. 19.
    Hubner KF, Andrews GA, Buonocore E et al (1979) Carbon-11-labeled amino acids for the rectilinear and positron tomographic imaging of the human pancreas. J Nucl Med 20:507–513Google Scholar
  20. 20.
    Atkins HL, Christman DR, Fowler JS, Hauser W, Hoyte RM, Klopper JF, Lin SS, Wolf AP (1972) Organic radiopharmaceuticals labeled with isotopes of short half-life. V. 18F-labeled 5- and 6-fluorotryptophan. J Nucl Med 13:713–719Google Scholar
  21. 21.
    Heiss WD, Wienhard K, Wagner R, Lanfermann H, Thiel A, Herholz K, Pietrzyk U (1996) F-Dopa as an amino acid tracer to detect brain tumors. J Nucl Med 37:1180–1182Google Scholar
  22. 22.
    Wester HJ, Herz M, Weber W et al (1999) Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med 40:205–212Google Scholar
  23. 23.
    Weber WA, Wester HJ, Grosu AL et al (2000) O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med 27:542–549CrossRefGoogle Scholar
  24. 24.
    Orlefors H, Sundin A, Ahlstrom H et al (1998) Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors. J Clin Oncol 16:2534–2541CrossRefGoogle Scholar
  25. 25.
    Diksic M, Young SN (2001) Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan. J Neurochem 78:1185–1200CrossRefGoogle Scholar
  26. 26.
    Juhasz C, Chugani DC, Muzik O, Shah A, Asano E, Mangner TJ, Chakraborty PK, Sood S, Chugani HT (2003) Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 60:960–968CrossRefGoogle Scholar
  27. 27.
    Juhasz 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 26:345–357CrossRefGoogle Scholar
  28. 28.
    Juhasz C, Mittal S (2015) Molecular imaging of tryptophan metabolism in tumors. In: Mittal S (ed) Targeting the broadly pathogenic kynurenine pathway. Springer, Switzerland, pp 373–389CrossRefGoogle Scholar
  29. 29.
    Chugani DC, Chugani HT, Muzik O, Shah JR, Shah AK, Canady A, Mangner TJ, Chakraborty PK (1998) Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann Neurol 44:858–866CrossRefGoogle Scholar
  30. 30.
    Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S, Nakai A, Debonnel G, Blier P, Benkelfat C (2004) Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 61:556–563CrossRefGoogle Scholar
  31. 31.
    Juhasz C, Dwivedi S, Kamson DO et al (2014) Comparison of amino acid positron emission tomographic radiotracers for molecular imaging of primary and metastatic brain tumors. Mol Imaging 13.
  32. 32.
    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 20:2–9CrossRefGoogle Scholar
  33. 33.
    Lukas RV, Juhasz C, Wainwright DA et al (2019) Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod. J Neuro-Oncol 141:111–120CrossRefGoogle Scholar
  34. 34.
    Li R, Wu SC, Wang SC, Fu Z, Dang Y, Huo L (2010) Synthesis and evaluation of l-5-(2-[18F]fluoroethoxy)tryptophan as a new PET tracer. Appl Radiat Isot 68:303–308CrossRefGoogle Scholar
  35. 35.
    Kramer SD, Mu L, Muller A, Keller C, Kuznetsova OF, Schweinsberg C, Franck D, Muller C, Ross TL, Schibli R, Ametamey SM (2012) 5-(2-18F-fluoroethoxy)-L-tryptophan as a substrate of system L transport for tumor imaging by PET. J Nucl Med 53:434–442CrossRefGoogle Scholar
  36. 36.
    Sun T, Tang G, Tian H, Wang X, Chen X, Chen Z, Wang SC (2012) Radiosynthesis of 1-[18F]fluoroethyl-L-tryptophan as a novel potential amino acid PET tracer. Appl Radiat Isot 70:676–680CrossRefGoogle Scholar
  37. 37.
    Chiotellis A, Mu L, Muller A et al (2013) Synthesis and biological evaluation of 18F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging. Eur J Med Chem 70:768–780CrossRefGoogle Scholar
  38. 38.
    He S, Tang G, Hu K, Wang H, Wang S, Huang T, Liang X, Tang X (2013) Radiosynthesis and biological evaluation of 5-(3-[18F]fluoropropyloxy)-L-tryptophan for tumor PET imaging. Nucl Med Biol 40:801–807CrossRefGoogle Scholar
  39. 39.
    Chiotellis A, Muller A, Mu L, Keller C, Schibli R, Krämer SD, Ametamey SM (2014) Synthesis and biological evaluation of 18F-labeled Fluoroethoxy tryptophan analogues as potential PET tumor imaging agents. Mol Pharm 11:3839–3851CrossRefGoogle Scholar
