Advertisement

The Radiopharmaceutical Chemistry of the Radioisotopes of Lutetium and Yttrium

  • Elaheh Khozeimeh Sarbisheh
  • Eric W. PriceEmail author
Chapter

Abstract

When harnessing radiometals for medical applications, both the aqueous chemistry of the metal ion (e.g. its coordination number, Lewis acidity, solvent activation, pKa) and the properties of the chelator (e.g. donor atoms, denticity, charge, polarity) should be carefully considered to ensure the stable in vivo sequestration of the radionuclide. The decay properties of the radiometal—including its radioactive half-life as well as the type, yield, and energy of its emissions—must also be matched to the biomolecular vector as well as the intended medical application. The most medically relevant radionuclides of lutetium and yttrium are lutetium-177 ([177Lu]Lu3+), yttrium-86 ([86Y]Y3+), and yttrium-90 ([90Y]Y3+). In this chapter, we will discuss the radioactive properties of these nuclides as well as their fundamental coordination chemistry. In addition, we will address the most effective chelators for each radiometal, the biological factors relating to their use in medicine, prominent examples of 177Lu- and 86/90Y-labeled radiopharmaceuticals, potential pitfalls in their use, and tips for radiolabeling with these radionuclides.

Keywords

Lutetium-177 Yttrium-90 Yttrium-86 [177Lu]Lu3+ [90Y]Y3+ [86Y]Y3+ Radionuclide therapy Single photon emission computed tomography (SPECT) Positron emission tomography (PET) Theranostics 

