- What is an isotope and what is a radioisotope?
- How do we produce radioisotopes?
- What is a half-life?
- What are medical isotopes and how are they used?
- Where are medical isotopes made?
- What is Technetium-99m or Tc-99m?
- 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 element is defined by the number of protons in the nucleus. 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 neutrons. The number of neutrons can vary without changing the element. Thus, Mo-98 and Mo-99 are isotopes of Mo; both have 42 protons, but one has 46 neutrons and the other has 47.
Stable isotopes of an element do not change over time.
Atoms of unstable isotopes – radioisotopes – change into other elements over time through radioactive decay. Radioisotopes are used in many medical imaging and diagnostic procedures. For example, Tc-99m is used in over 80% of all nuclear medicine imaging procedures.
Radioisotope production involves converting the atoms of one type into another. This conversion involves altering the number of protons and/or neutrons in the nucleus. If a neutron is added without the emission of proton(s), then the resulting nuclide has the same chemical properties as the original, differing only in mass (see “What is an isotope?”). If, however, a target nucleus is bombarded by a charged particle such as 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 and energy of the bombarding particle. Nuclei are held together by a ‘glue’ measured in energy units called electron volts (eV). A typical nucleus is bound with an energy on the order of 8 million eV (8 MeV). Therefore, if the bombarding particle has more than this amount of energy, the resulting reaction will cause other particles to be ejected from the target. By carefully selecting the target nucleus, the bombarding particle, and its energy, it is possible to produce a specific radionuclide.
Half-life is the time interval over which one half of the atoms in a particular sample transform from an unstable isotope into another through nuclear decay.
A medical isotope is an unstable (i.e. radioactive) atom derived from a stable one.
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 the diagnosis and staging of disease. The main tools for molecular imaging are single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans that tag specific biomolecules (biologically active molecules) with medical isotopes. When medical isotopes decay, they emit particles that can be detected and used to pinpoint their location. By chemically connecting a medical isotope to a biomolecule and injecting that compound into a human body, clinicians can “see” where the body is using the biomolecule.
For example, if an incoming patient is thought to have had a heart attack, a doctor might inject a patient with Tc-99m attached to a biomolecule called teboroxime (this combination is called a “radiotracer”). The patient might then perform a rest-and-stress treadmill test. The Tc-99m will go 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.
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 better established, is prevalent in every hospital, and is presently cheaper than PET. PET is an emerging technology that offers higher resolution scans and access to more sophisticated biological information.
Of the approximately 200 medical isotopes commonly available today, almost all are artificially created. Medical isotopes come either from nuclear reactors or cyclotrons. The most significant quantities of radioisotopes rich in neutrons (i.e. Mo-99) come from neutron bombardment in a nuclear reactor. Cyclotrons are used to produce isotopes rich in protons. Some cyclotron-produced isotopes are used for radiation therapy, while others are used for SPECT and PET imaging.
Nordion’s Vancouver site (located on the TRIUMF campus) currently uses three cyclotrons 24/7 year-round to produce non-Mo-99 medical isotopes. Total production exceeds 2 million patient doses per year.
Using nuclear reactors to produce medical isotopes introduces a number of challenges. Aging reactors suffer outages that give rise to shortages. In addition, the use of highly enriched uranium as the target material is a major security concern; many nations, including Canada and the United States, are actively working to eliminate its use in civilian applications. Isotope-generating reactors also create other by-products that persist as long-lived nuclear waste.
Tc-99m is a medical isotope used in approximately 5,500 medical scans a day in Canada alone. It is combined with 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, and the brain for function, as well as for a number of specialized tests such as immunoscintigraphy, ventriculography, and spleen function.
Tc-99m comes from the parent atom Molybdenum-99 (Mo-99). Mo-99 is produced in nuclear reactors by irradiating highly enriched “weapons-grade” uranium (U-235). Mo-99 has a relatively long half-life, taking on average 66 hours for half of a sample to decay to Tc-99m. Tc-99m has a half-life of six hours.
With a 66-hour half-life for Mo-99, much of the resulting Tc-99m ends up being wasted as it decays during shipment from far-flung reactors to pharmaceutical companies to hospitals.
A cyclotron is an electromagnetic device that accelerates charged particles (ions) to sufficiently high speed (energy), so that when they impinge upon a target, the atoms in the target are transformed into other elements. 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 one of the most prevalent forms of accelerators.
Most cyclotrons produce beams of protons, although some produce beams of alpha particles or other, heavier nuclei. Medical cyclotrons are used around the world to produce medical isotopes such as Fluorine-18 and Carbon-11. Other cyclotrons are used to generate beams of radiation for the treatment of cancer. TRIUMF has five different cyclotrons on site for a variety of industrial, commercial, medical, and research applications. Advanced Cyclotrons Systems, Inc., located in Richmond, BC, is a leading manufacturer of medical-isotope cyclotrons.
The principle of the cyclotron is based on the application of small repeating accelerating voltages. Hollow cavities called “dees” (because of their shape) serve as the electrodes for acceleration. A radio frequency (RF) oscillator is connected to the dees so that their electrical potential alternates rapidly 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 particles accelerate in a circular path. As the particle gains energy it moves in a spiral outward from the center.
