1. Medical Radionuclides February 17 SNAL. Robert Avakian Yerevan Physics Institute

2. Medical Radionuclides, Applications, Producers and Consumers Current Production Issues New concept advantage - introducing electron accelerators Next steps Agenda

3. Technetium 99m Tc 99m is the most commonly used radionuclide (80%) Tc is the chemical symbol of technetium. 99 is its mass number. The m denotes 'metastable', Technetium, which is not found in nature, was first discovered by Perrier and Segre in 1937 in a sample of molybdenum that had been irradiated in the Berkeley cyclotron. It is useful for several reasons: It can be easily combined with several pharmaceuticals. Its half-life of six hours is long enough to allow practical imaging but not so long that the patient, public and environment are over-burdened with radiation. It gives off gamma rays at 140keV which is a good match to the sensitivity range of the Gamma Camera. It is a pure gamma emitter.

4. Technetium 99m Applications Application of radionuclides in diagnostics and medical treatment gave start to nuclear medicine. It is used primarily to locate tumors in the body, monitor cardiac function following heart attacks, map blood flow in the brain and guide surgery. The influence of the ionizing radiation on the biological objects led to the modern technology that allows physicians to irradiate only selected cells of tumor instead of the entire area. The advantage of the radionuclide therapy is the absorption of radiation by pathological centers so that the sound tissues remain intact. Demand for Purity Medical radionuclides have to have high radiochemical purity, which demands complicated radiochemical technology.

5. Technetium 99m Consumers Technetium-99m became widely used in the late 1960s and early 1970s, and its use has grown dramatically ever since. It is by far the dominant radioisotope for diagnostics; demand for 99m Tc is expected to grow by ~ 8-20 % per year over the long term. 80% of all nuclear medical procedures currently performed in the United States use the radioisotope Technetium-99m More than 17 million 99mTc scans are performed annually in the United State, providing diagnostic images of almost every organ in the body. The average dose about 20 mCi. Thus, the total amount of 99mTc annually administered in the USA is 350000 CI. Problem: Because 99mTC decays so rapidly, a substantial portion of total production quantity is lost before it can be administered.

6. Technetium 99m Producers The two main sources in the world (particularly for 99mTc which is used in 80% of scans) are: In Europe the High Flux Reactor in Petten the Netherlands. For the North America the National Research Universal Reactor in Chalk River Ontario Canada. National Research Universal Reactor Chalk River Ontario Canada High Flux Reactor Petten the Netherlands

7. Technetium 99m Procedure The reactors use highly enriched uranium, as fuel source and a source material from which to create 99Mo.  99Mo has a half-life of 66 hours, it progressively decays to technetium-99m. Molybdenum-99 (99Mo)  Technetium-99m (99mTc) Technetium 99m generators are supplied to hospitals from the nuclear reactor where the isotopes are made.  lead pot enclosing a glass tube containing the radioisotope.  contain molybdenum-99, with a half-life of 66 hours, which progressively decays to technetium-99m.  Tc-99m is washed out of the lead pot by saline solution when it is required.  After two weeks or less the generator is returned for recharging.

8. Medical Radionuclides, Applications, Producers and Consumers Current Production Issues New concept advantages, introducing electron accelerators Next steps Agenda

9. Current Production Issues Reliabilty & Availabilty Physicians and patients around the world are increasingly anxious about the shortage of nuclear isotopes used in medical imaging. The two main reactors are relatively old and it’s not clear how long they might last. In 2007 in 2008 both reactors have anticipated and unanticipated shutdowns and subsequent Isotope shortage become subject of public outcry. There are no near term or even long term solutions being implemented that could provide a reliable and adequate supply for Europe and North America National Research Universal Reactor Chalk River Ontario Canada High Flux Reactor Petten the Netherlands

10. Current Production Issues Ecology & Security The current 99 Mo production technology relies on the nuclear fission of 235 uranium The entire assortment of fission products is produced along with the 99 Mo, therefore the quantity of radioactive by- products produced with fission product 99 Mo is far more than the quantity of 99Mo obtained. Most of these by-products are useless, and this causes a large amount of radioactive waste to be created along with desired 99 Mo product. Worldwide concerns about the transport of weapons-grade material (anti-terrorism)

11. Current Production Issues Cost effectiveness The reactors themselves are expensive. The price of the product needs to be subsidized The average cost of new reactor according Thomas Ruth, Nature 29Jan.2009 ia $500 Mln-$1 billion.