References

  1. 1.
    Pearson RG. Hard and soft acids and bases, HSAB, part I: fundamental principles. J Chem Educ. 1968;45(9):581.Google Scholar
  2. 2.
    Shannon R. Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Crystallogr. 1976;A32(5):751–67.Google Scholar
  3. 3.
    Barnum DW. Hydrolysis of cations. Formation constants and standard free energies of formation of hydroxy complexes. Inorg Chem. 1983;22(16):2297–305.Google Scholar
  4. 4.
    Liu S. The role of coordination chemistry in the development of target-specific radiopharmaceuticals. Chem Soc Rev. 2004;33(7):445–61.PubMedGoogle Scholar
  5. 5.
    Price EW, Orvig C. Matching chelators to radiometals for radiopharmaceuticals. Chem Soc Rev. 2014;43(1):260–90.PubMedGoogle Scholar
  6. 6.
    Baes CF, Mesmer RE. The thermodynamics of cation hydrolysis. Am J Sci. 1981;281(7):935–62.Google Scholar
  7. 7.
    Baes CF Jr, Mesmer RE. The hydrolysis of cations. New York: Wiley-Interscience; 1976.Google Scholar
  8. 8.
    Martell AE, Smith RM. Critical stability constants. Vol. 3: other organic ligands. New York: Plenum Press; 1977.Google Scholar
  9. 9.
    Holland JP, Williamson MJ, Lewis JS. Unconventional nuclides for radiopharmaceuticals. Mol Imaging. 2010;9(1):1–20.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Walrand S, Jamar F, Mathieu I, De Camps J, Lonneux M, Sibomana M, et al. Quantitation in PET using isotopes emitting prompt single gammas: application to yttrium-86. Eur J Nucl Med Mol Imaging. 2003;30(3):354–61.PubMedGoogle Scholar
  11. 11.
    Lederer CM, Shirley VS. Table of isotopes. 7th ed. New York: Wiley; 1978.Google Scholar
  12. 12.
    Walrand S, Flux G, Konijnenberg M, Valkema R, Krenning E, Lhommel R, et al. Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging? Eur J Nucl Med Mol Imaging. 2011;38(1):57–68.Google Scholar
  13. 13.
    Nayak TK, Garmestani K, Milenic DE, Baidoo KE, Brechbiel MW. HER1-targeted 86Y-panitumumab possesses superior targeting characteristics than 86Y-cetuximab for PET imaging of human malignant mesothelioma tumors xenografts. PLoS One. 2011;6(3):e18198.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Palm S, Enmon RM, Matei C, Kolbert KS, Xu S, Zanzonico PB, et al. Pharmacokinetics and biodistribution of 86Y-trastuzumab for 90Y dosimetry in an ovarian carcinoma model: correlative microPET and MRI. J Nucl Med. 2003;44(7):1148–55.PubMedGoogle Scholar
  15. 15.
    Herzog H, Rösch F, Stöcklin G, Lueders C, Qaim SM, Feinendegen LE. Measurement of pharmacokinetics of yttrium-86 radiopharmaceuticals with PET and radiation dose calculation of analogous yttrium-90 radiotherapeutics. J Nucl Med. 1993;34(12):2222–6.PubMedGoogle Scholar
  16. 16.
    Forrer F, Waldherr C, Maecke HR, Mueller-Brand J. Targeted radionuclide therapy with 90Y-DOTATOC in patients with neuroendocrine tumors. Anticancer Res. 2006;26(1B):703–7.PubMedGoogle Scholar
  17. 17.
    Volkert WA, Goeckeler WF, Ehrhardt GJ, Ketring AR. Therapeutic radionuclides: production and decay property considerations. J Nucl Med. 1991;32(1):174–85.PubMedGoogle Scholar
  18. 18.
    Baum RP, Kluge AW, Kulkarni H, Schorr-Neufing U, Niepsch K, Bitterlich N, et al. [(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-octreotide ((177)Lu-DOTATOC) for peptide receptor radiotherapy in patients with advanced neuroendocrine tumours: a Phase-II study. Theranostics. 2016;6(4):501–10.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Sadeghi M, Aboudzadeh M, Zali A, Mirzaii M, Bolourinovin F. Radiochemical studies relevant to 86Y production via 86Sr(p,n)86Y for PET imaging. Appl Radiat Isot. 2009;67(1):7–10.PubMedGoogle Scholar
  20. 20.
    Reischl G, Rösch F, Machulla HJ. Electrochemical separation and purification of yttrium-86. Radiochim Acta. 2002;90(4):225–8.Google Scholar
  21. 21.
    Disselhorst JA, Brom M, Laverman P, Slump CH, Boerman OC, Oyen WJG, et al. Image-quality assessment for several positron emitters using the NEMA NU 4-2008 standards in the Siemens Inveon Small-Animal PET Scanner. J Nucl Med. 2010;51(4):610–7.PubMedGoogle Scholar
  22. 22.
    Jødal L, Loirec CL, Champion C. Positron range in PET imaging: an alternative approach for assessing and correcting the blurring. Phys Med Biol. 2012;57(12):3931.PubMedGoogle Scholar
