- What is an isotope?
- What is a radionuclide?
- How do we produce radionuclides?
- What is a half-life?
- What are medical isotopes?
- What is Technetium-99m or Tc-99m?
- How are medical isotopes used?
- Where are medical isotopes made?
- Where does Tc-99m come from?
- What is a cyclotron?
- How does a cyclotron work?
- What is a target?
- What is the history of cyclotron-produced medical isotopes?
- Can we use other types of accelerators to produce Tc-99m?
- What are the advantages of accelerator-based production of medical isotopes?
- What is the business of medical isotopes?
- What is the future of Tc-99m production?
- What is the future of medical isotopes?
The nucleus of an atom is composed of protons and neutrons. The number of protons in the nucleus defines what element the atom is. For example, a nucleus with 8 protons makes it the element oxygen. Molybdenum (Mo) has 42 protons and Technetium (Tc) has 43 protons. The total mass of the nucleus is the sum of the number of protons and the neutrons. The number of neutrons in the nucleus can vary without changing the element. Thus Mo-98 and Mo-99 are isotopes of Mo, both having 42 protons but one has 46 neutrons and the other 47 neutrons.
Stable isotopes of an element do not change over time. Atoms of unstable isotopes – also called radioisotopes--change into other elements over time through radioactive decay. Radioisotopes are used in many medical imaging and diagnostic procedures, with the isotope Tc-99m being used in 80 percent of tests.
A radionuclide is an isotope of an element that is radioactive. The radioactive nucleus emits energy in the form of light rays or particles to form a stable (non-radioactive) form. Tc-99m is an example of a radionuclide.
Radionuclide production is indeed true alchemy, that is, converting the atoms of one element into those of another. This conversion involves altering the number of protons and/or neutrons in the nucleus (target). If a neutron is added without the emission of proton(s) then the resulting nuclide will have the same chemical properties as the target nuclide---differing only in mass. If, however, the target nucleus is bombarded by a charged particle, for example a proton, the resulting nucleus will usually be that of a different element. The exact type of nuclear reactions that a target undergoes depends on a number of parameters including the type of bombarding particle and the energy of this projectile.
The binding energy per nucleon in the nucleus is on the order of 8 MeV. Therefore, if the incoming projectile has more than this amount of energy, the resulting reaction will cause other particles to be ejected from the target nucleus. By carefully selecting the target nucleus, the bombarding particle and its energy, it is possible to produce a specific radionuclide.
The time interval over which one half of the atoms present disappear through nuclear decay.
Modern healthcare routinely requires examining a patient with more than the unaided eye. Molecular imaging-the imaging of molecules, biochemical processes, and physiological activity within the human body-is rapidly becoming one of the most powerful tools for diagnosis and staging of disease. The main tools for molecular imaging are the SPECT and PET scans that tag (or "label") specific biologically active molecules (biomolecules) with medical isotopes. A medical isotope is an unstable (i.e., radioactive) atom derived from a stable one. When the unstable atom decays, it emits a particle that can be detected and used to pinpoint its location. By chemically connecting the medical isotope to a biomolecule and injecting the compound into the human body, one can then "see" where the body is using the biomolecule.
A CAT scan cannot, for instance, tell if a patient is dead or alive because it only shows anatomy and structure. A PET or SPECT scan indicates what biochemistry is happening inside the body. An MRI has some capability to see activity but is primarily used for anatomical study.
PET and SPECT scans differ by the type of decay of the isotope and therefore use different "cameras" to image or "scan" the patient. SPECT is the better established modality and is prevalent in every hospital and is presently cheaper than PET. PET is the emerging technology and offers higher resolution scans and access to more sophisticated biology in the body.
In Canada alone, Tc-99m is used in approximately 5,500 medical scans a day. This medical isotope or radionuclide is combined with any of a variety of biologically active molecules to perform non-invasive, real-time imaging of the human body. A typical dose of Tc-99m for a medical procedure uses 10-30 mCi. Tc-99m can be used to perform imaging of:
- The heart for myocardial perfusion studies;
- Bones for identifying cancerous lesions;
- Brain function; and
- A number of specialized tests such as immunoscintigraphy, ventriculography, spleen function, and so on.
Tc-99m is the most commonly used medical isotope. It is used in hospitals all over North America to create the radiopharmaceuticals used in patients.
For example, if an incoming patient is thought to have had a heart attack, a doctor will often inject the patient with Tc-99m attached to biomolecule called teboroxime (the combination is called a "radiotracer"). The patient will then typically perform a rest-and-stress treadmill test. The Tc-99m goes to the heart because the teboroxime molecule is designed to accumulate there. When the heart is imaged with a SPECT camera, the picture will tell the doctor if the heart muscle has been damaged.
Another medical isotope, Iodine (such as I-123 for imaging and I-131 for therapy), accumulate in the thyroid when injected into the body. The patient is imaged with a SPECT camera and the thyroid functionality is evident. Doctors can then identify what part of the thyroid gland is working properly, and areas that aren't. If you have ever known anyone who has battled thyroid cancer, they were likely diagnosed and treated successfully as a result of advancements made because of medical isotopes.
