Accelerator-Produced Therapeutic Radionuclides

  • F. F. (Russ) Knapp
  • Ashutosh Dash


Particle accelerators have played a key role for the production of radioisotopes since the 1940s, and medical cyclotrons (11–20-MeV protons), in particular, are currently of central importance for the production of short-lived positron emitters for diagnostic applications in nuclear medicine. Commercially, cyclotrons in the 20–35-MeV proton energy range are used to produce a variety of gamma-emitting radioisotopes. In addition, many high-energy accelerators of several different types which accelerate primarily protons play a role in the production of medical radioisotopes, including those which have important roles in therapy. In this chapter, the basic fundamentals of accelerator production and yield calculations are discussed in addition to key therapeutic radioisotopes and comments on their applications as unsealed sources radiopharmaceuticals in nuclear medicine.


Radiochemical Separation Anion Exchange Column Chlorinate Cobalt Dicarbollide Isopropyl Ether Natural Bismuth 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aardaneh K, Shirazi B. Rapid separation of radiogallium from Zn and Cu targets using anion exchange technique. J Radioanal Nucl Chem. 2005;265:4.CrossRefGoogle Scholar
  2. Apostolidis C, Molinet R, Rasmussen G, Morgenstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem. 2005;77:6288–91.PubMedCrossRefGoogle Scholar
  3. Boll RA, Malkemus D, Mirzadeh S. Production of actinium- 225 for alpha particle mediated radioimmunotherapy. Appl Radiat Isot. 2005;62:667–79.PubMedCrossRefGoogle Scholar
  4. Brown LC, Beets AL. Cyclotron production of carrier free indium-111. Int J Appl Radiat Isot. 1972;23:57–63.CrossRefGoogle Scholar
  5. Chattopadhyay S, Das MK, Sarkar BR, Ramamoorty N. Radiochemical separation of high purity 111In from cadmium, copper, aluminium and traces of iron: use of a cation exchange resin with hydrobromic acid and hydrobromic acid. Appl Radiat Isot. 1997;48(8):1063–7.CrossRefGoogle Scholar
  6. Das SK, Guin R, Saha SK. Carrier-free separation of 111In from a silver matrix. Appl Radiat Isot. 1996;47(3):293–6.CrossRefGoogle Scholar
  7. Das MK, Chattopadhayay S, Sarkar BR, Ramamoorthy N. A cation exchange method for separation of 111In from inactive silver, copper, traces of iron and radioactive gallium and zinc isotopes. Appl Radiat Isot. 1997;48(1):11–4.CrossRefGoogle Scholar
  8. Dasgupta AK, Mausner LF, Srivastava SC. A new separation procedure for 67Cu from proton irradiated Zn. Appl Radiat Isot. 1991;42:371–6.CrossRefGoogle Scholar
  9. Dolley SG, Walt TN, Steyn GFE, Szelecseny F, Kovacs Z. The production and isolation of Cu-64 and Cu-67 from zinc target material and other radionuclides. Czech J Phys. 2006;56:D539–44.Google Scholar
  10. Dumortier R, Weber ME, Vera JH. Removal and recovery of gallium from aqueous solutions by complexation with sodium di-(n-octyl) phosphinate. Hydrometallurgy. 2005;76:207–15.CrossRefGoogle Scholar
  11. Eberle SH. Gmelin handbook of inorganic chemistry – astatine. 8th ed. Berlin: Springer; 1985. p. 183–209.Google Scholar