12. Medical Radionuclides, Applications, Producers and Consumers Current Production Issues New concept, electron accelerators, feasibility, advantages Next steps Agenda

13. New Concept Electron Accelerators System New concept for the production of 99m Tc and many other isotopes based on distributed electron accelerators system. The radioactive decay parent of 99m Tc, 99 Mo is produced from 100 Mo by photoneutron reaction..

14. New Concept Feasibility Experimental research of feasibility of using electron accelerator for medical isotope production.  JINR Russia,  PTI Kharkov Ukraine  NEEL Idaho USA  YerPhi Yerevan Armenia. 99mTc 123 I, 225Ac, 236Pu, SPECT Isotopes and 11C, 13N, 15O, 18F PET isotopes could be produced by  n reaction on electron accelerator. Neutron beam for neutron boron therapy also could be produced on electron accelerator. Experiments have been performed to verify the technical feasibility of the production and assess the efficiency of the extraction processes.

15. New Concept Feasibility Technetium-99 can be obtained in the course of photonuclear processes with 100 Mo used as a target according to following reaction: Threshold of reaction- 9.1 MeV  + 100 Mo  99 Mo+ n  T 1/2 = 67 hours  99m Tc (T 1/2 =6 hours)

16. New Concept Feasibility Production Quantity Appropriate doses of 99m Tc vary according to the specific application, but the average dose of the 17 million scans administered each year in the United States is ~ 20 mCi. Thus, the total amount of 99m Tc annually administered in the United States is ~ 350000 Ci. Because 99m Tc decays so rapidly, a substantial portion of the total production quantity is lost before it can be administered. The extent of this loss depends on the timing of delivery and utilization of the product and on how well matched are the actual and anticipated utilization. Any system that supplies 99m Tc must produce sufficient 99 Mo to allow for attendant losses inherent in its processes.

17. New Concept Feasibility Purity Requirements The currently available products are routinely much purer than the US Pharmacopeia (USP) standards. To succeed in the market place, a new source of 99m Tc will have to meet or improve on the following customer expectations: 1. Radiopurity ~ 100 times better than USP requirements 2. Activity concentration 100 to 500 mCi 99m Tc per milliliter of eluate 3. “Cold” 99 Tc/ 99m Tc ratio of ~ 4 to 20 at the time of injection 4. Total (i.e., radioactive plus nonradioactive) molybdenum concentration comparable to or lower than that in the current product (~ 10 -5  g Mo per milliliter of eluate).

18. New Concept Feasibility Electron Accelerator Parameters: Beam power 20 kW Electron energy 40 MeV Electron beam diameter4 mm Yearly production of 99mTc 20000Ci

19. New Concept Feasibility Iodine-123 production method Recently another iodine isotope 123 I was produced in several countries. It is short-lived and radiates only  and X-rays, which decreases 100 fold the dose of radiation to which patients are exposed. The indication of high quality of the product of 123 I is small content of isotopes 124 I and 125 I. The isotope 124 I radiate high energy gamma deteriorate the solution of scintiograph. The long lived isotope 125 I radiates soft and less penetrating radiation and increases the dosage of radiation.

20. New Concept Feasibility Production of Iodine-123 at some Accelerators City, CountryParticles, E ReactionTargetActivity mC Vancouver, Canada p, 482 MeV, 10  A 137 Cs (p,2p9n) 123 Xe 123 Xe (E.C.)  123 I 0.9kg, met. Cs 76mmX100mm 1000 Karlsruhe, Germany p, 26 MeV, 15  A 124 Te (p,2n) 123 I450mg/cm**2, TeO 2,enriching, 124 Te 96.5% 400 Davis, USAp, 66 MeV, 20  A 127 I (p,5n) 123 Xe 123 Xe (E.C.)  123 I melted200-300 Rossendorf, Germany d, 14 MeV, 10  A 122 Te (d,n) 123 I70mg/cm**2, TeO 2, 3cm**2 enriching, 124 Te 87% 30

21. New Concept Feasibility The most pure isotope of 123 I is believed to be produced during following reaction: Threshold of reaction – 8.3 MeV  + 124 Xe  123 Xe+ n  T 1/2 = 2.2 hours 123 Xe  123 I (T 1/2 =13.3 hours)

22. New Concept Feasibility The effective cross-section for energy of photons about 15 MeV have a maximum equal 450 mbarn. The width of the excitation curve is about 5 Mev. The yield of 123 I can exceed 200  Ci/  A*h*gram of 124 Xe. Investigations performed in JINR (Dubna, Russia) for 10g of pure 124 Xe irradiated in the course of 8 hours by electron beam with energy of 25 MeV and current of 20  A, give 200mCi activity of 123 I. In case of 500MkA daily activity of 123 I will be 5 Ci.

