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Developing the 134Ce and 134La pair as companion positron emission tomography diagnostic isotopes for 225Ac and 227Th radiotherapeutics


Developing targeted α-therapies has the potential to transform how diseases are treated. In these interventions, targeting vectors are labelled with α-emitting radioisotopes that deliver destructive radiation discretely to diseased cells while simultaneously sparing the surrounding healthy tissue. Widespread implementation requires advances in non-invasive imaging technologies that rapidly assay therapeutics. Towards this end, positron emission tomography (PET) imaging has emerged as one of the most informative diagnostic techniques. Unfortunately, many promising α-emitting isotopes such as 225Ac and 227Th are incompatible with PET imaging. Here we overcame this obstacle by developing large-scale (Ci-scale) production and purification methods for 134Ce. Subsequent radiolabelling and in vivo PET imaging experiments in a small animal model demonstrated that 134Ce (and its 134La daughter) could be used as a PET imaging candidate for 225AcIII (with reduced 134CeIII) or 227ThIV (with oxidized 134CeIV). Evaluating these data alongside X-ray absorption spectroscopy results demonstrated how success relied on rigorously controlling the CeIII/CeIV redox couple.

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Fig. 1: The two readily accessible oxidation states of cerium make it an ideal elemental analogue for the actinides, actinium and thorium.
Fig. 2: Control of 134Ce oxidation state enables purification of 134Ce from a natLa target.
Fig. 3: XAS spectroscopy enables monitoring of the cerium oxidation state throughout the purification and labelling processes.
Fig. 4: Coronal maximum intensity projection PET images of 134Ce complexes evidence different excretion pathways depending on the chelator and cerium oxidation state.
Fig. 5: Biodistribution of 134CeIV-3,4,3-LI(1,2-HOPO) and 134CeIII-DTPA in selected organs confirm conclusions drawn from PET imaging.

Data availability

All data and experimental details supporting the findings discussed here are available within the paper and its Supplementary Information.


  1. Kratochwil, C. et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J. Nucl. Med. 57, 1941–1944 (2016).

    Article  CAS  Google Scholar 

  2. Jiang, Z., Revskaya, E., Fisher, D. R. & Dadachova, E. In vivo evaluation of free and chelated accelerator-produced actinium-225—radiation dosimetry and toxicity results. Curr. Radiopharm. 11, 215–222 (2018).

    Article  CAS  Google Scholar 

  3. McDevitt, M. R. et al. Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer. Nat. Commun. 9, 1629 (2018).

    Article  Google Scholar 

  4. Nikula, T. K. et al. Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry. J. Nucl. Med. 40, 166–176 (1999).

    CAS  PubMed  Google Scholar 

  5. Couturier, O. et al. Cancer radioimmunotherapy with alpha-emitting nuclides. Eur. J. Nucl. Med. Mol. Imaging 32, 601–614 (2005).

    Article  CAS  Google Scholar 

  6. Kim, Y.-S. & Brechbiel, M. W. An overview of targeted alpha therapy. Tumor Biol 33, 573–590 (2012).

    Article  CAS  Google Scholar 

  7. Thiele, N. A. & Wilson, J. J. Actinium-225 for targeted α therapy: coordination chemistry and current chelation approaches. Cancer Biother. Radiopharm. 33, 336–348 (2018).

    Article  Google Scholar 

  8. Mastren, T. E., Ferrier, M. G., Fassbender, M. E., Birnbaum, E. R. & John, K. D. The Heaviest Metals: Science and Technology of the Actinides and Beyond (Wiley, 2017).

  9. Becker, K. V. et al. Cross section measurements for proton induced reactions on natural La. Nucl. Instrum. Methods Phys. Res. B 468, 81–88 (2020).

    Article  CAS  Google Scholar 

  10. Kapoor, V., McCook, B. M. & Torok, F. S. An introduction to PET-CT imaging. Radiographics 24, 523–543 (2004).

    Article  Google Scholar 

  11. Mikolajczak, R., van der Meulen, N. P. & Lapi, S. E. Radiometals for imaging and theranostics, current production, and future perspectives. J. Label. Compd. Radiopharm. 62, 615–634 (2019).

    Article  CAS  Google Scholar 

  12. Boros, E., Dyson, P. J. & Gasser, G. Classification of metal-based drugs according to their mechanisms of action. Chem 6, p41-60 (2019).

  13. Brown, M. A., Paulenova, A. & Gelis, A. V. Aqueous complexation of thorium(iv), uranium(iv), neptunium(iv), plutonium(iii/iv), and cerium(iii/iv) with DTPA. Inorg. Chem. 51, 7741–7748 (2012).

    Article  CAS  Google Scholar 

  14. Nash, K. L. The chemistry of TALSPEAK: a review of the science. Solvent Extr. Ion Exch. 33, 1–55 (2015).

    Article  CAS  Google Scholar 

  15. Lamart, S. et al. Bringing up to date the french database of nuclear workers contaminated with plutonium and/or americium and treated with Ca-DTPA. BIO Web Conf. 14, 04011 (2019).

