1. Medical Isotope Production and Use -with a special view on the need for ISOLDE and other big science facilities Mikael Jensen Professor, Applied Nuclear Physics Hevesy Lab - Risø- Risø-DTU Campus Technical University of Denmark Presented at ISOLDE 50 th Anniversary Workshop CERN- December 2014 DTU-NUTECH

2. Center for Nuclear Technologies Radioecology Isotope research Radiation physics Radiopharmaceuticals Radiobiology Radiation Therapy Targets Former Risø- an ancient National Laboratory for Reactor Research, then ”Sustainable Energy”

3. My background: The Hevesy Laboratory- Medical use of accelerators Isotope production Radiation therapy George Hevesy 1885-1966

4. 5.5 MeV protons 1938 Early Isotope Separation on Line – 55 years ago

5. Isolde – Master of the Isotopes

7. Application of Radioactive Isotopes: MEDICAL ! “I must confess that one reason we have undertaken this biological work is that we thereby have been able to get financial support for all of the work in the laboratory. As you know, it is much easier to get funds for medical research.” —Lawrence to Niels Bohr, 1935

8. Why Radioactive Materials for injection into fellow living beings in 2014 ? 59 years post Hiroshima, 28 years post Chernoby, …….Fukushima still in clear memory !

9. Nuclear Medicine in vivo use of radioactivity Isotope uptake, dilution, excretion, Whole Body Counting Diagnostic = Gamma camera, SPECT and PET Therapeutic = Radionuclide Therapy ”The magic bullet” Non invasive Cheap International = Atoms for Peace, IAEA….

10. The Legacy Technology PUSHED from the National Laboratories or Big Science Cyclotron and artificial radioactivity Radiochemistry Scintillation counters Anger Camera Mo-99/ Tc-99m generator PET Camera F-18 FDG Isotopes far from stability line … (no medical pull of technology) !

11. Diagnostic Nuclear Medicine Functional  Metabolic  Molecular Requiring higher specific activity O-15 water F-18 DOPA

12. High specific activity A historical development: from 1913 ”indicators, and 1930 ”tracers” To ligands, radiometals for late stage chelation, radioactive antibodies and antibody fragments Requires : transmutation or very effective Slizard-Chalmers or hot atom isotope separators TBq / uMol

13. Halflife- Diagnostic Long enough to circulate and localize Short enough to keep radiation dose low Logistics of production, transport and labelling The generators: Mo-99/Tc-99m (Gamma Camera +SPECT) Rb-81/Kr-81m (Gamma Camera +SPECT) Ge-68/Ga68 (PET) Sr-82/Rb82 + Some more… 200 secs- 3 days Mother isotopes must be produced somewhere

14. Halflife - Therapeutic Most of dose to be delivered when optimal uptake has taken place T½ < Cell cycle life of target tissue

15. The clinical problem Nuclear medicine is about routine use Our isotope is part of a pharmaceutical Requires clinical trials and proof of merrit GMP, Safety and Efficacy Costly, slow, highly regulated

16. GMP is the opposite of Research

17. Preclinical- or Small animal imaging: Solution or Problem ?

18. F-18 Fluoride F-18 Fluoro Choline ”fastest growing medical technology ever….” PET-CT, a problem ?

19. The problem of economics and scale Very few (if any) radiopharmaceuticals can carry the full cost of development, registration and post market maintenance Many radiopharmaceuticals are orphan A clinical market should be served evenly across nations and territories No gaps in availability But the cost of the radiopharmaceutical is a surprisingly small part of total cost of a given procedure

20. Isotopes for nuclear medicine from where ? (1) Neutron rich : by fission or neutron capture Present generation of research reactors getting old and retiring. Acces to high flux, long time and transport difficult. Access to HEU getting difficult

21. A Mo-99 supply crisis: In October 2016 NRU in Chalk River, Canada closes Is it a North American Problem? No realistic replacements still in sight Much talk and many Klondyke efforts Possible results: Migration to CT and MRI Migration to PET A role for Ga-68 ? Worldwide loss of Nuclear Medicine infrastructure May have effects on other isotopes as well Underlying cause : Goverment neutrons have been too cheap !

22. Isotopes for nuclear medicine from where ? (2) (p,xn) from Cyclotrons, mostly About 11 MeVC-11,N-13,O15,F-18 for local use 16-18 MeVF-18 for distribution, all (p,n) products 30 MeV(p,2n) products, high yield In-111, Ga-67, I-123 70-100 MeV Sr-82, Ge-68 (shortage) Goverment Linacs

23. natural decay chains nuclear fuel / weapons cycle spallation accelerators - (At-211) Perhaps via generators, mother isotope from natural decay chains nuclear fuel / weapons cycle spallation accelerators Alpha emitters for nuclear medicine from where ? Fast growing interest beacuse of Ra-223 chloride (Alpharadin)

24. The cottage industry of small cyclotrons 16-18 MeV enough for F18 and the PET radiometals (Cu-64, Ga- 68, Zr-89 ) Theraputic doses can be made (Er-165) Tc-99m is possible in limited amounts 16-18 MeV enough for F18 and the PET radiometals (Cu-64, Ga- 68, Zr-89 ) Theraputic doses can be made (Er-165) Tc-99m is possible in limited amounts Logistics more simple Cheap infrastructure Flexible Lead time for changes smaller Logistics more simple Cheap infrastructure Flexible Lead time for changes smaller

25. 2013 PT 600 prototype, Hevesy Lab ”Point of demand” produktion A 7.8 MeV cyclotron F-18 C-11 N-13 perhaps Ga-68 YES ! Coffee makers ? (remember to add 10 t neutron shield)

26. α, β - and Auger radiation 26

27. Microinjection of cells in culture 27

28. Direct injection 28

30. 30 Claus E. Andersen

31. Gamma-H2AX assay Counting the number of DSB

32. Many lanthanides have good therapeutic properties Tunable half-life Tunable beta energy Or pure Auger cascade Or alpha (Tb-149 is example) Same chelation chemistry But- carrier free production needed for most Production and chemistry can be difficult Many good isotopes far from stability line Tunable half-life Tunable beta energy Or pure Auger cascade Or alpha (Tb-149 is example) Same chelation chemistry But- carrier free production needed for most Production and chemistry can be difficult Many good isotopes far from stability line

33. Isotopes for nuclear medicine from ISOLDE ? Spallation by itself is dirty Human use requires high radionuclidic purity Isotope separation needed, on- or off-line GBq will be needed at point of use Ce-134, Nd-140 recent examples Clinical trials require year round supply – for long periods ! A clinical trial should point to a commercial future Scalability, ownership Clinical trials require year round supply – for long periods ! A clinical trial should point to a commercial future Scalability, ownership

34. Help from ISOLDE ? Rapid Proof-of–principles Ultimate specific activity Labelling stability studies (recoil) Rapid extraction of radioactivity from solid targets ( example Ga-68) Selection of single isomer ( example Co-58m) Isotope production at ESS ? No ”ISOL” Thermal and fast neutrons Perhaps parasitic protons,- but only 100 MeV needed. Isotope production at ESS ? No ”ISOL” Thermal and fast neutrons Perhaps parasitic protons,- but only 100 MeV needed. For Science, Research and Development in Nuclear Medicine,- we can use ISOLDE

35. 13-aug-2008Præsentationens titel35 Thank you for your attention, ….. Questions ?