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Isotope Production

Radioisotope & Radionuclide Production

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. 

Producing Isotopes with Cyclotrons

It is ironic that 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. 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.


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.

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 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.

While the basic components of modern cyclotrons are essentially the same as the original designs (RF cavities, vacuum tank, magnet, ion source, extraction system,) there have been some innovations in the last few decades that have had a major impact on the design of the modern cyclotron. The two most significant changes have occurred in getting the ions into the cyclotron (ion source) and out of the cyclotron (extraction system).

Nearly all modern cyclotrons now use a negative ion source. Ions are generated by passing the source gas through an electric field that generates negative and positive ions (e.g. in the case of H2, the resulting ions will be H+ or protons and H- ions, a proton with 2 electrons). The advantage of negative ions resides in the ability to easily have a variable energy cyclotron, to have nearly 100% extraction (see below), and to be able to extract multiple beams, simultaneously. The design of the ion source has also changed in that the ion source can reside inside the cyclotron where the ions are generated at the center of the cyclotron (center region) or from outside of the cyclotron (external ion source) and subsequently injected into the center region for acceleration. There are obviously advantages and disadvantages to each approach. With an external ion source the vacuum can be operated at very low pressures with very little beam loss due to stripping of the negative ion by the residual gas. However, the vacuum system must be of a very clean nature to maintain this high vacuum. With an external ion source, maintenance can be performed without opening the cyclotron or breaking vacuum. In addition the center region is not disturbed as in the case of the internal ion source that is part of the center region.

The simplicity of the design for proton only cyclotrons resulted in cyclotrons which accelerate H- ions capable of two or more simultaneous beams of varying energies and intensities. The modern cyclotron is completely controlled by a computer and is capable of running for many days with minimal attention. The major drawback from these proton cyclotrons lies in the fact that in some cases an enriched target material must be used for sufficient product to be generated.

Regardless of the type of accelerator used to produce the radionuclides, the production rates depend on the flux of the bombarding particles, the number of target nuclei and the probability of the reaction occurring. The equation for the rate of production is

R = Iσt

where R is the rate of nuclei formed per second, I is the flux of the bombarding particles per second, σ is the cross section (probability of the reaction occurring) in cm2 and t is the target thickness expressed as the number of nuclei per square centimeter. It is of historical interest to note that the unit for cross section is the barn, which is equivalent to 10-24 cm2. The expression barn comes from the fact that the probability of a neutron interacting with a target is proportional to the area of the nucleus, which, compared to the size of the neutron, is as big as a barn.

The rate of production is, of course, affected by the fact that the resulting nuclide is radioactive and thus, undergoes radioactive decay. For short-lived nuclides the competing reaction rates, production, and decay will achieve equilibrium at sufficiently long bombardment times since the rate of decay is proportional to the number of radionuclei present. The point where equilibrium is reached is called saturation. This means that there is no benefit to longer irradiations, as the production rate equals the rate of decay, and therefore no additional product will be formed. At shorter irradiation times the fraction of product produced is related to the saturation factor given by (1 - e-λt), where λ is the decay constant of the decaying nuclide and t is the bombardment time. It is evident that an irradiation equivalent to one half-life would result in a saturation factor of 50%. For practical reasons, an irradiation rarely exceeds three half-lives (90% saturation) except for the shortest-lived radionuclides.

For long lived species, the quantity produced is usually expressed in terms of integrated dose or total beam flux (μA-hr). For example, with a long lived radionuclide such as 82Sr (t½ = 25 d) the amount produced will be essentially the same whether it is produced from 100 μA in 1 hour or 50 μA in 2 hours (both represent 100 μA-h of beam).
For further reading see - IAEA TecDoc “Theory and Practice of Production of Radioisotopes Using Cyclotrons”,  2007.

Reference:  T.J. Ruth, The uses of radiotracers in the life sciences. Rep. Prog. Phys. 72 016701 (2009).

Producing Isotopes with Electron Accelerators

The production of radionuclides via an electron machine follows the same principles as described above with a few exceptions. In this case instead of the bombarding particle being charged particles such as protons (or neutrons from a reactor) but 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.

Diagram of nuclear reactions used to produce Mo-99 using electrons to produce photons directed on either Mo-100 or U-238 target material.


High-energy photons known as bremsstrahlung radiation are produced by the electron beam 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


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).

Advantages & Disadvantages of the Accelerator-based Production of Medical Isotopes

There are advantages and disadvantages associated with the accelerator based production of medical isotopes. Some apply to both the cyclotron approach and the photon-neutron approach while others are particular to each separately.

The main advantages of this approach are:

  • There would be nearly no waste stream.
  • The facility would (likely) be a Class II nuclear facility per CNSC licensing consideration and could be sited in a “green-field” location. (The cyclotron approach would use existing facilities which already hold licenses for operation).
  • Higher predictability of schedule, cost, and licensing than for a reactor.
  • The main facility costs and licensing issues should be reasonably low in risk.
  • Scalable—can be built as a small (low power) facility or large facility.
  • Technology is equally useful over a wide range of powers.

The significant disadvantages of this approach are:

  • A major change in the generator technology would be needed because of the different target. (Direct production of Tc-99m eliminates this issue).
  • Health Canada/FDA approvals would be needed for new product.
  • The cost of manufacturing Mo-100 targets and the cost of separating Mo-100 from bulk Mo would likely be quite high. Mo-100 comprises less than 10% of naturally occurring molybdenum and separated isotope presently costs dollars per milligram.