The Radiopharmaceutical Chemistry of Nitrogen-13 and Oxygen-15

  • Vanessa Gómez-Vallejo
  • Luka Rejc
  • Fernando López-Gallego
  • Jordi LlopEmail author


Of all the cyclotron-produced positron-emitting radionuclides, 18F is by far the most widely used both in the preclinical and clinical settings. The use of 11C has increased significantly since the 1990s due to the proliferation of biomedical cyclotrons and the radiochemical possibilities of radiopharmaceuticals that can be directly produced in the cyclotron target. The application of other short-lived positron emitters—including nitrogen-13 (13N; t1/2 = 9.97 min) and oxygen-15 (15O; t1/2 = 122 s)—has remained somewhat more restricted. Because the stable analogues of both 13N and 15O—14/15N and 16/17/18O—are present in most biologically active molecules, the incorporation of these radionuclides into imaging agents has the potential to yield useful and interesting alternatives to 11C- and 18F-labeled radiopharmaceuticals. In this chapter, we cover the production methods used to create these two radionuclides as well as the radiochemical methods that have been developed for incorporating 13N and 15O into radiotracers. In addition, we provide numerous examples of 13N and 15O radiosyntheses from the literature, with particular emphasis on the aspects of the chemistry of these two radionuclides that differs from that of their non-radioactive isotopologues. Two works in particular that we believe illustrate applications of 13N and 15O that differ from conventional perceptions of radiochemistry are discussed in detail. Finally, future opportunities for the production and use of these two radionuclides are addressed, taking into account the impact that recent technological advances may have in the field.


