Systems and methods for isotope production via low-energy accelerator-driven fast neutron sources

Abstract

A method of producing a radioisotope, includes irradiating a proton target with a beam of protons to produce a beam of neutrons and irradiating at least one neutron target with the beam of neutrons to produce a specified radioisotope. In some embodiments, the proton target is beryllium, the neutron target is radium-226 and the specified radioisotope is radium-225. The proton beam may be produced with a charged particle accelerator or a medical cyclotron.

Description

Systems and Methods for Isotope Production via Low-Energy Accelerator- Driven Fast Neutron SourcesCross-Reference to Related Application

[0001] This application claims the benefit of US Provisional Application Serial No. 63 / 689188, filed August 30, 2024 entitled “SYSTEMS AND METHODS FOR ISOTOPE PRODUCTION VIA LOW-ENERGY ACCELERATOR-DRIVEN FASTNEUTRON SOURCES”, the contents of which are incorporated herein by reference.Technical Field

[0002] This disclosure relates generally to systems and methods used for producing radionuclides using accelerator-driven fast neutron sources, and more specifically to systems and methods for producing actinium-225 using an inherently-safe fast neutron source based on low energy proton accelerators used throughout the world to support positron emission tomography.Background

[0003] High flux (e.g., greater than 1012n / s / cm2) neutrons with energies between 8 and 30 MeV are needed for a number of applications including radioisotope production. However, none of the existing neutron sources available can fulfill these requirements. Neutron flux intensities from typical neutron sources using DT (Deuterium-Tritium fusion) are typically more than 2 orders of magnitude lower in intensity than what is needed for making production practical, DD (Deuterium- Deuterium fusion) sources provide a spectrum which is too low in energy to perform the nuclear reactions needed for isotope production, and high-energy proton accelerator-driven spallation sources produce isotopes with significant co-production of unwanted radioisotopes, due to a neutron spectrum which is far higher in energy than required. While accelerator-driven neutron sources using deuteron breakup have been shown to be a viable pathway for producing a range of isotopes including actinium-225 (see U.S. Patent Appl. Publ. No. US20220199276A1), a limited number of machines capable of producing >30 MeV deuteron beams exist commercially andin research institutions. Conversely, there are more than 1500 medical cyclotrons worldwide (see https: / / nucleus.iaea.org / sites / accelerators / Pages / Cyclotron.aspx), and more than 250 in the USA alone, routinely used for producing Fluorine- 18 and other isotopes used for positron emission tomography (PET), a type of diagnostic medical imaging. These machines, while lower in energy, commonly produce a range of diagnostic and therapeutic isotopes using low-energy (< 30 MeV) proton beams at high beam currents (> 100 uA).

[0004] However, an alternate method using an accelerator-driven fast neutron source based on the proton bombardment of a thick beryllium target is promising as a method for using this existing fleet of cyclotrons to produce a range of emerging radionuclides, including actinium-225. While these methods produce a neutron spectrum which is less intense than that from deuteron breakup, given that deuteron accelerators are less commercially available, these methods offer a pathway to utilize the large number of low-energy proton accelerators around the world to vastly increase production throughput of the valuable therapeutic radioisotope actinium-225, as well as a range of other established and emerging medical radioisotopes.Summary

[0005] Actinium-225 is a promising candidate as a therapeutic alpha-emitting radioisotope for the treatment of a range of cancers. Described herein are methods to produce actinium-225 that are efficient, avoid production of unwanted impurities that would hinder its use for clinical patients, and allow for simple production using a significant fraction of the world’s existing medical cyclotrons and accelerators. These methods involve the irradiation of the naturally-occurring isotope radium-226 with an energetic neutron beam, itself produced by the bombardment of a beryllium target with a proton beam. This irradiation converts a small portion of a radium-226 sample into the radioisotope radium-225, which decays to actinium-225, which can then be radiochemically separated from the remaining radium-226 for use in producing actinium-225 - based radiopharmaceuticals. The unused radium-226 can then be recovered and reused for further actinium-225 production. These methods can also be used for the design of systems, specifically a target assembly, which existing medical cyclotrons could utilize to produce both fluorine- 18 and actinium-225 using the same target assembly.