A target is the material that is irradiated by the beams from the cyclotron (or, in the case of a nuclear reactor, by beams of neutrons from the reactor’s core). The target contains atoms that are to be transformed by bombardment using the high-speed protons from the cyclotron.
The first artificially produced radioisotopes were created on E.O. Lawrence's cyclotrons starting in the 1930s (Lawrence won the 1939 the Nobel Prize in Physics for the invention and development of the cyclotron), but it was another 30 years before accelerator-produced radioisotopes began to play a major role in medically important radiopharmaceuticals.
Cyclotrons used for producing medical radioisotopes were initially designed primarily for physics experiments and were 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 radioisotopes 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 radioisotopes were installed in major hospitals.
Yes. The production of radioisotopes via electron machines follows the same principles as the cyclotron, with a few exceptions. In this case, the bombarding particles are photons or light rays. The photons are generated by directing an electron beam from a high-powered electron accelerator onto a converter, a heavy metal such as liquid mercury or water-cooled tungsten. The electron beam produces high-energy photons (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 converter, in this case Mo-100, to produce Mo-99. The produced Mo-99 is then incorporated into a generator system, which provides Tc-99m through the decay of the longer-lived Mo-99.
The principle advantage of accelerator-produced radioisotopes is the highly specific activities that can be obtained through the nuclear transformations. Another significant advantage is that a smaller amount of radioactive waste is generated from charged particle reactions in comparison to reactor production.
In addition, cyclotrons can be obtained at just a fraction of the cost of a nuclear reactor. Another advantage of accelerator technology is that it is scalable: the technology is equally useful over a wide range of machines and can be installed in a small or large facility.
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 worldwide business with a predicted growth of 1-4% per year for at least a decade.
In 2015, the TRIUMF-led consortium announced a breakthrough in technology to produce Tc-99m on a daily basis using medical cyclotrons already installed and operational in major hospitals across Canada. This solution allows existing cyclotrons to produce enough Tc-99m each night to meet the daily needs of most hospitals. With this technology in place, hospitals across Canada would be able to produce their own Tc-99m without having to source it from a reactor. Canada's would save money by producing isotopes locally under a full-cost recovery model.
The field of nuclear medicine has evolved into what can be considered its third generation. Generation-I originated in the 1950s, with several reactors producing large enough quantities of simple radioisotope formulations that could be distributed for use globally. This allowed for the launch of the era of modern nuclear medicine, and for the next thirty years the medical community developed and implemented dedicated cameras needed to image patients injected with gamma-emitting isotopes.
Generation-I radiopharmaceuticals were simple, perfusion-based compounds that distributed within the body based on simple properties such as molecular shape, size, and charge; and the isotopes injected were typically single photon emitters. The world came to adopt nuclear medicine as a cheap, yet powerful tool for the non-invasive diagnosis of disease.
Generation-II radiopharmaceuticals evolved during the 1980s and involved the development of compounds targeted to specific cellular biomarkers. With a rapid growth in understanding of the molecular basis of physiology and disease, and the expansion of a global cyclotron infrastructure, new and powerful positron-emitting compounds such as [18F]fluorodeoxyglucose, or FDG for short, were discovered and widely implemented for the safe and accurate diagnosis and evaluation of diseases affecting millions of patients. Over the next thirty years, the radiopharmaceutical research community spent an enormous amount of time and effort developing a myriad of targeted radiopharmaceuticals that have continued to feed our understanding of biology and medicine at the molecular level.
Today we are witnessing the evolution of Generation-III compounds, which have come to include both imaging and therapeutic isotopes. In a nearly synonymous way to which we came to appreciate the power and utility of imaging isotopes, therapeutic isotopes are now entering the active conscience of the medical community. The FDA has recently approved Xofigo (223RaCl2), a simple salt that has shown benefit for patients with late stage, castrate resistant prostate cancer. The compound localizes to bone metastases in a similar manner to how perfusion-based imaging agents were used in the 1950s. Radium chloride has a natural tendency to accumulate in bone tissue, and metastatic bone lesions have proven to be a preferred site for accumulation. The result is some reduction in cancer spread, but more importantly a dramatic reduction in pain and in increase in quality of life for patients.
While there have been a few therapeutic compounds ahead of their time (Adreview, Bexxar, Zevalin), a race has now been launched for the future of (targeted) therapeutic radiopharmaceuticals. In addition to Xofigo, the FDA is anticipated to approve at least one more compound (Lutathera, 177LuDOTATATE) within the next year; a compound targeted toward the somatostatin receptor – one that plays an important role in the physiology of neuroendocrine tumor growth. With that, the research community has set its sights on what it considers to be the most promising prospects. Amongst these are actinium-225, bismuth-212 and 213 and lead-212. The common denominator with these isotopes is that they emit alpha particles, which if they can be harnessed and targeted appropriately can deliver lethal doses of radiation to microscopic sites within the body, opening up new possibilities for disease treatment. Early studies have shown dramatic benefits in a limited number of patients.