  23. 23.
    Sadeghi M, Aboudzadeh M, Zali A, Zeinali B. 86Y production via 86Sr(p,n) for PET imaging at a cyclotron. Appl Radiat Isot. 2009;67(7):1392–6.PubMedGoogle Scholar
  24. 24.
    Jødal L, Loirec CL, Champion C. Positron range in PET imaging: non-conventional isotopes. Phys Med Biol. 2014;59(23):7419–34.PubMedGoogle Scholar
  25. 25.
    Lubberink M, Herzog H. Quantitative imaging of 124I and 86Y with PET. Eur J Nucl Med Mol Imaging. 2011;38(1):10–8.PubMedCentralGoogle Scholar
  26. 26.
    Rösch F, Herzog H, Qaim S. The beginning and development of the theranostic approach in nuclear medicine, as exemplified by the radionuclide pair 86Y and 90Y. Pharmaceuticals. 2017;10(2):56.PubMedCentralGoogle Scholar
  27. 27.
    Conti M, Eriksson L. Physics of pure and non-pure positron emitters for PET: a review and a discussion. EJNMMI Phys. 2016;3(1):8.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Dash A, Pillai MRA, Knapp FF. Production of (177)Lu for targeted radionuclide therapy: available options. Nucl Med Mol Imaging. 2015;49(2):85–107.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Baum RP, Kulkarni HR. Theranostics: from molecular imaging using Ga-68 labeled tracers and PET/CT to personalized radionuclide therapy – the Bad Berka experience. Theranostics. 2012;2(5):437–47.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Altai M, Membreno R, Cook B, Tolmachev V, Zeglis B. Pretargeted imaging and therapy. J Nucl Med. 2017;58(10):1553–9.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Förster GJ, Engelbach MJ, Brockmann JJ, Reber HJ, Buchholz HG, Mäcke HR, et al. Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of 86Y-DOTATOC and 111In-DTPA-octreotide. Eur J Nucl Med. 2001;28(12):1743–50.PubMedGoogle Scholar
  32. 32.
    Harris WR, Pecoraro VL. Thermodynamic binding constants for gallium transferrin. Biochemistry. 1983;22(2):292–9.PubMedGoogle Scholar
  33. 33.
    Harris WR, Chen Y. Difference ultraviolet spectroscopic studies on the binding of lanthanides to human serum transferrin. Inorg Chem. 1992;31(24):5001–6.Google Scholar
  34. 34.
    Harris WR, Yang B, Abdollahi S, Hamada Y. Steric restrictions on the binding of large metal ions to serum transferrin. J Inorg Biochem. 1999;76(3–4):231–42.PubMedGoogle Scholar
  35. 35.
    Harris WR. Binding and transport of nonferrous metals by serum transferrin. In: Clarke MJ, editor. Less common metals in proteins and nucleic acid probes. Structure and bonding, vol. 92. Berlin/Heidelberg: Springer; 1998. p. 121–62.Google Scholar
  36. 36.
    Sun H, Li H, Sadler PJ. Transferrin as a metal ion mediator. Chem Rev. 1999;99(9):2817–42.PubMedGoogle Scholar
  37. 37.
    Sun H, Cox M, Li H, Sadler P. Rationalisation of metal binding to transferrin: prediction of metal-protein stability constants. In: Hill H, Sadler P, Thomson A, editors. Metal sites in proteins and models. Structure and bonding, vol. 88. Berlin/Heidelberg: Springer; 1997. p. 71–102.Google Scholar
  38. 38.
    Li H, Sadler PJ, Sun H. Rationalization of the strength of metal binding to human serum transferrin. Eur J Biochem. 1996;242(2):387–93.PubMedGoogle Scholar
  39. 39.
    Ando A, Ando I, Hiraki T, Hisada K. Relation between the location of elements in the periodic table and various organ-uptake rates. Int J Rad Appl Instrum B. 1989;16(1):57–80.PubMedGoogle Scholar
  40. 40.
    Wang L, Shi J, Kim Y-S, Zhai S, Jia B, Zhao H, et al. Improving tumor-targeting capability and pharmacokinetics of 99mTc-labeled cyclic RGD dimers with PEG4 linkers. Mol Pharm. 2009;6(1):231–45.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Hancock RD. Chelate ring size and metal ion selection. The basis of selectivity for metal ions in open-chain ligands and macrocycles. J Chem Educ. 1992;69(8):615–21.Google Scholar
  42. 42.
    Camera L, Kinuya S, Garmestani K, Wu C, Brechbiel MW, Pai LH, et al. Evaluation of the serum stability and in vivo biodistribution of CHX-DTPA and other ligands for yttrium labeling of monoclonal antibodies. J Nucl Med. 1994;35(5):882–9.PubMedGoogle Scholar
  43. 43.
    Harrison A, Walker CA, Parker D, Jankowski KJ, Cox JPL, Craig AS, et al. The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates. Int J Rad Appl Instrum B. 1991;18(5):469–76.PubMedGoogle Scholar