Of the approximately 200 radioisotopes commonly available today, almost all are artificially created. Medical isotopes come either from nuclear reactors or special particle accelerators known as cyclotrons. The most significant quantities of radioisotopes rich in neutrons (e.g. Mo-99, I-131) come from neutron bombardment of elements in a nuclear reactor. Cyclotrons are used to produce isotopes rich in protons. Some cyclotron-produced isotopes are well-suited for radiation therapy. Others are used for nuclear imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET) technologies.
Nordion Vancouver Operations (based at TRIUMF) currently operate three cyclotrons 24/7 365 days a year to produce non-Mo-99 medical isotopes primarily for export. Total production exceeds 2.5 million patient doses per year.
Using nuclear reactors to produce medical isotopes introduces a number of challenges. Aging reactors are becoming increasingly unreliable and outages---such as the year-long outage of the NRU reactor at Chalk River---contribute to ongoing shortages. The use of highly-enriched uranium as the target material is also a major security and proliferation concern; many nations, including the United States, are actively working to eliminate its use in civilian applications. Since half of the Mo-99 decays every 66 hours, much of the resulting Tc-99m ends up being wasted as it decays during shipment from far-flung reactors, to pharmaceutical companies, and finally to hospitals. Isotope-generating reactors also create other by-products besides Mo-99 that persist as long-lived nuclear waste.
Tc-99m comes from the parent atom Molybdenum-99 or simply Mo-99. Mo-99 is produced in nuclear reactors (such as Canada's NRU reactor at Chalk River) by irradiating highly enriched "weapons-grade" uranium (U-235). The Mo-99 has a fairly long half-life (it takes on average 66 hours for half of a sample of Mo-99 to decay to Tc-99m). The Mo-99 decays into Tc-99m, which has a half-life of 6 hours.
Together with MDS Nordion, TRIUMF has demonstrated the technology of "photo-fission" to produce Mo-99 without a reactor by using a cyclotron.
A cyclotron is an electromagnetic device used to accelerate charged particles (ions) to sufficiently high speed (energy) so that when it impinges upon a target the atoms in the target are transformed into another element. A cyclotron differs from a linear accelerator in that the particles are accelerated in an expanding spiral rather than in a straight line.
Cyclotrons are used for many different applications in industry, medicine, and research are one of the most popular forms of accelerators. Most cyclotrons produce beams of protons although some produce beams of alpha particles or other heavier nuclei. Around Canada and around the world, medical cyclotrons are presently used to produce medical isotopes such as Fluorine-18 or Carbon-11. Other cyclotrons are used to generate the beams of radiation for treatment of cancer. TRIUMF has five different cyclotrons on site for a wide variety of industrial, commercial, medical, and research applications.
Advanced Cyclotrons Systems, Inc., in Richmond, BC, is one of the world's leading manufacturers of medical-isotope cyclotrons. Their original designs were inspired by collaborations with TRIUMF in the 1990s.
The principle of the cyclotron is based on the application of small accelerating voltages repeatedly. Hollow cavities called “dees,” because of their shape, serve as the electrodes for the acceleration. A radio frequency (RF) oscillator is connected to the dees such that the electrical potential on the dees is alternatively positive and negative with respect to each other. By placing the dees between the poles of a strong magnet so that the magnet field is perpendicular to the plane of motion, the charged particle undergoing acceleration will move in a circular path. As the particle gains energy it moves in a spiral outward from the center.
With the source of negative ions at a point in the center of the cyclotron, the positive dee will accelerate the ions toward that dee, with the magnetic field forcing them to move in a curved path. Once inside the cavity, the particles no longer experience an electric force. Continuing in the circular path, the particles will exit the dee and enter the gap between the dees where the second dee has changed its potential to be an attracting force, accelerating the particles to that dee. The dees reverse their potential when the particles are inside the dees so that at each crossing of the gap the particles receive an increase in energy of the order of 20-50 keV.
Lawrence discovered the equations defining this principle of operation in 1929 and built the first cyclotron in 1931:
Bev = mv2/r and r = mv/Be
Since angular velocity ω = v/r , then ω = Βe/m, where m is the mass of the ion, e is its charge and v its velocity; with B equaling the magnetic field and r is the radius of the ion’s orbit.
Thus the orbit of the particle is directly proportional to the particle momentum and the particle orbit frequency is constant and independent of energy. This principle breaks down under relativistic effects where the mass is not constant.
A target is the material which is irradiated by the beams from the cyclotron---or in the case of a nuclear reactor, the target would be irradiated by beams of neutrons from the reactor core. The target contains atoms that are to be transformed into another element after bombardment by the high-speed protons from the cyclotron. In the case of CycloMed99, the target material is made of molybdenum (Mo) and a fraction of this is converted into technetium (Tc). For this project, key research went in to developing robust, high-yield, and easy-to-handle targets so that Tc-99m can be produced reliably and efficiently using existing medical-isotope cyclotrons.
