MEDICIS- Promed Final Conference , 30 April – 4 May 2019, Erice , Sicily

1. Extraction chromatography method for the separation of 155Tb from radionuclide impurities for primary standardisation, nuclear data measurements and SPECT imaging MEDICIS-Promed Final Conference, 30 April – 4 May 2019, Erice, Sicily Peter IvanovNational Physical Laboratory, UK

2. Why terbium? 149Tb Alpha therapy 4.12 h 152Tb PET diagnostics 17.5 h 155Tb SPECT diagnostics 5.32 d 161Tb Beta/Auger therapy SPECT diagnostics 6.89 d

3. Production of 155Tb at CERN • Proton-induced spallation reaction • Tantalum target • On-line mass separation at 155 m/q • Isotopes collected in a zinc-coated gold disc

4. Impurities 155Gd STABLE 155Eu 4.75 a Beta- decay 139La STABLE 139Ce Electron Capture 137.6 d 155Dy Electron Capture 9.9 h 155Tb Electron Capture 5.3 d

5. Method development • Using stable element standards (159Tb, 140Ce) • ICP-MS analysis • Oxidation of cerium • Chromatographic separation from HNO3 • - Resin studies • - Kinetic studies • Column separation • Selective oxidation of cerium: • Ce(III)  Ce(IV) • Tb(III)  Tb(IV) = • (CPS)0 = counts per second before contact with resin • (CPS)t= counts per second after contact with resin • V = volume of HNO3 (mL) • m = mass of resin used (g)

6. Ce(III) selective oxidation • NaBrO3 oxidant • Cerium adsorption increased • Suggests that cerium is oxidised

7. Chromatography resin studies • Static conditions, stable tracers • 24 h equilibrium time • TEVA, UTEVA and TK100 extraction resins • AG1-X8 anion exchange resin TEVA • Best separation using: • UTEVAorTEVAresin • High HNO3 concentrations UTEVA

8. Elution profiles • Pre-packed 2 mL UTEVA cartridge • Terbium collected with 8 M HNO3 • Cerium eluted from column in 0.1 M HCl Elution profile @ flow rate ~ 0.3 mL/min

9. Separation procedure STEP 1: Foil dissolution STEP 2: Removal of Tb and Ce from Au and Zn matrix STEP 3: Isolation of Tb from Ce STEP 4: Conversion of Tb to chloride form

10. Active sample Supplied 155Tb = ~ 8.1 MBq Before separation = After separation = • No 139Ce detected after separation

11. 155Tb Primary standardisation • A set of six sources measured • For each the LSC channel efficiency varied by computer discrimination method • The activity determined by extrapolating to 100 % efficiency Preliminary activity at the reference time (572.7 ± 2.9) kBq g-1 (k = 1) Schematic of the NPL 4π(Liquid Scintillation)-γ(HPGe) Digital Coincidence Counting system

12. 155Tb Half-life measurement • The radioactive decay rate of 155Tb was observed over 18.6 days (or approximately 3.55 half-lives) using a HPGe γ-ray spectrometer. • A total of 131 measurements were made. • From each measurement the sum of the net peak areas of the 86.6 keV and 105.3 keV full-energy peaks was determined. • A non-linear weighted least squares fit was performed to the measured data points using the equation:

13. 155Tb Half-life measurement Half-life of 155Tb determined in this work and the uncertainty budget Comparison of published half-life determinations of 155Tb

14. 155Tb Emission probabilities • The normalised emission intensities of 89 emissions have been determined • Standard uncertainties have been typically reduced by a factor of four [4] Reich, C. W., 2005. Nuclear data sheets for A = 155. Nuclear Data Sheets 104, 1-282.

15. 155Tb SPECT Imaging Details in Sophia Pells’ presentation Quantified nuclear medicine imaging of 155Tb siemens-healthineers.com

16. (Semi-)Automated Lanthanide Separation • Column separation – Dy/Tb/Gd • Stable elemental tracers & ICP-MS analysis • LN resin • Column volume ~8 mL • Flow rate ~ 1 mL/min

17. Conclusions • Highly efficient chemical separation method has been derived for removing the 139Ce impurity from the 155Tb (Submitted to Nature Scientific Reports) • The world first primary standardisation of the potential theranostic SPECT radionuclide 155Tb has been performed at NPL which will provide traceability of the administered activities for any pre-clinical and clinical trials performed in the future. • A precise half-life of 155Tb has been determined, which was found to have a 1.5 % relative difference to the current recommended value. A factor of 5 increase in the precision over previous measurements has been achieved. • Precise measurements of the emission intensities of 89 -ray transitions have been performed. These make significant revisions to the currently recommended values with improved precision.

18. Acknowledgements Chemical separationBen Webster (Surrey/NPL) ICP-MS analysis Ben Russell (NPL) Active SamplesThierry Stora, Joao Pedro Ramos (CERN) Ulli Köster (ILL) Gamma Spectrometry Sean Collins (NPL) Primary standardisationArzuArinc, John Keightley (NPL) SPECT Imaging Andrew Robinson (NPL) This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 654002 Thank you for your attention! Questions?