    Article  Google Scholar 

  16. Yan, T.-T. et al. Pharmacological treatment of inhalation injury after nuclear or radiological incidents: the Chinese and German approach. Mil. Med. Res. 6, 10 (2019).

    Article  Google Scholar 

  17. Wilbur, D. S. in Radiopharmaceutical Chemistry 409–424 (Springer, 2019);

  18. Sturzbecher-Hoehne, M., Choi, T. A. & Abergel, R. J. Hydroxypyridinonate complex stability of group (iv) metals and tetravalent f-block elements: the key to the next generation of chelating agents for radiopharmaceuticals. Inorg. Chem. 54, 3462–3468 (2015).

    Article  CAS  Google Scholar 

  19. Deblonde, G. J.-P., Lohrey, T. D. & Abergel, R. J. Inducing selectivity and chirality in group iv metal coordination with high-denticity hydroxypyridinones. Dalt. Trans 48, 8238–8247 (2019).

    Article  CAS  Google Scholar 

  20. Deblonde, G. J.-P., Sturzbecher-Hoehne, M. & Abergel, R. J. Solution thermodynamic stability of complexes formed with the octadentate hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO): a critical feature for efficient chelation of lanthanide(iv) and actinide(iv) Ions. Inorg. Chem. 52, 8805–8811 (2013).

    Article  CAS  Google Scholar 

  21. Deri, M. A. et al. Alternative chelator for 89Zr radiopharmaceuticals: radiolabeling and evaluation of 3,4,3-(LI-1,2-HOPO). J. Med. Chem. 57, 4849–4860 (2014).

    Article  CAS  Google Scholar 

  22. Miederer, M., Scheinberg, D. A. & McDevitt, M. R. Realizing the potential of the actinium-225 radionuclide generator in targeted alpha particle therapy applications. Adv. Drug Deliv. Rev. 60, 1371–1382 (2008).

    Article  CAS  Google Scholar 

  23. Davis, I. A. et al. Comparison of 225actinium chelates: tissue distribution and radiotoxicity. Nucl. Med. Biol. 26, 581–589 (1999).

    Article  CAS  Google Scholar 

  24. Ramdahl, T. et al. An efficient chelator for complexation of thorium-227. Bioorg. Med. Chem. Lett. 26, 4318–4321 (2016).

    Article  CAS  Google Scholar 

  25. Benjamin, R. O. et al. In-vivo comparison of thorium-227 and zirconium-89 labeled 3,2-HOPO mesothelin antibody–chelator conjugate. J. Med. Imaging Radiat. Sci. 50, S26 (2019).

    Article  Google Scholar 

  26. Hagemann, U. B. et al. In vitro and in vivo efficacy of a novel CD33-targeted Thorium-227 conjugate for the treatment of acute myeloid leukemia. Mol. Cancer Ther. 15, 2422–2431 (2016).

    Article  CAS  Google Scholar 

  27. Hammer, S. et al. Abstract 5200. Preclinical pharmacology of the PSMA-targeted thorium-227 conjugate PSMA-TTC: a novel targeted alpha therapeutic for the treatment of prostate cancer. Cancer Res 77, 5200–5200 (2017).

    Google Scholar 

  28. Richmond, C. R. & London, J. E. Long-term in vivo retention of cerium-144 by beagles. Nature 211, 1179 (1966).

    Article  CAS  Google Scholar 

  29. Leggett, R. et al. Biokinetic data and models for occupational intake of lanthanoids. Int. J. Radiat. Biol. 90, 996–1010 (2014).

    Article  CAS  Google Scholar 

  30. Ewaldsson, B. & Magnusson, G. Distribution of radiocerium and radiopromethium in mice: an autoradiographic study. Acta Oncol. 2, 65–72 (1964).

    CAS  Google Scholar 

  31. Evans, W. J., Deming, T. J. & Ziller, J. W. The utility of ceric ammonium nitrate-derived alkoxide complexes in the synthesis of organometallic cerium(iv) complexes: synthesis and first X-ray crystallographic determination of a tetravalent cerium cyclopentadienide complex, (C5H5)3Ce(OCMe3). Organometallics 8, 1581–1583 (1989).

    Article  CAS  Google Scholar 

  32. Greco, A., Cesca, S. & Bertolini, W. New 7r-cyclooctate’I’raenyl and iT-cyclopentadienyl complexes of cerium. J. Organomet. Chem. 113, 321–330 (1976).

    Article  CAS  Google Scholar 

  33. Streitwieser, A., Kinsley, S. A., Rigsbee, J. T., Fragala, I. L. & Ciliberto, E. Photoelectron spectra and bonding in cerocene, bis(π-[8]annulene)cerium(iv). J. Am. Chem. Soc. 107, 7786–7788 (1985).

