Accelerator Production of Medical Radioisotopes: History, Status, and Future Solutions

1. Accelerator Production of Medical Radioisotopes Rob Edgecock • History • Current status • Future problems with availability • Our solution • Conclusions

2. Nuclear Medicine Two main diagnostic radioisotopes: PET

3. Nuclear Medicine Two main diagnostic radioisotopes: Single photon emitters - SPECT

4. History First cyclotron built by Ernest O. Lawrence & Stanley Livingston at Berkeley in 1932. Energy = 80 keV, Diameter = 13cm

5. History - Timeline

6. History - Timeline • 99MoO42- adsorbed into Al2O3 • Mo decays to 99mTcO4- (66 hrs) • Washed out with saline solution • 99mTc →99Tc + γ(141 keV) (6hrs)

7. History - Timeline

8. Status

9. Accelerator Production 550 in 2007 Growing at ~50/year

10. Accelerator Production 30 MeV, IBA 14-19 MeV, ACSI CERN-Ciemat AMIT 8-9 MeV, 10μA 20cm radius ABT Molecular 7.5 MeV, 5μA 60cm radius 16 MeV, GE 11 MeV, Siemens

11. Issue 1: 99mTc Production • Well-known 99mTc problems due to (old) reactor production High Flux Reactor Petten, Netherlands Built 1961 Belgian Reactor-2 Mol, Belgium Built 1961 National Research Universal Chalk River, Canada Built 1957 30% 40% 9% 3% OSIRIS Saclay, France Built 1964 10% Safari-1 Pelindaba, South Africa Built 1965 Google Maps

12. Issue 1: 99mTc Production • Well-known 99mTc problems due to (old) reactor production • Moly crisis in 2008/9 • Potential shortage in ≥2016 due NRU closure & LEU Various alternative production methods proposed, including accelerators BNMS & STFC Report, December 2014

13. Accelerator Production 100Mo target Reaction: 100Mo(p,2n)99mTc Proton accelerators 98Mo target Reaction: 98Mo(n,γ)99Mo Heavy nucleus target n 235U target Reaction: 235U(n,f)99Mo Particle accelerators 238U target Reaction: 238U(γ,f)99Mo Electron accelerators Bremsstrahlung target γ 100Mo target Reaction: 100Mo(γ,n)99Mo Deuteron accelerators Carbon target n 100Mo target Reaction: 100Mo(n,2n)99Mo Short term: <2017 Primary particle Secondary particle Med term: 2017-2025 Nuclear Energy Agency: direct production 100Mo(p,2n)99mTc Long term: >2025

14. Accelerator Production However, in context of the uncertainty about the future global supply of 99Mo, it is recommended that the UK should diversify its strategy of reliance on reactor-based 99mMo and support the development of novel technologies for the non-reactor production of 99mTc either directly or via its 99Mo precursor. Based on an assessment of the relative maturity of the different options and the possible co-use for purposes such as manufacture of other radioisotopes, it is concluded that the most promising technology for the provision of 99mTc in the UK is its direct production using proton cyclotron bombardment at moderate energies between 18 and 24 MeV. TR24: 24 MeV ~300 µA

15. Accelerator Production However, in context of the uncertainty about the future global supply of 99Mo, it is recommended that the UK should diversify its strategy of reliance on reactor-based 99mMo and support the development of novel technologies for the non-reactor production of 99mTc either directly or via its 99Mo precursor. Based on an assessment of the relative maturity of the different options and the possible co-use for purposes such as manufacture of other radioisotopes, it is concluded that the most promising technology for the provision of 99mTc in the UK is its direct production using proton cyclotron bombardment at moderate energies between 18 and 24 MeV. TR24: 24 MeV ~300 µA

16. Issue 2: Alternative isotopes • Replace 99mTc with other radioisotopes • PET, e.g. 18F, 82Rb, 68Ga, 11C, ? • Other SPECT isotopes, e.g. 123I, 87mSr, 113mIn, 81mKr, etc • Potential problem: increased production costs • Needs more cost effective accelerator production

17. Issue 3: Therapeutic Radioisotopes • All reactor produced • None in the UK • Supplycan be a problem • Someisotopes need α: 211At, 67Cu, 47Sc It is recommended that a national strategy for the use of radiotherapeutics for cancer treatment should be developed to address the supply of radiotherapeutics, projected costs of drugs and resources, the clinical introduction of new radioactive drugs, national equality of access to treatments and resource planning.