  12. El-Azony KM, Ferieg K, Saleh ZA. Direct separation of 67Ga citrate from zinc and copper target materials by anion exchange. Appl Radiat Isot. 2003;59:329.PubMedCrossRefGoogle Scholar
  13. Ermolaev SV, Zhuikov BL, Kokhanyuk V, Srivastava SC. Production of carrier-added Tin-117m from proton irradiated antimony. J Radioanal Chem. 2009;280:319–24.Google Scholar
  14. Filoosofov DV, Lebedev NA, Novogrodov A, et al. Production, concentration and deep purification of 111In radiochemicals. J Appl Radiat Isot. 2001;55:293–329.CrossRefGoogle Scholar
  15. Friedman AM, Zalutsky MR, Wung W, et al. Preparation of a biologically stable and immunogenically competent astatinated protein. Int J Nucl Med Biol. 1977;4:219–24.PubMedCrossRefGoogle Scholar
  16. Gul K. Calculations for the excitation functions of 3–26 MeV proton reactions on 66Zn, 67Zn and 68Zn. Appl Radiat Isot. 2001;54:311–8.PubMedCrossRefGoogle Scholar
  17. Guptna B, Deep A, Malik P. Liquid-Liquid extraction and recovery of Indium using Cyanex 923. Anal Chim Acta. 2004;513:463–71.CrossRefGoogle Scholar
  18. Ham GJ. Determination of actinides in environmental materials using extraction chromatography. Scien Tot Environ. 1995;173/174:19–22.CrossRefGoogle Scholar
  19. Henricksen G, Hoff P, Alstad J, Larsen RH. 223Ra for endoradiotherapeutic applications prepared from an immobilized 227Ac/227Th source. Radiochim Acta. 2001;89:661–6.Google Scholar
  20. Horowitz EE, Bond AH. Purification of radionuclides for nuclear medicine: the multicolumn selectivity inversion generator concept. Czech J Phys. 2003;53:A713–6.CrossRefGoogle Scholar
  21. Horwitz EP, Dietz ML. Concentration and separation of actinides from urine using a supported bifunctinal organophosphorus extractant. Anal Chim Acta. 1990;238:263–71.CrossRefGoogle Scholar
  22. Horwitz EP, Dietz ML, Fisher DE. Separation and pre concentration of strontium from biological, environmental, and nuclear waste samples by extraction chromatography using a crown ether. Anal Chem. 1991;63(5):522–5.PubMedCrossRefGoogle Scholar
  23. Horwitz EP, Chiarizia R, Dietz ML, et al. Separation and preconcentration of actinides from acidic media by extraction chromatography. Anal Chim Acta. 1993;281:361–72.CrossRefGoogle Scholar
  24. Horwitz EP, Dietz ML, Chiarizia R, et al. Separation and preconcentration of actinides by extraction chromatography using a supported liquid anion exchanger. Application to the characterization of high-level nuclear waste solutions. Anal Chim Acta. 1995;310:63–78.CrossRefGoogle Scholar
  25. Horwitz EP, Chiarizia R, Dietz ML, et al. DIPEX: a new extraction chromatographic material for the separation and Pre-concentration of actinides from aqueous solution. React Func Polym. 1997;33:25–36.CrossRefGoogle Scholar
  26. Inoue K, Yoshizuka K, Yamguchi S. Solvent extraction of indium 8 trialkylphosphine oxide from sulphuric acid solutions containing chloride. J Chem Engin Japan. 1994;27(6):737–40.CrossRefGoogle Scholar
  27. International Atomic Energy Agency (IAEA) Publication Technical Reports Series No. Cyclotron produced radionuclides: physical characteristics and production, 468. Vienna; 2009.Google Scholar
  28. Jalilian AR, Yousefnia H, Garousi J, et al. The development of radiogallium-acetylacetonate bis(thiosemicarbazone) complex for tumour imaging. Nucl Med Rev. 2009;12(2):65–71.Google Scholar