[0006] Details of one or more embodiments of the subject matter described in this specification are set forth in the accompanying drawings and the description below. Other features, aspects, and advantages will become apparent from the description, the drawings, and the claims. Note that the relative dimensions of the following figures may not be drawn to scale.Brief Description of the Drawings

[0007] FIG. 1 shows a flow diagram illustrating one example of a process for producing actinium-225.

[0008] FIG. 2 shows a graph of one example of the neutron emission spectrum from a proton beam of approximately 19 and 17 MeV, in comparison with the production rates (cross sections) for the226Ra(n,2n)225Ra reaction used for producing actinium- 225 using the methods described herein.

[0009] FIG. 3 shows a schematic diagram of an example of an arrangement to perform the methods described herein.

[0010] FIG. 4 shows a flow diagram illustrating one example of a process for producing additional radionuclides simultaneously with actinium-225.

[0011] FIG. 5 shows a schematic diagram of one example of an arrangement for producing flourine-18, actinium-225, and other radionuclides simultaneously using the methods described herein.

[0012] FIG. 6 shows a schematic diagram of tone example of the proton target used for producing a beam of neutrons.

[0013] FIG. 7 shows an example of a complete model of one embodiment of the proton target.Detailed Description

[0014] Reference will now be made in detail to some specific examples of the invention including the best modes contemplated by the inventors for carrying out the invention. Examples of these specific embodiments are illustrated in the accompanying drawings. While the invention is described in conjunction with these specific embodiments, it will be understood that it is not intended to limit the invention to the described embodiments. On the contrary, it is intended to coveralternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

[0015] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. Particular example embodiments of the present invention may be implemented without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present invention.

[0016] Various techniques and mechanisms of the present invention will sometimes be described in singular form for clarity. However, it should be noted that some embodiments include multiple iterations of a technique or multiple instantiations of a mechanism unless noted otherwise.

[0017] The terms “about” or “approximate” and the like are synonymous and are used to indicate that the value modified by the term has an understood range associated with it, where the range can be ± 20%, ± 15%, ± 10%, ± 5%, or ± 1%. The terms “substantially” and the like are used to indicate that a value is close to a targeted value, where close can mean, for example, the value is within 80% of the targeted value, within 85% of the targeted value, within 90% of the targeted value, within 95% of the targeted value, or within 99% of the targeted value.

[0018] Described herein are methods of producing actinium-225 that is free of contamination from both fission fragments and actinium-227. The fast-neutron method described herein can produce actinium-225 having a radiochemical purity of 99.9999% (i.e., three orders of magnitude better than the spallation method). This radiochemical purity of the actinium-225 can be further improved by means of chemical separations (i.e., at least with respect to the actinium-227 contaminant). These production methods could be used by pharmaceutical companies to produce 225 -actinium labeled to prostate-specific membrane antigen-617 (PSMA-617) for use in cancer treatment, as well as a range of other therapeutic radiopharmaceuticals incorporating actinium-225. These methods are thus not limited just for use with current radiopharmaceuticals, as they produce actinium-225 in sufficiently high purity to enable incorporation into a range of future radiopharmaceuticals as new developments are made.

[0019] The methods described herein use secondary neutrons from proton bombardment of a thick beryllium target to produce radioisotopes. The protons can be accelerated using a charged particle accelerator, such as a cyclotron, a Van de Graff accelerator, a pelletron, a radio frequency quadrupole (RFQ) linear accelerator (linac), a tandem linac, or a synchrotron, for example. Generating neutrons in this manner using a charged particle accelerator allows for the production of what is referred to in the art as a “forward-focused” neutron source, that is, a neutron source which focuses most of, a majority of, or all of the neutrons in approximately the same direction (one which is within approximately a few degrees of being parallel to the incident proton beam) at a target (e.g., a radium target), an advantage over reactor-based and neutron generator-based production techniques. Also, about 95 percent of the generated neutrons pass through a primary target (in some embodiments, with a mass of multiple grams), so there is the potential to use those neutrons to strike a secondary target.