18. Our Solution: FFAG CONFORM 20MeV electron proof of principle accelerator: EMMA

19. Our Solution: FFAG CONFORM

20. Our Solution: FFAG FFAG/strong focussing cyclotron Injection energy: 75 keV Extraction: 10 MeV – 102cm 14 MeV – 120cm 28 MeV – 170cm Isochronous to 0.3% Very flexible: protons, alphas, variable energy Huge beam acceptance Unique features: 20mA internal target

21. Performance

22. Target Options Internal: 200keV energy loss ≈ 10μm 100Mo Yield/turn = 0.1mCi/μAh at 14 MeV External target yield = 4.74mCi/μAh → 48 turns Internal target issues: cooling outgasing processing

23. Target Options External – two options: • Charge exchange extraction, as used in cyclotrons: - lossy - not possible for α’s - foil heating and lifetime can be a problem • Electrostatic deflector and septum

24. Radioisotope Production Looked the yields of various imaging isotopes using Talys for 1 hr at 2mA

25. Radioisotope Production

26. Work to be done on FFAG • Modelling: - optimise lattice - study internal targets - study extraction and beam delivery - look at central region and beam capture • Engineering: - magnet design - RF design - central region design - target design → Business case • Aim: - build it to make and sell radioisotopes - commercialise the FFAG

27. Work to be done on FFAG • Modelling: - optimise lattice - study internal targets - study extraction and beam delivery - look at central region and beam capture • Engineering: - magnet design- RF design - central region design - target design→ Business case • Aim: - build it to make and sell radioisotopes - commercialise the FFAG

28. LPA Option • “Established” • TNSA (Target Normal Sheath acceleration) Target Normal Sheath acceleration Fields TV/m • “Evolving” • RPA (Radiation Pressure Acceleration) • Light-sail • BOA (Breakout after-burner) • Collisionless shock-wave acceleration • ...... Front surface acceleration L < tc/2 ~ 5mm Recirculation, refluxing

29. Modelling F Benardet al; Implementation of Multi-Curie production of 99mTc by Conventional Medical Cyclotrons; J Nucl Med 2014; 55:1017-1022 18MeV Investigate the effect of bandwidth on the accelerated proton beam – maintaining acceptable contaminants Determine requirements of the source laser to be competitive in the future. TRIUMF analysis shows present isotopes post refinement are more critical than overall % refinement

30. Experimental Access Modify existing CLF ion spectrometers with adjustable slits for energy and bandwidth selection K. Leddinghamet al 2004 J. Phys. D: Appl. Phys. 37 2341 Natural and refined moly samples will be used to confirm modelling & reaction pathways.

31. 99mTc Confirmation Clear 140keV 99mTc emission observed from the 100Mo (p,2n) 99mTc reaction & excellent half-life match Other isomers present include 95mTc , 95mTc, 94mTc, 94Tc, 96Tc, 93Tc Calculations derive a 99mTc activity of 0.2μCi for a single-shot exposure. Based on a 10Hz system operating at the levels produced, saturation yields of 675mCi can be achieved using enriched 100Mo. 22mCi highest patient doses exceeded after < 20 min exposure times. Optimisation of proton beam could improve these figures. R.Clarke et al, SPIE Proceedings Vol 8779 87791C (2013)

32. Conclusions • Problems with future radioisotope supply: - 99mTc availability - cost effective production of PET and SPECT alternatives - Therapeutic radioisotope availability • Proposing a solution to all of these • Struggling to get funding to pursue it (as usual)