ERICH VOGT SYMPOSIUM TRIUMFS CURRENT AND FUTURE IMPACT

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

A Brief History of Nuclear Medicine • 1930 s: Discovery of artificial isotopes, notably Iodine-131 and Tc 99 m • First treatment in 1939 with phosphorus-32 • First treatment with iodine-131 in 1946 • Gamma camera (Anger) and Rectilinear Scanner (Cassen) in 1950 s • Thyroid imaging 1950 -1960 • Liver/spleen scanning, bone imaging, brain tumour localization 1960 -1970 s • Positron emission tomography in 1970 s+ for brain imaging • Cardiac imaging 1980 s+ • Cancer imaging in the 1990 s and beyond

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-99 m, 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, …

Technetium-99 m, the Medical Isotope of the 20 th 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, 1950 s: Tucker and Green developed the first 99 Mo/99 m. 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 99 m. Tc” Tucker and Richards In part from http: //www. bnl. gov/bnlweb/history/Tc-99 m. asp

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

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…

99 m. 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

The Technology

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 99 m. Tc production (3 -6 h irradiations) • Take advantage of existing infrastructure

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 Tc 99 m supply • More cyclotrons will facilitate the transition of nuclear medicine imaging infrastructure, from SPECT to PET • Complementary to LINAC/other sources of • Generators freed up for remote areas 99 Mo

The Technology • Daily irradiation of Tc 99 m • Regional/Supraregional distribution • 6 -hour half-life • Can be combined with 18 F-FDG distribution • Shipping by road or air • Processing and release currently takes ~2 h

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

June 3, 2014 Achieving Large Scale Production, Distribution, and Commercialization of Tc-99 m 14 Determinants of Tc-99 m yield • Proton beam current • Expressed in µA (microampers) • Proton beam energy • Expressed in Me. V (megaelectron-volts) • Production starts around 8 -10 Me. V, peaks at 15 Me. V • Higher energy means thicker proton penetration = higher yield • Examples of theoretical yields (6 h runs) • 130 µA, 16. 5 Me. V (GE cyclotron): 4. 9 Ci • 160 µA, 16. 5 Me. V (GE cyclotron): 6. 1 Ci • 300 µA, 18 Me. V (TR 19 cyclotron): 15. 4 Ci • 300 µA, 20 Me. V (TR 24 cyclotron): 18. 7 Ci • 500 µA, 20 Me. V (TR 24 cyclotron): 31. 1 Ci • 500 µA, 24 Me. V (TR 24 cyclotron): 39. 2 Ci • Practical net yields 85 -95% of theoretical

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

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

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

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

99 m. Tc Bone Scan 18 F PET Scan

Myocardial Imaging with PET Maddahi J. , J Nucl Cardiol 2012; 19, Suppl 1, S 30 -7 13 N-NH 82 Rb. Cl – Courtesy, University of Ottawa 3 and 18 F-FDG for viability

Cancer Imaging Targets BCCA/TRIUMF

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

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

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?