Nitrogen-13 Oxygen-15 Radiochemistry Radiolabeling Fundamentals 


  1. 1.
    Joliot F, Curie I. Artificial production of a new kind of radio-element. Nature. 1934;133(3354):201–2.Google Scholar
  2. 2.
    Cockcroft JD, Gilbert CW, Walton ETS. Production of induced radioactivity by high velocity protons. Nature. 1934;133(3357):328.Google Scholar
  3. 3.
    Livingston MS, McMillan E. The production of radioactive oxygen. Phys Rev. 1934;46(5):437–8.Google Scholar
  4. 4.
    Tilbury RS, Dahl JR. 13N species formed by proton irradiation of water. Radiat Res. 1979;79(1):22–33.Google Scholar
  5. 5.
    Firouzbakht ML, Schlyer DJ, Wolf AP, Fowler JS. Mechanism of nitrogen-13-labeled ammonia formation in a cryogenic water target. Nucl Med Biol. 1999;26(4):437–41.PubMedGoogle Scholar
  6. 6.
    Wieland B, Bida G, Padgett H, Hendry G, Zippi E, Kabalka G, et al. In-target production of [13N]ammonia via proton irradiation of dilute aqueous ethanol and acetic acid mixtures. Appl Radiat Isot. 1991;42(11):1095–8.Google Scholar
  7. 7.
    DeGrado TR, Hanson MW, Turkington TG, Delong DM, Brezinski DA, Vallée JP, et al. Estimation of myocardial blood flow for longitudinal studies with 13N-labeled ammonia and positron emission tomography. J Nucl Cardiol. 1996;3(6):494–507.PubMedGoogle Scholar
  8. 8.
    Straatmann MG, Welch MJ. Enzymatic synthesis of nitrogen 13 labeled amino acids. Radiat Res. 1973;56(1):48–56.PubMedGoogle Scholar
  9. 9.
    Gómez-Vallejo V, Gaja V, Gona KB, Llop J. Nitrogen-13: historical review and future perspectives. J Labelled Comp Radiopharm. 2014;57(4):244–54.PubMedGoogle Scholar
  10. 10.
    Peter Wolk C, Austin SM, Bortins J, Galonsky A. Autoradiographic localization of 13N after fixation of 13N-labeled nitrogen gas by a heterocyst-forming blue-green alga. J Cell Biol. 1974;61(2):440–53.PubMedCentralGoogle Scholar
  11. 11.
    Wellman TJ, Winkler T, Costa ELV, Musch G, Harris RS, Venegas JG, et al. Measurement of regional specific lung volume change using respiratory-gated PET of inhaled 13N-nitrogen. J Nucl Med. 2010;51(4):646–53.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Le Bars D. A convenient production of [13N]nitrogen for ventilation studies using a nitrogen gas target for 11C production. J Labelled Comp Radiopharm. 2001;44(1):1–5.Google Scholar
  13. 13.
    Finn RD, Christman DR, Wolf AP. A rapid synthesis of nitrogen-13 labelled amphetamine. J Labelled Comp Radiopharm. 1981;18(6):909–13.Google Scholar
  14. 14.
    Tominaga T, Inoue O, Irie T, Suzuki K, Yamasaki T, Hirobe M. Preparation of 13N-β-phenethylamine. Appl Radiat Isot. 1985;36(7):555–60.Google Scholar
  15. 15.
    Tominaga T, Inoue O, Suzuki K, Yamasaki T, Hirobe M. Synthesis of 13N-labelled amines by reduction of 13N-labelled amides. Appl Radiat Isot. 1986;37(12):1209–12.Google Scholar
  16. 16.
    Toshiaki I, Osamu I, Kazutoshi S, Toshiyoshi T. Labeling of 13N labeled adenosine and nicotinamide by ammonolysis. Appl Radiat Isot. 1985;36(5):345–7.Google Scholar
  17. 17.
    Kumata K, Takei M, Ogawa M, Kato K, Suzuki K, Zhang MR. One-pot radiosynthesis of [13N]urea and [13N] carbamate using no-carrier-added [13N]NH3. J Labelled Comp Radiopharm. 2009;52(5):166–72.Google Scholar
  18. 18.
    Elmaleh DR, Hnatowich DJ, Kulprathipanja S. A novel synthesis of 13N-L-asparagine. J Labelled Comp Radiopharm. 1979;16(1):92–3.Google Scholar
  19. 19.
    Benkovic SJ, Hammes-Schiffer S. A perspective on enzyme catalysis. Science. 2003;301(5637):1196–202.PubMedGoogle Scholar
  20. 20.
    Koshland DE. The key–lock theory and the induced fit theory. Angew Chem Int Ed. 1995;33(23–24):2375–8.Google Scholar
  21. 21.
    Chambers PJ, Pretorius IS. Fermenting knowledge: the history of winemaking, science and yeast research. EMBO Rep. 2010;11(12):914–20.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Barnett JA. A history of research on yeasts 5: the fermentation pathway. Yeast. 2003;20(6):509–43.PubMedGoogle Scholar
  23. 23.
    Cohen MB, Spolter L, Chang CC, MacDonald NS, Takahashi J, Bobinet DD. Immobilized enzymes in the production of radiopharmaceutically pure amino acids labeled with 13N. J Nucl Med. 1974;15(12):1192–5.PubMedGoogle Scholar
  24. 24.
    Brena B, González-Pombo P, Batista-Viera F. Immobilization of enzymes: A literature survey. Methods Mol Biol. 2013;1051:15–31.PubMedGoogle Scholar
  25. 25.
    da Silva ES, Gómez-Vallejo V, López-Gallego F, Llop J. Biocatalysis in Radiochemistry; Enzymatic Incorporation of PET radionuclides into molecules of biomedical interest. J Labelled Comp Radiopharm. 2017;61(4):332–54.Google Scholar
  26. 26.
    Llop J, Gómez-Vallejo V, Bosque M, Quincoces G, Peñuelas I. Synthesis of S-[13N]nitrosoglutathione (13N-GSNO) as a new potential PET imaging agent. Appl Radiat Isot. 2009;67(1):95–9.PubMedGoogle Scholar