[0020] A distinction between the methods of the present disclosure and production using reactor-based on neutron generator-based neutron sources should be noted, as these latter two methods are inherently not forward- focused, but, rather, are “isotropic” neutron sources, that is, ones where neutrons are emitted in all directions with approximately equal likelihood. Rather than the narrow “cone” of neutrons in a forward- focused source, isotropic sources are more of a “sphere”-shaped source, meaning that few of the produced neutrons are actually made incident upon the target to be used for production. This means that, either intentionally or unintentionally, nearly all isotropic sources inherently “moderate”, that is, reduce the average energy of each neutron, lowering the efficacy of production, as well as unintentionally producing unwanted contaminants through other nuclear reactions such as thermal neutron capture (also known as “(n, γ )”). An additional advantage of these methods is that the proton beam is never made incident upon the neutron target, as well as that fast neutrons do not deposit any appreciable heat (e.g., less than 0.1 mW) in the neutron target. These advantages mean that these methods do not suffer from the same issues with melting, burning, or target vaporization which other methods for actinium-225 production suffer from.

[0021] Over 1500 medical and research accelerators exist worldwide, and more than 250 exist in the USA as of 2019. While all of these accelerators are capable ofproducing proton beams, not all of them are capable of producing a neutron beam suitable for use in producing actinium-225 or other radioisotopes. Neutrons with a minimum energy of approximately 7 MeV are required to be able to perform the nuclear reactions for transmuting radium-226 into radium-225, namely the226Ra(n,2n)225Ra reaction. Only accelerators capable of producing proton beams of approximately 16 MeV or higher will be capable of producing neutrons of sufficient energy for making actinium-225 from a radium-226 target. Lower energy proton beams may have lower production rates, to the extent that such production rates are not feasible. At present, there are at least 120 cyclotrons in the USA capable of producing proton beams with an energy > 16 MeV, and thus capable of producing radium-225 and actinium-225 through these methods. Higher energy proton beams will increase the neutron yield, and thus, actinium-225 production rates, though above a certain energy, the produced neutrons will have sufficient energy to induce fission reactions in the radium-226, leading to a contaminated product. No such measurement of this energetic threshold has been performed to date, but theoretical predictions suggest it to occur for proton beams above 30 MeV.

[0022] The disclosed methods of producing actinium-225 use the226Ra(n,2n)225Ra reaction followed by β-decay of the radium-225 into actinium-225 (ti / 2=14.9±40.2 days). The actinium-225 is then chemically separated from the unreacted radium-226.

[0023] FIG. 1 shows an example of a flow diagram illustrating a process for producing actinium-225. Starting at block 102 of the method 100 shown in FIG. 1, a target is irradiated with a beam of protons to generate a beam of neutrons. In some embodiments, the beam of protons is about 0.5 centimeter (cm) to 5 cm in diameter, about 1 cm to 1.5 cm in diameter, or about 1.5 cm in diameter. In some embodiments, the target comprises a beryllium target. In some embodiments, the beryllium target is about 1 millimeter (mm) to 8 mm thick, or about 3 mm thick. Some advantages of using a beryllium target include beryllium being a relatively inexpensive material, the good mechanical and thermal properties of beryllium, beryllium not becoming radiologically activated with proton or neutron irradiation, and a high yield of neutrons out per proton in with proton irradiation. In some embodiments, the target is selected from a group consisting of a beryllium, aluminum, boron, carbon, tantalum, tungsten or a gold target if the goal is to optimize a different radionuclide.

[0024] In some embodiments, the target is disposed proximate to the radium-226 target. In some embodiments, the target is positioned about 0.5 millimeters to 1 millimeter from the radium-226 target. In some embodiments, the target is positioned about 0.5 millimeters to 10 millimeters from the radium-226 target. In some embodiments, the target is positioned about 10 millimeters from the radium-226 target. In some embodiments, the target and the radium-226 target are not in contact.

[0025] In some embodiments, the target is held in a water-cooled fixture. Power (e.g., about 100 Watts to 30,000 Watts) is deposited in the target when the target is irradiated with protons. This power causes the target to heat up. The water-cooled fixture can cool the target.