  29. Jamriska DJ, Taylor WA, Ott MA, et al. Activation rates and chemical recovery of 67Cu produced with low energy proton irradiation of enriched Zn targets. J RadioanaLl ucL Chem. 1995;195:263–70.CrossRefGoogle Scholar
  30. Johnson EL, Turkington TG, Jaszczak RJ, et al. Quantitation of 211At in small volumes for evaluation of targeted radiotherapy in animal models. Nucl Med Biol. 1995;22:45–54.PubMedCrossRefGoogle Scholar
  31. Katabuchi T, Watanabe S, Ishioka N, et al. Production of Cu-67 via the Zn-68(p,2p)Cu-67 reaction and recovery of Zn-68 target. J Radioanal Nucl Chem. 2008;277:467–70.CrossRefGoogle Scholar
  32. Kirby HW. Residue adsorption – III: mutual separation of 227Ac, 227Th and 223Ra. J Inorg Nucl Chem. 1969;31:3375–85.CrossRefGoogle Scholar
  33. Kirby HK. Gmelin handbook of inorganic chemistry – astatine. 8th ed. Berlin: Springer; 1985. p. 95–106.Google Scholar
  34. Knogler K, Grünberg J, Zimmermann K, et al. Copper-67 radioimmunotherapy and growth inhibition by anti L1-cell adhesion molecule monoclonal antibodies in a therapy model of ovarian cancer metastasis. Clin Cancer Res. 2007;13:603–11.PubMedCrossRefGoogle Scholar
  35. Lahiri S, Maiti M, Ghosh K. Production and separation of 111 In: an important radionuclide in life sciences: a mini review. J Radioanal Nucl Chem. 2013;297:309–18.CrossRefGoogle Scholar
  36. Lambrecht RM, Mirzadeh S. Cyclotron isotopes and radiopharmaceuticals – XXXV. Astatine-211. Int J Appl Radiat Isotop. 1985;36:443–50.CrossRefGoogle Scholar
  37. Larsen RH, Murud KM, Akabani G, et al. 211At- and 131I-labeled bisphosphonates with high in vivo stability and bone accumulation. J Nucl Med. 1999;40:1197–203.PubMedGoogle Scholar
  38. Levin VI, Kozlova MD, Malinin AB, et al. The production of carrier-free indium. Int J Appl Radiat Isot. 1974;25:286–8.CrossRefGoogle Scholar
  39. Lindegren S, Back T, Jensen H. Dry-distillation of astatine-211 from irradiated bismuth targets: a time-saving procedure with high recovery yields. Appl Radiat Isot. 2001;55:157–60.PubMedCrossRefGoogle Scholar
  40. Little FE, Lagunas-Solar MC. Cyclotron production of 67Ga. Cross sections and thick-target yields for the 67Zn (p, n) and 68Zn (p,2n) reactions. Int J Appl Radiat Isot. 1983;34(3):631–7.Google Scholar
  41. Martins ADA, Osso Jr JA. Thermal diffusion of 67Ga from irradiated Zn targets. Appl Radiat Isot. 2013;82:279–82.CrossRefGoogle Scholar
  42. Massaoud AA, Hanafi HA, Siyam T, Saleh ZA, Ali FA. Separation of Ga(III) from Cu(II), Ni(II) and Zn(II) in aqueous solution using synthetic polymeric resins. Cent Eur J Chem. 2008;6(1):39–45.Google Scholar
  43. Mausner LF, Kolsk KL, Joshi V, Srivastava SC. Radionuclide development at BNL for nuclear medicine therapy. Appl Radiat Isot. 1998;49:285–94.PubMedCrossRefGoogle Scholar
  44. Miederer M, Scheinberg DA, McDevitt MR. Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha particle therapy applications. Adv Drug Deliv Rev. 2008;60:1371–82.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Milesz S, Norseev YV, Szücs Z, Vasáros L. Characterization of DTPA complexes and conjugated antibodies of astatine. J Radioanal Nucl Chem Lett. 1989;137:365–72.CrossRefGoogle Scholar