  27. 27.
    Gómez-Vallejo V, Kato K, Oliden I, Calvo J, Baz Z, Borrell JI, et al. Fully automated synthesis of 13N-labeled nitrosothiols. Tetrahedron Lett. 2010;51(22):2990–3.Google Scholar
  28. 28.
    Sabaté CM, Delalu H. Synthesis and characterization of secondary nitrosamines from secondary amines using sodium nitrite and p-toluenesulfonic acid. Chem Asian J. 2015;10(3):674–8.Google Scholar
  29. 29.
    Gómez-Vallejo V, Kato K, Hanyu M, Minegishi K, Borrell JI, Llop J. Efficient system for the preparation of [13N]labeled nitrosamines. Bioorg Med Chem Lett. 2009;19(7):1913–5.PubMedGoogle Scholar
  30. 30.
    Gaja V, Gómez-Vallejo V, Puigivila M, Pérez-Campaña C, Martin A, García-Osta A, et al. Synthesis and evaluation of 13N-labelled azo compounds for β-amyloid imaging in mice. Mol Imag Biol. 2014;16(4):538–49.Google Scholar
  31. 31.
    Gómez-Vallejo V, Borrell JI, Llop J. A convenient synthesis of 13N-labelled azo compounds: a new route for the preparation of amyloid imaging PET probes. Eur J Med Chem. 2010;45(11):5318–23.PubMedGoogle Scholar
  32. 32.
    Joshi SM, Gómez-Vallejo V, Salinas V, Llop J. Synthesis of 13 N-labelled polysubstituted triazoles: via Huisgen cycloaddition. RSC Adv. 2016;6(111):109633–8.Google Scholar
  33. 33.
    Welch MJ, Ter-Pogossian MM. Preparation of short half-lived radioactive gases for medical studies. Radiat Res. 1968;36(3):580–7.PubMedGoogle Scholar
  34. 34.
    Nichols AB, Cochavi S, Hales CA, Strauss HW, McKusick KA, Waltman AC, et al. Scintigraphic detection of pulmonary emboli by serial positron imaging of inhaled 15O-labeled carbon dioxide. New Engl J Med. 1978;299(6):279–84.PubMedGoogle Scholar
  35. 35.
    Sajjad M, Liow JS, Moreno-Cantu J. A system for continuous production and infusion of [15O]H2O for PET activation studies. Appl Radiat Isot. 2000;52(2):205–10.PubMedGoogle Scholar
  36. 36.
    Powell J, O’Neil JP. Production of [15O]water at low-energy proton cyclotrons. Appl Radiat Isot. 2006;64(7):755–9.PubMedGoogle Scholar
  37. 37.
    Wunderlich G, Knorr U, Stephan KM, Tellmann L, Azari NP, Herzog H, et al. Dynamic scanning of 15O-butanol with positron emission tomography can identify regional cerebral activations. Hum Brain Mapp. 1997;5(5):364–78.PubMedGoogle Scholar
  38. 38.
    Ingvar M, Eriksson L, Greitz T, Stone-Elander S, Dahlbom M, Rosenqvist G, et al. Methodological aspects of brain activation studies: cerebral blood flow determined with [15O]butanol and positron emission tomography. J Cereb Blood Flow Metab. 1994;14(4):628–38.PubMedGoogle Scholar
  39. 39.
    Kabalka GW, Lambrecht RM, Sajjad M, Fowler JS, Kunda SA, McCollum GW, et al. Synthesis of 15O-labeled butanol via organoborane chemistry. Appl Radiat Isot. 1985;36(11):853–5.Google Scholar
  40. 40.
    Kabalka GW, Green JF, Goodman MM, Maddox JT, Lambert SJ. The synthesis of oxygen-15 butanol via the oxidation of tributylborane adsorbed on solid surfaces. J Labelled Comp Radiopharm. 1994;35:186–8.Google Scholar
  41. 41.
    Takahashi K, Murakami M, Hagami E, Sasaki H, Kondo Y, Mizusawa S, et al. Radiosynthesis of 15O-labeled hydrogen peroxide. J Labelled Comp Radiopharm. 1989;27(10):1167–75.Google Scholar
  42. 42.
    Joshi SM, De Cózar A, Gómez-Vallejo V, Koziorowski J, Llop J, Cossío FP. Synthesis of radiolabelled aryl azides from diazonium salts: experimental and computational results permit the identification of the preferred mechanism. Chem Commun. 2015;51(43):8954–7.Google Scholar
  43. 43.
    Pérez-Campaña C, Gómez-Vallejo V, Martin A, San Sebastián E, Moya SE, Reese T, et al. Tracing nanoparticles in vivo: a new general synthesis of positron emitting metal oxide nanoparticles by proton beam activation. Analyst. 2012;137(21):4902–6.PubMedGoogle Scholar
  44. 44.
    Gaja V, Gómez-Vallejo V, Cuadrado-Tejedor M, Borrell JI, Llop J. Synthesis of 13N-labelled radiotracers by using microfluidic technology. J Labelled Comp Radiopharm. 2012;55(9):332–8.Google Scholar
  45. 45.
    Maddaluno JF, Faull KF. Fast enzymatic preparation of l-DOPA from tyrosine and molecular oxygen: a potential method for preparing [15O]l-DOPA. Appl Radiat Isot. 1990;41(9):873–8.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Vanessa Gómez-Vallejo
    • 1
  • Luka Rejc
    • 2
  • Fernando López-Gallego
    • 3
    • 4
  • Jordi Llop
    • 2
    Email author
  1. 1.Radiochemistry Platform, Center for Cooperative Research in Biomaterials, CIC biomaGUNESan SebastiánSpain
  2. 2.Radiochemistry and Nuclear ImagingCenter for Cooperative Research in Biomaterials, CIC biomaGUNESan SebastiánSpain
  3. 3.Institute of Synthetic Chemistry and Catalysis (IQSCH)University of ZaragozaZaragozaSpain
  4. 4.Fundación ARAIDZaragozaSpain

Personalised recommendations