[0026] In some embodiments, protons in the beam of protons have an energy of about 12 megaelectron volts (MeV) to 30 MeV, or about 19 MeV. In some embodiments, the beam of protons is generated using a charged particle accelerator (e.g., a cyclotron). In some embodiments, the beam of neutrons has a flux of about 1x1010neutrons / cm2 / sec to 5x1014neutrons / cm2 / sec. In some embodiments, neutrons in the beam of neutrons have an energy of about 10 MeV or greater. In some embodiments, these neutrons are forward- focused, and not produced by a reactor or neutron generator. In some embodiments, production rates for225Ra and225Ac will increase with increasing proton beam energies above 19 MeV. In some embodiments, the neutron yield for proton beams below approximately 14 MeV will drop off to the point that production rates for225Ra and225Ac below this point will be insignificant to the point of having no practical value for production.

[0027] In some embodiments, an about 10 micro-A to 1 milli-A beam of protons having an energy of about 19 MeV irradiates a beryllium target. This generates a beam of neutrons having a flux of about 1x1010neutrons / cm2 / sec to 5x1014neutrons / cm2 / sec. The flux of the neutron beam is dependent on the incident energy and the intensity of the proton beam. Generally, the higher the incident energy of the beam of protons, the higher the flux of the beam of neutrons.

[0028] In some embodiments, the neutrons are not thermal neutrons generated in a nuclear reactor. In some embodiments, the neutrons are not generated by a spallation source. Thermal neutrons are generally considered to be neutrons with an energy of less than about 10 kiloelectron volts (keV). Thermal neutrons have an average energy of about 25 millielectron volts (meV). A large percentage (e.g., about 95% to 99%) ofthe neutrons generated with a cyclotron in the methods described herein are considered to be fast neutrons, or neutrons with an energy about 1 MeV and higher.

[0029] In some embodiments, an initial diameter of the beam of neutrons (i.e., a diameter of the neutron beam being emitted from the target) is about the diameter of the beam of protons, or about 1 cm to 5 cm in diameter, about 1 cm to 1.5 cm in diameter, or about 1.5 cm in diameter.

[0030] The beam of neutrons is forward-focused beam rather than isotropic. FIG. 2 shows an example of a graph of the percentage of neutrons in the neutron beam versus the neutron energy. 0 degrees is a neutron that is emitted in the same direction as a proton in the beam of protons. Overlaid onto this graph is the225Ac cross section, that is, the probability of the226Ra(n,2n)225Ra reaction as a function of the neutron energy. This shows that a large percentage of the neutrons produced with these methods have enough energy to produce actinium-225 efficiently. This percentage also clearly increases with higher proton energy.

[0031] Turning back to FIG. 1, at block 104, a radium-226 target is irradiated with the beam of neutrons to generate radium-225. Radium-226 is a naturally-occurring radioactive isotope of radium. In some embodiments, the radium-226 target reacts to form the radium-225 by a (n,2n) reaction. In some embodiments, the radium-226 target is not positioned in a nuclear reactor, a neutron generator, or a spallation neutron source. In some embodiments, the radium-226 target is irradiated with the beam of neutrons for a time period of at least 1 day. In some embodiments, the radium-226 target is about 1 mm to 30 mm thick.

[0032] In some embodiments, the radium-226 target comprises a radium-226 salt. Radium-226 salts include radium nitrate (Ra(NO3)2) and radium chloride (RaCh). In some embodiments, the radium-226 salt target has a mass of about 1 milligram (mg). For larger scale production of actinium-225, the radium-226 salt target may have a mass of about 100 mg to 1 gram (g), or about 100 mg to 10 g. In some embodiments, the radium-226 target may be sealed in a variety of containers to avoid the loss or spread of radium-226 before, during, or after irradiation, and / or to assist in handling and / or shipping of the radium-226 target. In some embodiments, this container may be a container of aluminum, a container of niobium, a container of quartz, a container of glass, a container of borosilicate glass, or the like. In some embodiments, this container may have a wall thickness between 1 mm and 20 mm, or about 10 mm. Insome embodiments, this sealed container of radium-226 may be shipped following irradiation, for offsite separation of actinium-225 from the irradiated radium-226 target.

