Over 10,000 hospitals worldwide use radioisotopes in medicine. The vast majority of these isotopes is produced by research reactors. Currently, there are 232 operational research reactors in 56 IAEA member states.20 Most of these reactors are used for nuclear research, including the ones involved in isotope production. Only 78 out of these 232 research reactors in 41 IAEA member states are used for isotope production.21 Twelve research reactors, distributed over 11 member states, are temporary shutdown22, of which three of them are involved in isotope production.23 The IAEA database mentions that seven research reactors are under construction or planned in 6 member states.24 It is not clear how many of these are involved in isotope production. More than half of the research reactors involved in isotope production (43 out of 78) is 40 years old or older.41
There are about 40 neutron-activated radioisotopes and five fission product ones made in reactors. By 1970, 90% of the radioisotopes in the US, the largest consumer of medical radioisotopes, utilized either iodine-131 (131I), cobalt-60 (60Co), or technetium- 99m (99mTc). 60Co was used for over 4 million therapeutic irradiations a year, 131I for diagnosis and treatment more than 2 million times a year, and 99mTc in nearly one million annual diagnostic procedures. Today the statistics are somewhat different.25
Technetium-99m (99mTc) is now the worldwide workhorse of nuclear medicine. In the next 40 years there will be steady increase in the demand for cyclotron-produced PET isotopes in the worldwide production of radiopharmaceuticals.
Cyclotron-produced radionuclides are generally prepared by bombarding stable target material (either a solid, liquid, or gas) with protons and are therefore proton-rich, decaying by β+-emission. These radionuclides have applications for diagnostic imaging with planar scintigraphy, PET and SPECT. Different cyclotron models for the energy range 10- 12 MeV with moderate beam intensity are used for production of carbon-11 (11C), nitrogen-13 (13N), oxygen-15 (15O) and fluorine-18 (18F) isotopes widely applied in PET. The search for new and more effective isotopes continues until today. The share of fluorine-18 (18F) in diagnostic imaging is estimated at 10% of the nearly 25 to 30 million procedures performed in 2006.26 18F-FDG is a versatile radiopharmaceutical with major applications in oncology, neurology, and cardiology.
3.1 Radioisotopes used in imaging
Radioisotopes used in cancer imaging
Of the many different radionuclides used in diagnostic procedures, only a few are valuable in diagnosing cancer. PET/CT is currently accepted to be the most accurate way to stage and monitor many types of cancer. It is used routinely in detecting tumors of thyroid and primary or metastatic tumors of the bone, brain and liver or spleen. Globally, the vast majority of these investigations are performed using the glucose analogue, 18F-FDG. This radiotracer allows cancers to be seen as ‘hot spots’ on the PET scan. 18F-FDG PET is emerging as a useful tool in the treatment of breast, colorectal, esophageal, head and neck, lung, pancreatic, and thyroid cancer; lymphoma, melanoma, and sarcoma; and unknown primary tumor. Gallium-68 (68Ga) has been used experimentally in the staging of lymphoma and shows a great deal of promise in bone scanning.27
Though PET and PET/CT imaging is becoming a dominant modality in cancer imaging, SPECT isotopes, such as technetium-99 (99mTc) and iodine- 123 (123I) are more common for use in cancer imaging. Other isotopes used in cancer imaging are: chromium-51 (51Cr), gold-198 (198Au), indium-113m (113mIn), iodine-125 (125I), iodine-131 (131I), mercury- 197 (197Hg), mercury-203 (203Hg), selenium-75 (75Se), and Ytterbium-169 (169Yb). Except 123I, all of these radioisotopes are currently produced by research reactors.
Radioisotopes used in cardiac imaging
It is thought that PET imaging may be able to overcome the limitations of the currently used perfusion tracers thallium-201 (201Tl) and technetium-99m (99mTc) in SPECT. Gallium-68
(68Ga) and copper-64 (64Cu) are named as potentially attractive PET tracers for this purpose.28 Other perfusion agents are: 11C (in CO2), 15O, 13N (in NH3) and rubidium-82 (82Rb). Thallium-201 (201Tl), used in cardiac scintigraphy and SPECT, is also used for diagnosis of other heart conditions such as heart muscle death and for location of low-grade lymphomas.
