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The Future of Advanced Nuclear Technologies
Interdisciplinary Research Team Challenges

Advanced Nuclear Technologies Interdisciplinary Research Challenge 1: Identify improvements in technology and other approaches that will ensure the future development and supply of radionuclides and radiopharmaceuticals for diagnostic imaging and therapy.
 
Challenge Summary
This challenge has several related parts: 1. Maintaining a reliable supply of Technetium-99m (Tc-99m) for single photon imaging; 2. Availability and further development of PET radiopharmaceuticals; and 3. Expanding the supply of PET radionuclides beyond C-11, N-13, O-15, and F-18.
 
Technetium-99m is the work horse of single photon imaging. Its precursor is reactor-produced molybdenum-99(Mo-99). Production of Mo-99 has a history of several problems: 1. Most has been produced by reactor irradiation of HEU, which has required the sole export of such materials from the United States. Alternate reactor production is available using LEU and there are now efforts to make this the only method of reactor production. 2. There have been a number of interruptions in the supply of Mo-99 as ageing reactors have been removed from service. 3. U.S. supplies of Mo-99 have had to rely on foreign sources (Canada, The Netherlands, South Africa, etc.) and there has been considerable effort to develop a sustainable supply in this country (see American Medical Isotope Production Act of 2012). Also, there has been recent interest in alternative methods for the production of Tc-99m using accelerators but issues of expense, specific activity, and distribution need to be addressed.
 
(Another radionuclide with desirable properties for single photon imaging is I-123. This iodine isotope brings with it the advantages of halide chemistry and avoids the bulky coordination cage properties of technetium. In the past, its accelerator production had its own problems including cost, purity and availability, but these seem to have been mostly solved. It has never enjoyed the anticipated uses predicted for it outside of iodide for thyroid imaging. Newly developed radiopharmaceuticals such as Ioflupane [DaTscan™] might expand its utility.) 
 
Radiopharmaceuticals labeled with positron emitting radionuclides are now used to map a number of cellular functions including glucose metabolism, oxygen utilization, cell proliferation, amino acid uptake, and neurotransmitter status, to name a few. Produced, on-site, by cyclotrons capable of making Carbon-11, Nitrogen-13, Oxygen-15 and Fluorine-18 the most available compounds are primarily labeled with Fluorine-18 (F-18). This is partly due to its longer half-life (110 minutes) than the others and partly because of relatively facile fluorine chemistry. Carbon-11 labeled agents, despite the centrality of carbon compounds as biological substances, have been less used, in part because the short half-life (20 minutes) requires very rapid syntheses to produce pure products with high specific activity.
 
At present, there is a robust commercial supply of F-18 labeled FDG and NaF. Commercial supplies of other F-18 labeled compounds are severely limited.  As a greater repertoire of tracers is developed for more specific diagnoses and monitoring response to therapy, the management of patients outside of academic medical centers is certain to be compromised unless an economic pathway for these can be developed.
 
In addition to the light elements (C, N, O, F), longer-lived positron-emitting radionuclides are likely to be desired for medical application. Some already showing promise are Cu-64, Zr-89, and I-124. These radionuclides are produced by cyclotrons or linear accelerators. Except for I-124, which can be used as iodide for thyroid studies, all need to be incorporated into complex organic compounds for imaging purposes.
 
For all medical imaging procedures there is a need to minimize the radiation dose received by patients without sacrificing diagnostic accuracy. The realization that medical imaging from CT and nuclear studies now represent the major source of public radiation exposure has mobilized the profession of Radiology into campaigns for minimizing exposure (viz.  Imaging Gently and Imaging Wisely).
 
In addition to imaging, certain radionuclides are used for therapy. These include I-131 for thyroid disease, Sm-153 and Sr-89 for bone pain, Y-90 for liver metastases, In-111 and Lu-177 for neuroendocrine tumors. Newer ones, such as the alpha particle emitter Ra-223, have been used in research. Some are produced in reactors others in accelerators. For their full potential to be realized, continued availability of the radionuclides will need to be assured and specific delivery systems will need to be devised.
 
Key Questions  
Is the American Medical Isotope Production Act of 2012 sufficient to secure the continued need for Tc-99m? Should alternative methods of production continue to be pursued? Given the superior resolution of F-18 labeled agents, what advances in SPECT/CT technology will be required to justify the continued use of Tc-99m?

As newer more specific PET agents are created, how will the manufacture and distribution of these be accomplished for use by other than major academic medical centers? The time for new agents to go from bench-to-bedside/clinic is quite a bit shorter in Germany and Japan than in the United States. What are the impediments to such transfer in this country, regulatory and otherwise, and how might they be eliminated? 

Is the use of radiopharmaceuticals labeled with longer lived positron-emitting radionuclides likely to be employed other than in research? If so, how are they to be produced and distributed?

As optimization of radiation dose in medicine becomes dictum, efforts will be made to use diagnostic nuclear medical studies appropriate to the clinical questions asked. In addition, technologies are, and will be, developed to reduce amounts of administered radioactivity without loss of diagnostic accuracy? What will these be, how much will they add to cost, and are the limits to these?

For a number of reasons, the use of radionuclides in therapy has been relatively restricted. What factors have limited their use (even when their efficacy has been demonstrated) and what might be done to overcome these hurdles? 

Suggested Reading
Atcher RW. Medical radio-isotopes – what steps can we take to ensure a secure supply?Journal of Nuclear Medicine 2009; 50(4):17-18N.
 
Congress passes American isotope production act. Journal of Nuclear Medicine 2013; 54(2):11N.
 
Fowler JS, Wolf AP. The synthesis of carbon-11, fluorine-18 and nitrogen 13 labeled radiotracers for biomedical applications. Nuclear Science 1982: NAS-NRS Monographs.
 
Goske MJ, Applegate KE, Bulas D, et al. Image Gently 5 years later: what goals remain to be accomplished in radiation protection for children? American Journal of Roentgenology 2012; 199(3):477 479.
 
Hricak H, Brenner DJ, Adelstein SJ et al. Managing radiation use in medical imaging: a multifaceted challenge. Radiology 2011: 258(3):889-905.
 
Isotopes for medicine and the life sciences. Report of Committee on Life Sciences, Division of Health Science Policy; Institute of Medicine. The National Academies Press: Washington, DC, 1995.
 
James ML, Gambhir SS. A molecular Imaging primer: modalities, imaging agents, and applications. Physiological Reviews 2012; 92(2):897-965.
 
Kircher MF, Hricak H, Larson SM. Molecular imaging for personalized cancer care. Medical Oncology 2012; 6(2):182-195.
 
Medical isotope production without HEU. The National Academies Press: Washington, DC, 2008.
 
Mettler FA Jr, Bhargavan M, Faulkner et al. Radiologic and nuclear medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources – 1950-2007. Radiology 2009; 253(2):520-531.
 
Peplow M.  Technetium: Nuclear Medicine's Crisis. Proto Summer 2013.

Sheehy N, Tetrault T, Zurakowski D, et al. Pediatric 99mTc-DMSA SPECT using iterative reconstruction with isotropic resolution recovery: improved image quality and reduction in radiopharmaceutical administered activity. Radiology 2009; 251:511-516.        
 
Statement on dose optimization for nuclear medicine and molecular imaging procedures.Society for Nuclear Medicine: June 2012.
 
Tu Z, Mach RH. C-11 radiochemistry in cancer imaging applications. Current Topics in Medicinal Chemistry 2010; 10(11):1060-1095.