1. ERICH VOGT SYMPOSIUM TRIUMF’S CURRENT AND FUTURE IMPACT IN NUCLEAR MEDICINE AND MOLECULAR IMAGING OF CANCER Dr. François Bénard BC Leadership Chair in Functional Cancer Imaging

2. A Brief History of Nuclear Medicine 1930s: Discovery of artificial isotopes, notably Iodine-131 and Tc99m First treatment in 1939 with phosphorus-32 First treatment with iodine-131 in 1946 Gamma camera (Anger) and Rectilinear Scanner (Cassen) in 1950s Thyroid imaging 1950-1960 Liver/spleen scanning, bone imaging, brain tumour localization 1960-1970s Positron emission tomography in 1970s+ for brain imaging Cardiac imaging 1980s+ Cancer imaging in the 1990s and beyond

3. Some Definitions SPECT: Single photon emission computed tomography Three dimensional images acquired from the single photon emission produced by gamma emission decay Typical isotopes: Tc-99m, In-111, Tl-201, I-123,… PET: Positron emission tomography Three dimensional images acquired from the dual photon emission produced by the annihilation of a positron Typical isotopes: C-11, F-18, Ga-68, O-15, Rb-82, …

4. Technetium-99m, the Medical Isotope of the 20th Century Element 43 discovered by Carlo Perrier and Emilio Segrè in 1936 Technetium-99 discovered by Seaborg and Segrè at the Berkeley Radiation Laboratory BNL, 1950s: Tucker and Green developed the first 99 Mo/ 99m Tc generator BNL, 1960: Powell Richards, presented the first paper on the generator. Richards met with Paul Harper on the flight to Rome and spent the flight “extolling the merits of 99m Tc” In part from http://www.bnl.gov/bnlweb/history/Tc-99m.asp Tucker and Richards

5. Single Photon Emitters in Oncology 99m Tc MDP Bone Scan 99m Tc Sulfur Colloid Sentinel Node Detection 111 In Pentetreotide for neuroendocrine cancers 99m Tc Sestamibi Breast Cancer Detection

6. Accelerator Produced Single Photon Emitters Iodine-123 Thyroid imaging Thyroid cancer detection Gallium-67 Infection/inflammation imaging Indium-111 Infection imaging, tumour imaging with peptides and antibodies Thallium-201 Cardiac imaging All made at TRIUMF…

8. 99m Tc Production by Cyclotrons Concept proven by several authors in past 40 years at low proton beam currents Beaver and Hupf, J Nucl Med 1971; 12:739-741 Lagunas-Solar et al., Appl Radiat Isot 1991; 42:543 Levkovskii N et al. 1991 Scholten et al., Appl Rad Isot 1999; 6-80 J Nucl Med 1971; 12: 739-741

9. The Technology

10. Can Cyclotrons help prevent isotope shortages? Distribution model established for 18 F-Fluorodeoxyglucose (110 min half-life) Mixed model possible for 18 F (1 h irradiation) and 99m Tc production (3-6 h irradiations) Take advantage of existing infrastructure

11. Vision Paradigm well suited to central radiopharmacies Cyclotron capability can be tailored to market Multiple cyclotrons provide redundancy Synergy between PET & SPECT Utilize existing PET cyclotrons to diversify Tc99m supply More cyclotrons will facilitate the transition of nuclear medicine imaging infrastructure, from SPECT to PET Complementary to LINAC/other sources of 99 Mo Generators freed up for remote areas

12. Daily irradiation of Tc99m Regional/Supraregional distribution 6-hour half-life Can be combined with 18F-FDG distribution Shipping by road or air Processing and release currently takes ~2 h The Technology

13. Canadian Cyclotron Infrastructure 24 Cyclotrons in Canada 6 in Vancouver 4 in Toronto 3 in Montreal 2 each in Hamilton, Edmonton, Sherbrooke 1 in Winnipeg, London (ON), Ottawa, Halifax, Saskatoon 3 new cyclotrons planned or purchased Thunder Bay, St-John’s, Vancouver Worldwide: 889 cyclotrons in 2013

14. Determinants of Tc-99m yield Proton beam current Expressed in µA (microampers) Proton beam energy Expressed in MeV (megaelectron-volts) Production starts around 8-10 MeV, peaks at 15 MeV Higher energy means thicker proton penetration = higher yield Examples of theoretical yields (6 h runs) 130 µA, 16.5 MeV (GE cyclotron): 4.9 Ci 160 µA, 16.5 MeV (GE cyclotron): 6.1 Ci 300 µA, 18 MeV (TR19 cyclotron):15.4 Ci 300 µA, 20 MeV (TR24 cyclotron):18.7 Ci 500 µA, 20 MeV (TR24 cyclotron):31.1 Ci 500 µA, 24 MeV (TR24 cyclotron):39.2 Ci Practical net yields 85-95% of theoretical June 3, 2014 Achieving Large Scale Production, Distribution, and Commercialization of Tc-99m 14

20. Preclinical images – 99m Tc-MDP (bone scan) Mouse injected 24 h after production

21. Will Other Modalities Replace 99m Tc? The Supply of Medical Radioisotopes, Nuclear Energy Agency, OECD, 2011

22. How TRIUMF helped other PET programs in Canada Started the UBC PET program for neuroimaging Sent radioisotopes to Edmonton to help them start their PET program on cancer imaging Allowed BCCA to setup 18 F-FDG production at TRIUMF to ship isotopes for cancer imaging Helped the Ottawa Heart Institute setup their 82 Sr/ 82 Rb generator which started their cardiac PET program Set up 64 Cu production at Sherbrooke

23. Replacement of 99m Tc with PET studies 17% of nuclear medicine studies are bone scans Can be replaced with 18 F-NaF 56% myocardial perfusion studies Can be replaced with 82 Rb, 18 F-Flurpiridaz, 18 F- phosphonium cations

24. 99m Tc Bone Scan 18 F PET Scan

25. Myocardial Imaging with PET Maddahi J., J Nucl Cardiol 2012; 19, Suppl 1, S30-7 13 N-NH 3 and 18 F-FDG for viability 82 RbCl – Courtesy, University of Ottawa

26. Cancer Imaging Targets BCCA/TRIUMF

27. Future radiotracers for cancer imaging 24 hr 48 hr 72 hr 5 days 7 days s l th 68 Ga-bradykinin imaging Radiolabeled antibodies 68 Ga CA-IX imaging 18 F-bombesin imaging

28. Erich Vogt - Bridging the gap between Physics and Medicine Pilfered from http://vogt.physics.ubc.ca/vogt/gallery/

29. TRIUMF’s Contributions for the Future Continue developments in radiochemistry and imaging probes Secure radioisotope supply for British Columbia for all nuclear medicine radioisotopes Development of alpha emitter radionuclide therapy Development of exotic medical radioisotopes Expansion of proton therapy?