(Radioisotopes used in brain imaging -picture: Understanding the Atom Series, US Atomic Energy Commission, 1966)
Carbon-11 (11C), nitrogen-13 (13N), oxygen-15 (15O) and fluorine-18 (18F) are used in PET for studying brain physiology and pathology, in particular for localizing epileptic focus, and in dementia, psychiatry and neuropharmacology studies. The most widely used radioisotope in brain imaging is 99mTc (SPECT).
Radioisotopes used in thyroid imaging
Thyroid imaging tests are used to diagnose or monitor thyroid conditions such as hyperthyroidism, thyroid nodules, thyroid cancer, enlarged thyroid gland (goiter) and thyroiditis. These tests can help a physician to determine the most effective treatment approach for a patient’s condition. Types of thyroid imaging tests include isotope imaging with PET and SPECT. PET uses iodine-124 (124I), gallium-68 (68Ga) and fluorine-18 (18F) and shows better results than the more commonly used gamma camera with iodine-131 (131I) or indium-111 (111In) and SPECT with 201Tl and 131I.29 The iodine-isotopes 123I and 131I remain the most frequently used radionuclides for thyroid imaging in the diagnosis and treatment of well-differentiated thyroid carcinomas (WDTC), which account for almost 90% of thyroid cancers. Although 131I is superior to 201Tl in the detection of lung metastasis, 201Tl may detect metastases not visualized with 131I, and the sensitivity of planar 201Tl may be improved with SPECT from 60 to 85%sensitivity. Imaging with 201Tl has been of value when 131I scans are negative in the presence of known thyroid cancer. 201I has been shown to be useful in patients with WDTC and elevated thyroglobulin levels, despite a negative 131I scan.30
Radioisotopes used in renal imaging
There are two types of commonly used scintigraphies to assess the kidney function. Cortical Renal Scintigraphy, an exam used to measure and evaluate the functioning kidney tissue, and Diuretic Renal Scintigraphy, an exam used to detect blockages in the kidney. For these purposes and renal SPECT imaging 99mTc is the most widely used radioisotope.
The main advantage of PET is that images provide quantitative information on tracer kinetics. Kinetic parameters that correlate with biologically defined processes can be calculated for the entire renal cortex or as pixel-based parametric images. Renal PET studies can be classified as functional (metabolic) imaging studies. Such as determinations of renal blood flow studies with 15O labeled water, 13N labeled ammonia, 64Cu and 82Rb pharmaceuticals. Other isotopes used in renal function imaging are: 55Co and 68Ga.31
3.2 Therapeutic radioisotopes
Therapeutic radiopharmaceuticals in brachytherapy are used for primary cancer treatment or targeted cancer therapy, bone pain palliation and radiosynovectomie. Primary cancer treatment make use of low-dose rate and high-dose rate radionuclides. The low-dose rate isotopes used are: cesium-131 (131Cs), iodine-125 (125I) and Palladium- 103 (103Pd). High-dose rate isotopes are: iridium-192 (192Ir), yttrium-90 (90Y), strontium-90 (90Sr) and cesium-137 (137Cs). Pain treatment in palliative care focuses on pain from skeletal metastases of cancer patients who have developed metastasis in bones in the advanced stage of their diseases. Radioisotopes used in this treatment are: strontium-89 (89Sr), samarium-153 (153Sm) and rhenium-186/188 (186Re/188Re) and yttrium-90 (90Y). Radiosynovectomie is a technique used for patients that are suffering from joint pain. The therapeutic radiopharmaceutical is delivered into the interior of joints that is lubricated by fluid, as in the case of rheumatoid arthritis. Beta-emitting radiolabelled colloids are widely used for this purpose. These radiopharmaceuticals use among others phosphorus- 32 (32P), yttrium-90 (90Y), samarium-153 (153Sm), holmium-166 (166Ho), erbium-169 (169Er), and rhenium-186 (186Re). The radiation properties of each radioisotope determine their respective use and applicability for the joint size. Lutetium-177 (177Lu) is a recent and promising isotope in bone pain palliation. 177Lu is also used in targeted cancer therapy. The shorter radius of penetration than 90Y makes 177Lu also an ideal candidate for radioimmunotherapy for smaller, soft tumors. 177Lu is projected to become as important as iodine-131 (131I), the second most used medical radioisotope. Several countries have already begun or are planning medium to large scale production of this radioisotope.32
Cancer treatment with radioimmunotherapy and PET