  44. 44.
    Price EW, Carnazza KE, Carlin SD, Cho A, Edwards KJ, Sevak KK, et al. 89Zr-DFO-AMG102 immuno-PET to determine local HGF protein levels in tumors for enhanced patient selection. J Nucl Med. 2017;58(9):1386–94.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Price EW, Edwards KJ, Carnazza KE, Carlin SD, Zeglis BM, Adam MJ, et al. A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal 90Y. Nucl Med Biol. 2016;43(9):566–76.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Price EW, Cawthray JF, Adam MJ, Orvig C. Modular syntheses of H4octapa and H2dedpa, and yttrium coordination chemistry relevant to 86Y/90Y radiopharmaceuticals. Dalton Trans. 2014;43(19):7176–90.PubMedGoogle Scholar
  47. 47.
    Price EW, Zeglis BM, Cawthray JF, Lewis JS, Adam MJ, Orvig C. What a difference a carbon makes: H4octapa vs. H4C3octapa, ligands for In-111 and Lu-177 radiochemistry. Inorg Chem. 2014;53(19):10412–31.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Price EW, Zeglis BM, Cawthray JF, Ramogida CF, Ramos N, Lewis JS, et al. H4octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy. J Am Chem Soc. 2013;135(34):12707–21.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kang CS, Chen Y, Lee H, Liu D, Sun X, Kweon J, et al. Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using90Y or177Lu. Nucl Med Biol. 2015;42(3):242–9.PubMedGoogle Scholar
  50. 50.
    McMurry TJ, Brechbiel M, Kumar K, Gansow OA. Convenient synthesis of bifunctional tetraaza macrocycles. Bioconjug Chem. 1992;3(2):108–17.PubMedGoogle Scholar
  51. 51.
    Wu C, Kobayashi H, Sun B, Yoo TM, Paik CH, Gansow OA, et al. Stereochemical influence on the stability of radio-metal complexes in vivo. Synthesis and evaluation of the four stereoisomers of 2-(p-nitrobenzyl)-trans-CyDTPA. Bioorg Med Chem. 1997;5(10):1925–34.PubMedGoogle Scholar
  52. 52.
    Hohloch K, Zinzani PL, Linkesch W, Jurczak W, Deptala A, Lorsbach M, et al. Radioimmunotherapy with 90Y-ibritumomab tiuxetan is a safe and efficient treatment for patients with B-cell lymphoma relapsed after auto-SCT: an analysis of the international RIT-Network. Bone Marrow Transplant. 2010;46(6):901–3.PubMedGoogle Scholar
  53. 53.
    Brechbiel MW, Gansow OA, Atcher RW, Schlom J, Esteban J, Simpson D, et al. Synthesis of 1-(p-isothiocyanatobenzyl) derivatives of DTPA and EDTA. Antibody labeling and tumor-imaging studies. Inorg Chem. 1986;25(16):2772–81.Google Scholar
  54. 54.
    Pauwels S, Barone R, Walrand S, Borson-Chazot F, Valkema R, Kvols LK, et al. Practical dosimetry of peptide receptor radionuclide therapy with 90Y-labeled somatostatin analogs. J Nucl Med. 2005;46(1 suppl):92S–8S.PubMedGoogle Scholar
  55. 55.
    Kunikowska J, Pawlak D, Bąk MI, Kos-Kudła B, Mikołajczak R, Królicki L. Long-term results and tolerability of tandem peptide receptor radionuclide therapy with 90Y/177Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study. Ann Nucl Med. 2017;31(5):347–56.PubMedGoogle Scholar
  56. 56.
    Schneider DW, Heitner T, Alicke B, Light DR, McLean K, Satozawa N, et al. In vivo biodistribution, PET imaging, and tumor accumulation of 86Y- and 111In-antimindin/RG-1, engineered antibody fragments in LNCaP tumor-bearing nude mice. J Nucl Med. 2009;50(3):435–43.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Rösch F, Herzog H, Stolz B, Brockmann J, Köhle M, Mühlensiepen H, et al. Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-d Phe1-Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue. Eur J Nucl Med Mol Imaging. 1999;26(4):358–66.Google Scholar
  58. 58.
    Salako QA, O’Donnell RT, DeNardo SJ. Effects of Radiolysis on Yttrium-90-Labeled Lym-1 Antibody Preparations. J Nucl Med. 1998;39(4):667–70.PubMedGoogle Scholar
  59. 59.
    Barone R, Walrand S, Konijnenberg M, Valkema R, Kvols LK, Krenning EP, et al. Therapy using labelled somatostatin analogues: comparison of the absorbed doses with 111In-DTPA-D-Phe1-octreotide and yttrium-labelled DOTA-D-Phe1-Tyr3-octreotide. Nucl Med Commun. 2008;29(3):283–90.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of SaskatchewanSaskatoonCanada

Personalised recommendations