23. New Concept Feasibility How Good is Electron Accelerator for Therapy. Production of micro-sources for brachy-therapy is also important and this is a very efficient therapeutic method against cancer of the prostate gland Demand for radionuclides that generate particles with limited track length and large energy of ionization. They can be used in initial stages of lung cancer, leukemia and others. One of these isotopes is bismuth 213 Bi. The need for these isotopes is very large.

24. New Concept Feasibility 213 Bi originates during the decay of actinium 225 Ac. The following three new approaches could be used for 225 Ac production: -Using Cyclotron proton beam through the reaction 226 Ra(p,2n) 225 Ac -Using photon beam of linear electron accelerator through reaction 226 Ra( ,n) 225 Ra/ 225 Ac -Triple neutron capture in 226 Ra leading to the production 225 Ac/ 213 Bi.

25. New Concept Feasibility Ac-225 Production: Traditional Method 232 Th (n; , 2  ) 233 U : This is the current method and involves bombarding Th-232 with thermal neutrons to produce U-233, which will then follow the U-233 decay chain leading to Ac-225. However, the U-233 must be aged ~20 years to produce sufficient Th-229 for efficient extraction.

26. New Concept Feasibility

27. An efficient method for production of Ac-225 would use a high current electron accelerator to drive the photonuclear reaction 226 Ra +   225 Ra + n. The reaction threshold is of 6.4 MeV, the cross section of the reaction increases up to a maximum of 532 mb at an energy 13.75 MeV. Produced after irradiation Ra-225 will be at a maximum and will decay slowly over time, the half-life being 14.9 days, producing Ac-225 by beta emission: 225 Ra  225 Ac + e - With the use of electron linear accelerator it is possible to produce isotope Ac-225 in commercially-relevant amounts suitable for medical application.

28. New Concept Feasibility On Electron Accelerator It is also possible to create neutron beam using gamma neutron and gamma fission reaction. Energy spectra and yeild of neuton Picted. Boron neutron capture therapy (BNCT) Boron neutron capture therapy is very appealing due to its potential for selective cell killing. This therapy is being investigated for several types of cancers including melanoma and glioblastoma multiforme, a highly malignant and therapeutically persistent brain tumour, for which conventional therapies like chemotherapy, surgery, and radiotherapy are not successful.. The 10 B(n,  ) 7 Li reaction has large cross section for thermal neutrons. A boronated compound such as K 2 B 12 H 12 is injected into the synovial membrane of the diseased knee, which is then exposed to a low-energy neutron beam. 10 Boron atoms undergo fission reactions release high-linear-energy-transfer alpha particles and lithium nuclei, which deposit their energy locally (typically 2,3 to 2,8 MeV within 4 to 9  m) damaging or killing cells along their paths. The dose to the synovium is significantly enhanced by the higher concentration of 10 B in the synovium.

29. New Concept Feasibility

31. Boron neutron capture synovectomy for the treatment of rheumatoid arthritis,

32. New Concept Economics A system based on electron accelerator technology enables the economical supply of 99m Tc for a large nuclear pharmacy. Twenty such production centers distributed near major metropolitan areas could produce the entire US supplied of 99m Tc at a cost less than the current subsidized price. Fixed costs Capital Facility (1600 ft 2 ) $1040000 Laboratory equipment 345000 Accelerator 2000000 Target inventory 450000 Total capital $3715000 Variable costs per year Cost of capital(20%/yr) $745000 Salaries (six technicians) 355000 Utilities 65000 Maintenance and repair 35000 Supplies and services 100000 Total variable $1300000 Yearly production of 99mTc 20000Ci,

33. New Concept Advantages Production medical radionuclides on electron accelerators offers clear improvements over the current technology in environmental impact, economics, and reliability of supply. Only small amounts of radioactive by-products are produced in this process, and it is not necessary to remove them from the recyclable 100 Mo target material. Environmental Security Reliability and Availability Economics Purity

34. Next Step Need Collaboration for design and building the prototype of electron accelerator with mentioned parameters and all other complementary system for turn-key equipment for production mentioned list of Isotopes. Collaboration could involve: SNAL. DESY. NEEL. Triumf. YerPhi.

35. Medical Radionuclides, Applications, Producers and Consumers Current Production Issues New concept, electron accelerators, feasibility, advantages Next steps Agenda