68Ga-PET is not only employed for imaging in the management of neuroendocrine tumors and neural crest tumors, but also for therapeutic use, where it complements present radiologic and scintigraphic procedures. Diagnosis and radiotherapy treatment planning for meningiomas (the second most common primary tumor of the central nervous system) in pertinent clinical setting is another potential use of 68Ga-PET. Therefore, current experience tends to open a new horizon for the clinical utility of 68Ga-PET imaging in future.33
Immuno-PET as a quantitative imaging procedure before or concomitant with radioimmunotherapy is an attractive option to improve confirmation of tumor targeting and especially assessment of radiation dose delivery to both tumor and normal tissues. Immuno-PET combines the high resolution and quantitative aspects of PET with the high specificity and selectivity of monoclonal antibodies. This makes immuno-PET an attractive imaging modality for tumor detection. Moreover, immuno-PET has the potential to supersede gamma-camera imaging in combination with radioimmunotherapy, because it enables the sensitive confirmation of tumor targeting and a more reliable estimation of radiation dose delivery to both tumor and normal tissues. Because PET is believed to be superior to SPECT with respect to quantification, several PET radioisotopes have been suggested as substitutes for gamma-emitting radionuclides used in radioimmunoscintigraphy. Theoretically, this could enable easy conversion from a SPECT to a PET procedure. Examples of PET/SPECT radioisotope pairs are 94mTc/99mTc, 67Ga/68Ga, and 124I/123I, and examples of PET/radioimmunotherapy radioisotope pairs are 64Cu/67Cu, 86Y/90Y, and 124I/131I.34 68Ga can be produced – such as 99mTc - from a generator system with the parent radionuclide Germanium-68. 68Ge has a long half-life of 271 days which allows the production of long-lived, potentially very cost-effective generator systems. 67Ga en 68Ga have the same medical applications, whereas 67Ga is used with SPECT/CT and 68Ga with PET/CT.
Other therapies
There are also other internal therapies with radionuclides for relieving pain of secondary cancers in the bone. For example a pharmaceutical of samarium-153 (153Sm) is injected into a vein and distributes throughout the body. It lodges in areas where cancer has invaded the bone. It emits beta particles which kill the nearby cancer cells. It is commonly used in lung cancer, prostate cancer, breast cancer, and osteosarcoma.
A method known as peptide receptor radionuclide therapy (PRRT) involves the development and use of radiolabelled peptides as molecular vectors for targeted therapy. When labeled with the 90Y and 177Lu, the most frequently used isotopes, peptide molecules have the potential to destroy receptor-expressing tumors.35
Other radioisotopes used in medicine
Bismuth-213 ( 213Bi)
213Bi is used for targeted alpha therapy, especially in treatments of cancers, including leukemia.
Chromium-51 (51Cr)
51Cr is used to label red blood cells and quantify gastrointestinal protein loss. Sodium Chromate is indicated for use in determining red blood cell volume or mass, studying red blood cell survival time (in conditions such as hemolytic anemia), and evaluating blood loss. Another 51Cr pharmaceutical is indicated for the determination of glomerular filtration rate in the assessment of renal function.
Copper-64 (64Cu)
64Cu is used to study genetic diseases affecting copper metabolism, such as Wilson's and Menke’s diseases which are caused by genetical disorders affecting the metabolism of copper in the body. In Wilson disease, copper builds up in the liver, brain, eyes, and other organs. Over time, high copper levels can cause life-threatening organ damage. Menke's disease primarily affects male infants. Symptoms include floppy muscle tone, seizures, and failure to thrive.36 The isotope is also used for PET imaging of tumors, and therapy and is considered for routine production
Indium-111 (111In)
111In is used for specialized diagnostic studies, for example brain studies, infection and colon transit studies. Other applications include the labeling of platelets for thrombus detection, labeled leukocytes (type of white blood cells) for localization of inflammation and abscesses, as well as leukocyte kinetics.37
Krypton-81m (81mKr)
81mKr from rubidium-81 (81Rb): 81mKr gas can yield functional images of pulmonary ventilation, e.g. in asthmatic patients, and for the early diagnosis of lung diseases and function.