The first artificially produced radionuclides were created on Lawrence's cyclotrons (Lawrence 1932, Lawrence 1940), but it took another 30 years before accelerator produced radionuclides began to play a major role in production of medically important radiopharmaceuticals.
Cyclotrons used for producing medical radionuclides were initially designed for physics experiments and used only part time for medical applications. These cyclotrons were capable of accelerating protons, deuterons, 3He+2 and α-particles (the nucleus of 4He). PET radionuclides are produced from either proton or deuteron reactions. In the early eighties, small compact proton-only cyclotrons became available and cyclotrons specifically designed for producing PET radionuclides were installed in a few hospitals.
Yes. The production of radionuclides via an electron machine follows the same principles as in the cyclotron with a few exceptions. In this case, instead of the bombarding particle being charged particles such as protons (or neutrons from a reactor), they are photons or light rays. The photons are generated by directing an electron beam from a high-powered electron accelerator onto a heavy metal such as liquid mercury or water-cooled tungsten called a converter. The electron beam produces high-energy photons, known as bremsstrahlung radiation, as it interacts and loses energy in the converter target. The photons can then be used to irradiate another target material placed just behind the convertor, in this case Mo-100, to produce Mo-99 via the reaction: 100Mo(γ,n)99Mo.
The produced Mo-99 would then be incorporated into a generator system, which provides Tc-99m periodically through the decay of the longer lived Mo-99 (66 hours) as compared to the half-life of Tc-99m (6 hours).
The principle advantage of accelerator-produced radionuclides is the high specific activities that can be obtained through the (p,xn) and (p,α) reactions that result in the product being a different element than the target. Another significant advantage is that a smaller amount of radioactive waste is generated from charged particle reactions in comparison to reactor production. There is higher predictability of schedule, cost, and licensing with accelerators than for a reactor. In fact, the cyclotron approach to creating Tc-99m would use existing facilities which already hold licenses for operations. Another advantage of accelerator technology is that it is scalable: the technology is equally useful over a wide range of powers, so can be installed in a small or large facility.
Canada first became a leader in the use of medical isotopes for healthcare diagnosis and treatment in 1951 (Canadians were involved in the world's first nuclear reactor built by Enrico Fermi in Chicago). Presently, medical imaging technology using medical isotopes plays an important role in the diagnosis and treatment of everything from neurological diseases to cancer. It drives a multi-billion dollar business per year worldwide with growth is predicted to be 1-4% per year for at least a decade.
Tc-99m is used in 85% of all nuclear medicine procedures, 20 million per year, around the world. Canada creates Moly-99 at the NRU reactor at Chalk River; the Mo-99 is extracted by AECL and then shipped to MDS Nordion where it is purified. The Mo-99 is then transported to two manufacturers in the U.S. who create the Tc-99m-generating device which is sold to hospitals.
CycloMed99 announced in 2015 a breakthrough in technology that uses medical cyclotrons already installed and operational in major hospitals across Canada to produce Tc-99m on a daily basis. This solution allows existing cyclotrons to produce enough Tc-99m in just one night to meet the daily needs of most hospitals. With this technology in place in the near future, hospitals all over Canada and the world will produce their own Tc-99m without having to source it from a reactor. Thus Canada's healthcare system will save money by producing isotopes locally under a full-cost recovery model.
Two categories of development are driving the future business of medical isotopes. Canada has a strong position in both.
- The emerging technology of PET which may eventually supplant the current SPECT technology.
- The development of more and more advanced "radiotracers" (medical isotopes with the added-value of sophisticated biomolecules) which will allow clinicians to quickly and precisely identify-and eventually treat-cancer and neurodegenerative disease in patients.
SPECT technology stands for Single Photon Emission Computed Tomography and uses a particular set of medical isotopes (e.g., Tc-99m) and a particular type of camera. PET technology stands for Positron Emission Tomography and uses different medical isotopes (e.g., F-18) and a different camera. There are several medical isotopes, and the number is growing, that are imaged with a PET camera. At present, SPECT is lower resolution but cheaper than PET. As a result, nearly every hospital in North America has a SPECT system.
It turns out that PET isotopes are easier to work with than Tc-99m, and so more molecules are available for PET than SPECT with Tc-99m. As the number of these special molecules increases, hospitals are increasingly buying PET cameras rather than SPECT. Last year in the U.S., purchases of PET cameras were greater than SPECT for the first time. In Canada, the number of installed SPECT cameras is about 2,000; there are only 22 PET cameras. As the field advances, this gap will close and over the course of a decade, PET will dominate everywhere.
The half life of PET isotopes is usually quite short. The most widely used PET radiotracer is FDG (F-18-fluro-deoxyglucose), an isotope-labelled sugar, however there are several other "radiotracers" that are emerging for use in cancer diagnosis, staging, and therapy. For example, FES (fluoroestrodiol) is a PET radiotracer and determines whether a breast cancer tumour has estrogen receptors. If this is the case, then the doctor orders a particular therapy: hormone therapy, benefitting the patient and saving the cost of an incorrect and ineffective therapy.
Related information at TRIUMF
- The role of chemistry in nuclear medicine