[0033] Irradiating the radium-226 target with a beam containing thermal neutrons may generate radium-227. Radium-227 beta-decays to actinium-227 with a 42 minute half-life, allowing it to be separated from the sample prior to the harvesting of the actinium-225 from the decay of radium-225, which has a 14.9 day half-life . In some embodiments, irradiating the radium-226 target with the beam of fast neutrons does not generate any actinium-227 or any species that decays to actinium-227.

[0034] At block 106, at least some of the radium-225 is allowed to decay to actinium- 225 over a period of time. In some embodiments, the radium-225 decays to actinium- 225 by beta decay. In some embodiments, the generation of actinium-225 by beta decay of radium-225 is what avoids the generation of actinium-227 and leads to the high purity of the generated actinium-225. In some embodiments, the period of time is at least about 30 days or about 30 days. In some embodiments, the period of time is at least about 15 days or about 15 days.

[0035] In some embodiments, when actinium-227 is present or may be present in the radium-226 target, about 1 hour to 5 hours, or about 2 hours, after the radium-226 target is irradiated with neutrons, a chemical process is used to separate actinium from the radium. This actinium is disposed of, as this actinium will contain most of or all of the actinium-227 produced from beta-decay as a result of the irradiation. Following this chemical separation, all subsequent actinium collected from this irradiation will be actinium-225 because radium-225 has a much longer half-life than radium-227. As a result, most of the actinium-225 will still be available for separation without the actinium-227 contaminant. Then, at least some of the radium-225 decays to actinium- 225 over a period of time.

[0036] Turning back to FIG. 1, at block 108, the actinium-225 is separated from unreacted radium-226 and the radium-225. In some embodiments, the actinium-225 is separated from unreacted radium-226 and the radium-225 using a chemical separation process. In some embodiments, after separating the actinium-225 from unreacted radium-226 and the radium-225, the actinium-225 does not include any actinium-227. In some embodiments, after separating the actinium-225 from unreacted radium-226 and the radium-225, the actinium-225 consists essentially of actinium-225. Furtherdetails regarding illustrative methods for separation of actinium-225 from radium-226 and radium-225 can be found in U.S. Patent Application No. 16 / 329,178 filed February 27, 2019, U.S. Patent Application No. 16 / 365,132 filed March 26, 2019, and U.S. Patent Application No. 16 / 336,665 filed March 26, 2019, all of which are herein incorporated by reference.

[0037] In some embodiments, prior to irradiating the radium-226 target with the beam of neutrons, the radium-226 target is chemically cleaned to remove any radium-228 and any thorium-228 from the radium-226 target. This cleaning may be performed with a chemical process. Removing radium-228 and thorium-228 from the target prevents actinium-228 from forming and keeps actinium-228 out of the actinium-225 that is generated.

[0038] FIG. 3 shows an example of a schematic diagram of a setup to perform the methods described herein. As shown in FIG. 3, a charged particle accelerator 205 generates a beam of protons 210. The beam of protons 210 irradiate or impinge on a proton target 215 (e.g., a target of beryllium) to generate a beam of neutrons 220. The beam of neutrons 220 has spread of an angle 225 of about 15 degrees. About 30% of the neutrons generated from the proton target 215 are within the cone having the spread of about 15 degrees. The beam of neutrons 220 irradiates a radium-226 target 230.

[0039] In some embodiments, either prior to or after irradiating the beryllium target with the beam of protons, the beam of protons passes through a liquid water target. In some embodiments, the water target may have a cavity volume between about 1 mL and 8 mL, or approximately 4 mL. In some embodiments, passing protons through a water target where the water is water enriched in oxygen- 18 (“18O water”) produces the fluorine- 18 radioisotope by a (p,n reaction). In some embodiments, this fluorine- 18 may be collected for use in preparing the radiopharmaceutical [18F]Fluorodeoxyglucose (FDG, or18FDG). In some embodiments, passing protons through a water target where the water is water enriched in hydrogen-2 (“deuterated water” or “heavy water”) produces a neutron beam with a spectrum similar to that produced by proton bombardment of a beryllium target. In some embodiments, this neutron beam may be used to supplement, along with the neutron beam produced by the beryllium target, to irradiate the same radium-226 target to produce radium-225,which decays to actini um-225. However, in these embodiments, the beryllium target still remains the “primary” target for production of the majority of neutrons.