Strontium-82/Rubidium-82 (82Sr/82Rb)
82Sr is used as the mother isotope in a generator to produce 82Rb which is a convenient PET agent in myocardial perfusion imaging. 82Rb chloride is used in heart imaging (see images below). It is rapidly taken up by heart muscle cells, and therefore can be used to identify regions of heart muscle that are receiving poor blood flow in a technique called PET perfusion imaging.38 82Rb behaves like 201Tl and is a highly promising alternative for 201Tl or 99mTc SPECT imaging.
Zinc-65 (65Zn)
65Zn is used in brain cancer imaging and is considered as a tumor suppressor agent in prostate cancer. It is also used as a tracer in studies of zinc metabolism.39
Xenon-133 (133Xe)
133Xe is used for pulmonary (lung) ventilation studies.
General Source: Radioisotopes in Medicine (October 2009), WNA http://www.world-nuclear.org/info/inf55.html
20 http://www-naweb.iaea.org/napc/physics/research_reactors/database/R R%20Data%20Base/datasets/category/status_operational_r eactors.html
21 http://www-naweb.iaea.org/napc/physics/research_reactors/database/R R%20Data%20Base/datasets/utilization/isotope_prod.html
22 http://www-naweb.iaea.org/napc/physics/research_reactors/database/R R%20Data%20Base/datasets/category/status_temp_shutdo wn_reactors.html
23 http://www-naweb.iaea.org/napc/physics/research_reactors/database/R R%20Data%20Base/datasets/utilization/isotope_prod_list. html
24 http://www-naweb.iaea.org/napc/physics/research_reactors/database/R R%20Data%20Base/datasets/category/status_reactors_con struction.html
25 Prof. G.T. Seaborg - Hundred Years of X-rays and Radioactivity (RON-BEC-100) http://www.rca.iaea.org/regional/newFiles/news.html
26 Nuclear Technology Review 2008, IAEA. pp.39-40
27 Putzer, Daniel et al.; Bone Metastases in Patients with Neuroendocrine Tumor: 68Ga-DOTA-Tyr3-Octreotide PET in Comparison to CT and Bone Scintigraphy. Journal of Nuclear Medicine Vol. 50 No. 8 1214-1221
28 Jain, Diwakar et al; Developing a new PET myocardial perfusion tracer. Journal of Nuclear Cardiology Volume 16, Number 5 689-690/ October, 2009
29 Phan, Ha T. T. et al.; The diagnostic value of 124I-PET in patients with differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2008 May; 35(5): 958–965.
30 Avram, Anca M. et al.; Alternative Thyroid Imaging. Thyroid Cancer - A Comprehensive Guide to Clinical Management. Humana Press 2007. p.35
31 Prigent, Alain, and Piepsz, Amy; Functional Imaging in Nephro-Urology. Taylor & Francis, 2005.
32 Nuclear Technology Review 2009, IAEA. p.45
33 Khan, M. et al.; Clinical indications for Gallium-68 positron emission tomography imaging. European Journal of Surgical Oncology (EJSO), Volume 35, Issue 6, Pages 561-567.
34 Verel, PhD., Iris et al.; The Promise of Immuno-PET in Radioimmunotherapy. Journal of Nuclear Medicine (2005) Vol. 46 No. 1 (Suppl) 164S-17 http://jnm.snmjournals.org/cgi/content/full/46/1_suppl/164 S
35 de Jong, PhD, Marion; Combination Radionuclide Therapy Using 177Lu- and 90Y-Labeled Somatostatin Analogs. Journal of Nuclear Medicine Vol. 46 No. 1
(Suppl) 13S-17S. http://jnm.snmjournals.org/cgi/content/full/46/1_suppl/13S
36 Wilson Disease - http://digestive.niddk.nih.gov/ddiseases/pubs/wilson/NINDS Menkes Disease Information Page - http://www.ninds.nih.gov/disorders/menkes/menkes.htm
37 In-111 Fact Sheet, MDS Nordion: www.mdsnordion.com/documents/products/In- 111_Can.pdf
38 Rubidium-82 chloride: http://en.wikipedia.org/wiki/Rubidium-82_chloride
39 Costello, Leslie C., and Franklin, Renty B.; The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer. 2006; 5: 17. Published online 2006 May 15. doi: 10.1186/1476- 4598-5-17. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1481516/