  46. Mirzadeh S, Mausner LF, Srivastava SC. Production of no carrier-added Cu-67. Appl Radiat Isot. 1986;37:29–36.CrossRefGoogle Scholar
  47. Mushtaq A, Karim H, Khan M. Production of no-carrier-added 64Cu and 67Cu in a reactor. J. RadioanaL Nucl Chem. 1990;141:261–9.CrossRefGoogle Scholar
  48. Naidoo C, Van der Walt TN. Cyclotron production of 67Ga (III) with a tandem natGe–natZn target. Appl Radiat Isot. 2001;54:915–9.PubMedCrossRefGoogle Scholar
  49. Neirincks RD. The separation of cyclotron-produced 111In from a silver matrix, radio. Chem Radioanal Lett. 1971;4(2):153–5.Google Scholar
  50. Nelson F, Michelson DC. Ion-exchange procedures ix Cation exchange in HBr solutions. J Chromatogr. 1966;25:414.CrossRefGoogle Scholar
  51. Novgorodov AF, Beyer GJ, Zelinski A, et al. Simple method for high temperature release of 111In from silver. J I N R (Dubna). 1984;6(84):609.Google Scholar
  52. Paiva AP. Recovery of indium from aqueous solutions by solvent extraction. Sep Sci Technol. 2001;36(7):1395–419.CrossRefGoogle Scholar
  53. Polak P, Geradts J, Van der Vlist R, Lindner L. Photonuclear production of 67Cu from ZnO Targets. Radiochim Acta. 1986;40:169–74.Google Scholar
  54. Rajeh N, Subramainan MS. Extractive separation and determination of thallium and indium by liquid scintillation counting. Analyst. 1994;119:2071–4.CrossRefGoogle Scholar
  55. Roy K, Basu S, Ramaswami A, Nayak D, Lahiri S. Incorporation of thiosemicarbazide in Amberlite IRC-50 for separation of astatine from α-irradiated bismuth oxide. Appl Radiat Isotop. 2004;60:793–9.CrossRefGoogle Scholar
  56. Sadeghi M, Mokhtari L. Rapid separation of 67,68Ga from 68Zn target using precipitation technique. J Radioanal Nucl Chem. 2010;284:471–3.CrossRefGoogle Scholar
  57. Scheinberg DA, McDevitt MR. Actinium-225 in targeted alpha-particle therapeutic applications. Curr Radiopharm. 2011;4:306–20.PubMedCrossRefGoogle Scholar
  58. Schomakher K, Schwratzbach R, Beyer G-J, Novogorodov AF. A further simplified method for the separation of 111In from Silver targets by thermo chromatography. Appl Radiat Isot. 1988;39(6):483–5.CrossRefGoogle Scholar
  59. Schwarzbach R, Zimmermann K, Blaeuenstein P, et al. Development of a simple and selective separation of 67Cu from irradiated zinc for use in antibody labelling: a comparison of methods. Appl Radiat Iso. 1995;46:329–36.CrossRefGoogle Scholar
  60. Sharma HL, Smith A. The short-lived radioisotope production program at Manchester. J Radioanal Chem. 1981;64(1, 2):249–55.CrossRefGoogle Scholar
  61. Shigeta N, Matsuoka H, Osa A, Koizumi M, Izumo M, Kobayashi K, Hashimoto K, Sekine T, Lambrecht RM. Production method of no-carrier-added 186Re, J Radioanal Nucl Chem. 1996;205:85–92.Google Scholar
  62. Shikata E. Research of radioisotope production with fast neutrons. vi. preparation of Cu-67. J Nucl Sci Technol (Tokyo, Jpn). 1964;1:177–80.CrossRefGoogle Scholar
  63. Smit JA, Myburgh JA, Neirinckx RD. Specific inactivation of sensitized lymphocytes in vitro using antigens labelled with astatine-211. Clin Exp Immunol. 1973;14:107–16.PubMedPubMedCentralGoogle Scholar