  40. 40.
    Shih IH, Duan XD, Kong FL et al (2014) Automated synthesis of 18F-fluoropropoxytryptophan for amino acid transporter system imaging. Biomed Res Int 2014:492545CrossRefGoogle Scholar
  41. 41.
    Weiss PS, Ermert J, Castillo Melean J et al (2015) Radiosynthesis of 4-[18F]fluoro-L-tryptophan by isotopic exchange on carbonyl-activated precursors. Bioorg Med Chem 23:5856–5869CrossRefGoogle Scholar
  42. 42.
    Chiotellis A, Muller Herde A, Rossler SL et al (2016) Synthesis, radiolabeling, and biological evaluation of 5-Hydroxy-2-[18F]fluoroalkyl-tryptophan analogues as potential PET radiotracers for tumor imaging. J Med Chem 59:5324–5340CrossRefGoogle Scholar
  43. 43.
    Henrottin J, Lemaire C, Egrise D, Zervosen A, van den Eynde B, Plenevaux A, Franci X, Goldman S, Luxen A (2016) Fully automated radiosynthesis of N1-[(18F)]fluoroethyl-tryptophan and study of its biological activity as a new potential substrate for indoleamine 2,3-dioxygenase PET imaging. Nucl Med Biol 43:379–389CrossRefGoogle Scholar
  44. 44.
    Schafer D, Weiss P, Ermert J, et al. (2016) Preparation of no-carrier-added 6-[F-18]fluoro-l-tryptophan via Cu-mediated radiofluorination. Eur J Org Chem:4621–4628Google Scholar
  45. 45.
    Abbas A, Beamish C, McGirr R et al (2016) Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas. F1000Res 5:1851CrossRefGoogle Scholar
  46. 46.
    Tang T, Gill HS, Ogasawara A, Tinianow JN, Vanderbilt AN, Williams SP, Hatzivassiliou G, White S, Sandoval W, DeMent K, Wong M, Marik J (2017) Preparation and evaluation of L- and D-5-[18F]fluorotryptophan as PET imaging probes for indoleamine and tryptophan 2,3-dioxygenases. Nucl Med Biol 51:10–17CrossRefGoogle Scholar
  47. 47.
    Giglio BC, Fei H, Wang M, Wang H, He L, Feng H, Wu Z, Lu H, Li Z (2017) Synthesis of 5-[18F]fluoro-alpha-methyl tryptophan: new Trp based PET agents. Theranostics 7:1524–1530CrossRefGoogle Scholar
  48. 48.
    Xin Y, Cai H (2017) Improved Radiosynthesis and biological evaluations of L- and D-1-[18F]fluoroethyl-tryptophan for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism. Mol Imaging Biol 19:589–598CrossRefGoogle Scholar
  49. 49.
    Michelhaugh SK, Muzik O, Guastella AR, Klinger NV, Polin LA, Cai H, Xin Y, Mangner TJ, Zhang S, Juhász C, Mittal S (2017) Assessment of tryptophan uptake and kinetics using 1-(2-18F-fluoroethyl)-l-tryptophan and alpha-11C-methyl-l-tryptophan PET imaging in mice implanted with patient-derived brain tumor xenografts. J Nucl Med 58:208–213CrossRefGoogle Scholar
  50. 50.
    Zlatopolskiy BD, Zischler J, Schafer D et al (2018) Discovery of 7-[18F]fluorotryptophan as a novel positron emission tomography (PET) probe for the visualization of tryptophan metabolism in vivo. J Med Chem 61:189–206CrossRefGoogle Scholar
  51. 51.
    Xin Y, Gao X, Liu L, Ge WP, Jain MK, Cai H (2019) Evaluation of L-1-[18F]fluoroethyl-tryptophan for PET imaging of Cancer. Mol Imaging Biol.
  52. 52.
    Palacin M, Estevez R, Bertran J, Zorzano A (1998) Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev 78:969–1054CrossRefGoogle Scholar
  53. 53.
    Castagna M, Shayakul C, Trotti D, Sacchi VF, Harvey WR, Hediger MA (1997) Molecular characteristics of mammalian and insect amino acid transporters: implications for amino acid homeostasis. J Exp Biol 200:269–286Google Scholar
  54. 54.
    Imai H, Kaira K, Oriuchi N et al (2010) Inhibition of L-type amino acid transporter 1 has antitumor activity in non-small cell lung cancer. Anticancer Res 30:4819–4828Google Scholar
  55. 55.
    Alkonyi B, Mittal S, Zitron I, Chugani DC, Kupsky WJ, Muzik O, Chugani HT, Sood S, Juhász C (2012) Increased tryptophan transport in epileptogenic dysembryoplastic neuroepithelial tumors. J Neuro-Oncol 107:365–372CrossRefGoogle Scholar
  56. 56.
    Zitron IM, Kamson DO, Kiousis S, Juhász C, Mittal S (2013) In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1. Cancer Biol Ther 14:333–339CrossRefGoogle Scholar
  57. 57.
    Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, Kühn LC (1999) LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem 274:34948–34954CrossRefGoogle Scholar
  58. 58.
    Bodoy S, Martin L, Zorzano A, Palacin M, Estevez R, Bertran J (2005) Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem 280:12002–12011CrossRefGoogle Scholar
  59. 59.
    Michael AF, Drummond KN, Doeden D, Anderson JA, Good RA (1964) Tryptophan metabolism in man. J Clin Invest 43:1730–1746CrossRefGoogle Scholar
  60. 60.
    Nowak EC, de Vries VC, Wasiuk A, Ahonen C, Bennett KA, le Mercier I, Ha DG, Noelle RJ (2012) Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J Exp Med 209:2127–2135CrossRefGoogle Scholar
  61. 61.
    Bosnyak E, Kamson DO, Guastella AR et al (2015) Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas. Neuro-Oncology 17:1284–1292CrossRefGoogle Scholar
  62. 62.
    John F, Bosnyak E, Robinette NL et al (2019) Multimodal imaging-defined subregions in newly-diagnosed glioblastoma: impact on overall survival. Neuro-Oncology 21:264–273CrossRefGoogle Scholar
  63. 63.
    Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (2015) Research progress of indoleamine 2,3-dioxygenase inhibitors. Future Med Chem 7:185–201CrossRefGoogle Scholar
  64. 64.
    Basran J, Rafice SA, Chauhan N, Efimov I, Cheesman MR, Ghamsari L, Raven EL (2008) A kinetic, spectroscopic, and redox study of human tryptophan 2,3-dioxygenase. Biochemistry 47:4752–4760CrossRefGoogle Scholar
  65. 65.
    Henrottin J, Zervosen A, Lemaire C, Sapunaric F, Laurent S, van den Eynde B, Goldman S, Plenevaux A, Luxen A (2015) N1-Fluoroalkyltryptophan analogues: synthesis and in vitro study as potential substrates for indoleamine 2,3-dioxygenase. ACS Med Chem Lett 6:260–265CrossRefGoogle Scholar
  66. 66.
    Guastella AR, Michelhaugh SK, Klinger NV, et al (2016) Tryptophan PET imaging of the kynurenine pathway in patient-derived xenograft models of glioblastoma. Mol Imaging 15.
  67. 67.
    Juhasz C, Nahleh Z, Zitron I et al (2012) Tryptophan metabolism in breast cancers: molecular imaging and immunohistochemistry studies. Nucl Med Biol 39:926–932CrossRefGoogle Scholar
  68. 68.
    Leeds JM, Brown PJ, McGeehan GM et al (1993) Isotope effects and alternative substrate reactivities for tryptophan 2,3-dioxygenase. J Biol Chem 268:17781–17786Google Scholar
  69. 69.
    Juhasz C, Buth A, Chugani DC et al (2013) Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus. Neurosurg Focus 34:E5. CrossRefGoogle Scholar
  70. 70.
    Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, la Fougère C, Pope W, Law I, Arbizu J, Chamberlain MC, Vogelbaum M, Ellingson BM, Tonn JC (2016) Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro-Oncology 18:1199–1208CrossRefGoogle Scholar
  71. 71.
    Yu CP, Pan ZZ, Luo DY (2016) TDO as a therapeutic target in brain diseases. Metab Brain Dis 31:737–747CrossRefGoogle Scholar
  72. 72.
    Winters M, DuHadaway JB, Pham KN et al (2019) Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase. Eur J Med Chem 162:455–464CrossRefGoogle Scholar
  73. 73.
    Yang L, Chen Y, He J, Njoya EM, Chen J, Liu S, Xie C, Huang W, Wang F, Wang Z, Li Y, Qian S (2019) 4,6-Substituted-1H-indazoles as potent IDO1/TDO dual inhibitors. Bioorg Med Chem 27:1087–1098CrossRefGoogle Scholar
  74. 74.
    Markham A (2017) Telotristat ethyl: first global approval. Drugs 77:793–798CrossRefGoogle Scholar

Copyright information

© World Molecular Imaging Society 2019

Authors and Affiliations

  1. 1.Department of PediatricsWayne State University and PET Center and Translational Imaging Laboratory, Children’s Hospital of MichiganDetroitUSA
  2. 2.Department of NeurologyWayne State UniversityDetroitUSA
  3. 3.Department of NeurosurgeryWayne State UniversityDetroitUSA
  4. 4.Karmanos Cancer InstituteDetroitUSA
  5. 5.Fralin Biomedical Research Institute, Virginia Tech Carilion School of MedicineRoanokeUSA
  6. 6.Virginia Tech School of NeuroscienceBlacksburgUSA

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