That gives me an opportunity to introduce to you the first of two tools that I think are necessary to talk about radionuclide production, and that's the chart of the nuclides. This chart is the periodic table for physicists. Many people in the room will be very familiar with it, but for those who aren't, each row on the chart of the nuclides is a box on the periodic table. Stability, or matter that we can touch, which doesn't decay, tends to locate near the center of this, as you march from the bottom left corner up to the top right. And atoms with shorter and shorter half-lives tend to locate along the periphery, as you move towards the outer edges.
If stellar nucleosynthesis were to stop at the iron wall, this would be the extent of known matter in the universe. Fortunately, the universe is old. And because the universe is old, we can make use of the densification of stars and extremely chaotic interstellar events like the collision of humongous neutron stars and kilonova to induce additional processes which are essentially long chains of successive neutron capture.
And this gives me a chance to introduce the second tool that I need to talk to you about radionuclide production: a nuclear reaction. A nuclear reaction is probably best thought of as a collision between a cue ball and a billiard rack on a pool table. The incident particle or projectile A is the cue ball. It hits the rack X, and ejects in the resulting particles B, forming nucleus product nucleus Y. In the example that I'm showing on the slide, a silver-109 nucleus undergoes a neutron capture reaction before decay to cadmium-110. Cadmium-110 undergoes five successive neutron capture reactions to form cadmium-115, which decays to indium-115, and the process continues. In this way, the S-process crawls up the central region of the nuclide chart, forming successively heavier and heavier radionuclides in the process.
The S-process is called the S-process because it's the slow process. That means it happens primarily in large, dying stars. The R-process is fast. It's the rapid process. Physicists are really creative with our nomenclature. And as a result, it can access radionuclides which are very, very short-lived, far out towards the periphery of the chart of the nuclides. It's more akin to the reactions that take place in a tokamak than reactions that take place in a reactor. And that's the distinction in my mind between the S- and the R-processes for the purposes of this talk.
Now, why did I take us on that circuitous trajectory? It's because I think that radionuclide production approximately mirrors stellar nucleosynthesis, and I'll make that case using the two tools that I've just introduced to you.
The schematic on the slide starts with an original target nucleus, and undergoes nuclear reactions in order to produce the products which are shown in pink and blue on the slide. Charged-particle-induced reactions initiated in cyclotrons or linear accelerators are the source of the radionuclide products that are north of the valley of stability, or in pink. These tend to decay by positron emission or electron capture, which means that they are fundamentally essential as diagnostic radionuclides in nuclear medicine.
On the other hand, reactions that are introduced are in reactors, primarily neutron capture reactions of the ones that I just described for the S-process, predominantly form beta-decaying radionuclides, which are mainly useful for therapy. So I'll talk about those two main infrastructure tool sets that we use to make radionuclides.
Everyone here is familiar with the idea of a reactor, and the details aren't important for this talk. Basically, we get a large flux of neutrons. That large flux of neutrons, as in the Stellar S-process, mainly produces N-gamma reactions, neutron capture reactions. Those capture reactions are fundamentally carrier-added. The product isotope is of the same element as the original target that we put into the reactor. The only way to get around this is for there to be a subsequent decay process, usually a beta decay, just like in stellar nucleosynthesis.
And the case study for this is the production of high-specific-activity and low-specific-activity lutetium-177. Lutetium-176 can be directly captured upon to produce lutetium-177 directly, that's the low-specific-activity route. And ytterbium-176 can be neutron captured upon to produce ytterbium-177, which then beta decays to lutetium-177, with direct consequences mainly in terms of the injected mass of the formulated radiopharmaceutical to the patient, and consequent uptake of the drug.
The alternative case scenario is a cyclotron, and this is a beautifully simple machine whose elegance derives mainly from the fact that a single frequency of accelerating voltage is all that's necessary to bring charged particles from the center of the device and kiloelectron volt energies, up to megaelectron volt energies at the periphery for extraction and impingement on a target.
Cyclotrons come in many flavors, from the small violin-shaped and approximately violin-sized machine that Ernest Lawrence first made in California in the 1950s, to the larger ones that he installed at Davis and Berkeley, to the largest cyclotron currently used in the world for radionuclide production, which sits at Canada's flagship nuclear physics installation at TRIUMF in Vancouver. There's a strong energy dependence to the radionuclides that you can make as a result of charged particle irradiations.
The lower the energy, the fewer the ejectiles, and the closer to your original target nucleus in mass you will inevitably be at the end of the reaction. If you add energy, you knock out more ejectiles and you get farther away. If you add mass or change the particle, for example, to a deuteron, a combination of a proton and a neutron, you can access other reaction channels, and still other reaction channels if you convert to higher and higher mass beams.
Now, at this point in any talk that I give, people are usually starting to wonder, "What about the alpha emitters?" And I feel like I have to talk about them separately, because the case is so unique. I'm showing here a chart, a subsection of the chart of the nuclides, which extends from lead up to uranium. And my main message is that alpha emitters are hard to find and to make. The desired products for application in nuclear medicine at present are highlighted in green. Actinium-225, radium-223, astatine-211, and lead-212. I'm being a little injudicious with my selection of these, but we'll simplify for the sake of brevity.
There are a few ways that stellar nucleosynthetic processes, from way back in the beginning of the talk, give us stable starting materials, that we can use, or thought, hoped we could use in the beginning of this exploration, and they're the primordial decay chains. The first of these is uranium-238. U-238 decays by a whole bunch of successive alpha and beta decay processes, ultimately winding up at stable lead-206, but going through polonium-210, which was Litvinenko's demise.
U-235 is a second decay chain, which starts at U-235 and goes through a similarly long chain of decay processes before winding up at stable lead-207. Importantly, it's the first decay chain that directly interacts with one of the desired products for nuclear medicine. And it's for this reason that radium-223 was first developed into a reliable supply of an isotope that could be applied in the clinic.
Finally, the decay chain that starts with thorium-232 directly makes lead-212, but it makes lead-212 with one problem. It goes through thorium-228. And so we have another version of the carrier-added, no carrier-added problem that I talked about earlier in the lecture, where in order to process thorium-228 to recover lead-212, you have to process kilograms of thorium-232 unless you found some way to separate or independently create the thorium-228 first.
The viable target materials for anthropogenic, human-made, production of these radionuclides are now highlighted in red. And so the vast majority of the research in radionuclide production over the last five to 10 years has occurred centered around the target nucleus radium-226. With neutron capture or radiations, you can produce thorium-228 for lead-212. You can produce actinium-227, which ultimately makes the variety of useful radionuclides, and with proton, photon, or fast-neutron irradiations, you can directly form actinium-225.
However, the challenge of making something starting with a highly radioactive target material is probably the strongest evidence of the difficulty of this process and the reason for such a long period of development of radium targets. Astatine-211, before I forget, sits out alone, with only the need for a naturally monoisotopic target materials irradiation, and a simple alpha-2N nuclear reaction on a commercial cyclotron to produce.
This is Dr. Watabe's slide. I only wanted to highlight that at Wisconsin, we're going to start doing astatine-211 in 2028. And so with the prohibition on plugs for the things that you do at home, I'll point only to the fact that there are a variety of very specific and advanced technologies which will ultimately be brought to bear on radionuclide production, but at present, these are in a nascent state of development. And I thank you very much for your time.