  64. Starovoitova VN, Tchelidze L, Wells DP. Production of medical radioisotopes with linear accelerators. Appl Radiat Isot. 2014;85:39–44.PubMedCrossRefGoogle Scholar
  65. Stoll T, Kastleiner S, Shubin YN, Coenen HH, Qaim SM. Excitation functions of proton induced reactions on 68Zn from threshold up to 71 MeV, with specific reference to the production of 67Cu. Radiochim Acta. 2002;90:309–13.CrossRefGoogle Scholar
  66. Turlera A, Huenges E, Henkelmann R, et al. Method for purification of 225Ac from irradiated 226Ra-targets. United States Patent No. US 2013/0266475 A1, 10 Oct 2013.Google Scholar
  67. Weidner JW, Mashnik SG, John KD, et al. 225Ac and 223Ra production via 800 MeV proton irradiation of natural thorium targets. Appl Radiat Isot. 2012;70:2590–5.PubMedCrossRefGoogle Scholar
  68. Yagi M, Kondo K. Preparation of carrier-free 67Cu by the 68Zn(g, p) reaction. Int J Appl Radiat Isot. 1978;29:757–9.CrossRefGoogle Scholar
  69. Yamamoto K, Matsumoto A. Liquid-Liquid distribution of ion associates of tetrabromoindate (III) with quaternarymoniun counter ions. Talanta. 1977;44:2145–50.CrossRefGoogle Scholar
  70. Yordanov AT, Deal K, Garmestani K, Kobayashi H, et al. Synthesis and biodistribution study of a new 211At-calix[4]arene complex. J Label Compd Radiopharm. 2000;43:1219–25.CrossRefGoogle Scholar
  71. Yordanov AT, Pozzi O, Carlin S, et al. Wet harvesting of no-carrier-added 211At from an irradiated 209Bi target for radiopharmaceutical applications. J Radioanalyt Nucl Chem. 2004;262:593–9.CrossRefGoogle Scholar
  72. Zaitseva NG, Knotek O, Kowalew A, et al. Excitation functions and yields for 111In production using. 113,114, natCd(p, xn)111In reaction with 65 MeV protons. Appl Radiat Isot. 1990;41:177–83.CrossRefGoogle Scholar
  73. Zalutsky MR, Bigner DD. Radioimmunotherapy with alpha-particle emitting radioimmunoconjugates. Acta Oncol. 1996;35:373–9.PubMedCrossRefGoogle Scholar
  74. Zalutsky MR, Pruszynski M. Astatine-211 – production and availability. Curr Radiopharm. 2011;4(3):177–85.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Zhang X, Lp W, Fang K, He W, Sheng R, Ying D, Hu W. Excitation functions for natW(p, xn)181-186Re reactions and production of no-carrier-added. 186Re via 186W(p, n)186Re reaction. Radiochim Acta. 1999;86:11–6.Google Scholar
  76. Zhang X, Li Q, Li W, Sheng R, Shen S. Production of no-carrier-added 186Re via deuteron induced reactions on isotopically enriched 186W. Appl Radiat Isot. 2001;54:89–92.Google Scholar
  77. Zheng WI, Sipes IG, Carter DE. Determination of parts-per-billion concentrations of indium in biological materials by electrothermal atomic absorption spectrometry following Ion pair extraction. Anal Chem. 1993;65:2174–6.PubMedCrossRefGoogle Scholar
  78. Zhuikov BL, Kalmykov SN, Ermolaev SV, et al. Production of 225Ac and 223Ra by irradiation of Th with accelerated protons. Radiochem. 2011;53(1):73–80.CrossRefGoogle Scholar

Copyright information

© Springer India 2016

Authors and Affiliations

  • F. F. (Russ) Knapp
    • 1
  • Ashutosh Dash
    • 2
  1. 1.Nuclear Security and Isotope DivisionOak Ridge National LaboratoryOAK RIDGEUSA
  2. 2.Isotope Production and Applications DivisionBhabha Atomic Research CentreMumbaiIndia

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