    Article  CAS  Google Scholar 

  34. Klamm, B. E. et al. Experimental and theoretical comparison of transition-metal and actinide tetravalent schiff base coordination complexes. Inorg. Chem. 57, 15389–15398 (2018).

    Article  CAS  Google Scholar 

  35. Qiao, Y. & Schelter, E. J. Lanthanide photocatalysis. Acc. Chem. Res. 51, 2926–2936 (2018).

    Article  CAS  Google Scholar 

  36. Wong, W.-H. et al. Synthesis, structure, and reactivity of tetravalent cerium complexes containing oxidizing oxyanion ligands. J. Organomet. Chem. 899, 120902 (2019).

    Article  CAS  Google Scholar 

  37. Assefa, M. K. et al. Synthesis, characterization, and electrochemistry of the homoleptic f element ketimide complexes [Li]2[M(N=CtBuPh)6] (M = Ce, Th). Inorg. Chem. 58, 12654–12661 (2019).

    Article  CAS  Google Scholar 

  38. Li, K., Chen, J., Zou, D., Deng, Y. & Li, D. Recovery of cerium(iv) in acidic nitrate solutions by solvent extraction with a novel extractant tris(2-ethylhexyl)phosphine oxide. Hydrometallurgy 190, 105155 (2019).

    Article  CAS  Google Scholar 

  39. Cary, S. K. et al. Advancing understanding of the +4 metal extractant thenoyltrifluoroacetonate (TTA): synthesis and Structure of MIVTTA4 (MIV = Zr, Hf, Ce, Th, U, Np, Pu) and Miii(TTA)4–. Inorg. Chem. 57, 3782–3797 (2018).

    Article  CAS  Google Scholar 

  40. Stevenson, P. C. & Nervik, W. E. The Radiochemistry of the Rare Earths, Scandium, Yttrium, and Actinium Nuclear Science Series (National Academy of Science National Research Council, 1961).

  41. Neirinckx, R. D. The purification of cyclotron-produced carrier-free 139Ce. Int. J. Appl. Radiat. Isot. 21, 681–682 (1970).

    Article  CAS  Google Scholar 

  42. Mayer, G. D., van der Walt, T. N., Böhmer, R. G. & Andersen, P. Separation of 139Ce from lanthanum cyclotron targets using anion exchange chromatography with a bromic acid/nitric acid system. Radiochim. Acta 34, 207–210 (1983).

    CAS  Google Scholar 

  43. Allott, L. et al. Evaluation of DFO-HOPO as an octadentate chelator for Zirconium-89. Chem. Commun. 53, 8529–8532 (2017).

    Article  CAS  Google Scholar 

  44. Ravel, B. & Newville, M. ATHENA, ARTEMIS, HEPHAESTUS: data analysis for X-ray absorption spectroscopy using IFEFFIT. J. Synchrotron. Rad. 12, 537–541 (2005).

    Article  CAS  Google Scholar 

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We thank M. Janabi for help with the μ-PET instrument and G.J.-P. Deblonde for discussions. This research was supported by the US Department of Energy (DOE) Isotope Program, managed by the Office of Science for Nuclear Physics (LBNL contract DE-AC02-05CH11231; LANL Contract 89233218CNA000001). LANL is an affirmative action/equal opportunity employer managed by Triad National Security, LLC, for the National Nuclear Security Administration of the US DOE. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, was supported by the DOE, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. We acknowledge additional support from a DOE Integrated University Program graduate research fellowship (K.M.S.) and a Nuclear Regulatory Commission Faculty Development Grant (NRC-HQ-84-14-G-0052; R.J.A.).

Dedication: We dedicate this work to the memory of our colleague and friend Dr. J. P. O’Neil.

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T.A.B., V.M., K.M.S., J.W.E., F.D.W., C.V., S.A.K. and R.J.A. conceived and designed the experiments. T.A.B., V.M., K.M.S., D.D.A., A.C.A., M.B., J.C.C., M.E.F, S.S.G., A.L.L., F.M.N., E.M.O., S.L.T., C.V. and S.A.K. performed the experiments. T.A.B., V.M., K.M.S., F.D.W., C.V., S.A.K. and R.J.A. analysed the data and co-wrote the paper. T.A.B., V.M. and K.M.S. contributed equally to this work. All authors discussed the results and commented on the manuscript.

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Correspondence to Christiaan Vermeulen, Stosh A. Kozimor or Rebecca J. Abergel.

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Supplementary Discussion, Figs. 1–2 and Tables 1–2.

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Bailey, T.A., Mocko, V., Shield, K.M. et al. Developing the 134Ce and 134La pair as companion positron emission tomography diagnostic isotopes for 225Ac and 227Th radiotherapeutics. Nat. Chem. 13, 284–289 (2021).

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