[0040] Irradiating other targets with secondary neutrons from the proton bombardment of a beryllium target and / or a heavy water target can be used to produce other radioisotopes. For example, a zinc target (i.e., zinc-64 and zinc-67) irradiated with this neutron beam would produce copper-64 and copper-67. Other radioisotopes that could be produced include, bismuth-213, gallium-68, radium-223, thorium-229 and thorium-227, lead-212, and the like. Yet further radioisotopes that could be produced are listed below in Table 1, including the isotope to be irradiated and the reaction to form the radioisotope.Table 1 : Radionuclide production pathways

[0041] FIG. 4 shows an example of a flow diagram illustrating a process for producing a radionuclide. At block 402 of the method 400 shown in FIG. 4, a target is irradiated with a beam of protons to generate a beam of neutrons, as detailed in FIG. 1 previously. At block 404, a target selected from a group of targets consisting of a radium-226 target, a sulfur target, a zinc target, an yttrium target, a palladium target, a samarium target, a europium target, a terbium target, a dysprosium target, an erbium target, a thulium target, a lutetium target, a hafnium target, a molybdenum target, a germanium target, a tantalum target, and an osmium target is irradiated with the beam of neutrons.

[0042] FIG. 5 shows an example of a schematic diagram of a setup to perform the methods described herein. As shown in FIG. 5, a charged particle accelerator 505 generates a beam of protons 510. The beam of protons 510 irradiate or impinge on a target assembly 560 that includes a beryllium target 517, a window foil 519 and a water target 515. The beam of protons 510 irradiates or impinges on the berylliumtarget 517 before irradiating or impinging the window foil 519 before irradiating or impinging the water target 515 (e.g., a heavy water target or18O water target) to generate a beam of neutrons 520. In some embodiments, this water target may be of a cylindrical or conical geometry. In some embodiments, this water target may have a fill volume of approximately 0.5 mL to 8 mL of water, or approximately 3 mL. In some embodiments, a fast neutron beam will be generated in the beryllium target 517 (as described in FIG. 1), and / or in the window foil 519, and / or in the water target 515. The relative neutron flux generated in these three targets are dependent upon the thickness of each target and the proton beam energy, as described previously above. In some embodiments, the window foil may be a foil of Havar, a foil of titanium, or a foil of niobium. In some embodiments, the window foil 519 is about 10 um to 200 um thick, or about 50 um thick. In some embodiments, the beam of neutrons 520 irradiates a plurality of targets. Shown in FIG. 5 are a first neutron target 530, a second neutron target 535, and a third neutron target 540, selected from those listed in block 404 of FIG. 4. More targets could be included. In some embodiments, the targets 430, 435, and 440 are each about 0.1 mm to 0.5 mm thick, or about 1 mm to 20 mm thick. In some embodiments, the beryllium target 519 and / or window foil 519 may be cooled using water, helium gas, or cold helium gas.[0043 J The neutrons do not lose much energy passing through a single target and most of the neutrons in the beam of neutrons do not interact with a single target. The majority of neutrons pass through most matter with no electronic interactions. For a target that the neutrons impinge on, a very thick target could be used (e.g., up to about 10 cm thick), a plurality of target materials as shown in FIG. 4 could be used (e.g., up to about 10 cm thick, depending on the density of the material of the targets), or combinations thereof.

[0044] In some embodiments, a target assembly 560 as described in FIG. 5 may be used to produce fluorine- 18 at the same time as radium-225 and / or actinium-225, and / or the other radioisotopes listed in Table 1. In some embodiments, a target as described in FIG. 5 may be used to produce radium-225 and / or actinium-225, and / or the other radioisotopes listed in Table 1, after finishing production of fluorine- 18 in a water target. In both cases, this is because a forward- focused and fast neutron flux (as described previously above) will be generated in both the beryllium target, window foil, and water target. This neutron flux may be used to irradiate or impinge on one ormore targets for the production of radium-225 and / or actinium-225, and / or the other radioisotopes listed in Table 1, while the protons irradiating or impinging upon the water target produces fhiorine-18 via the18O(p,n)18F reaction. In some embodiments, the beryllium target may be removed out of the path of the proton beam to irradiate or impinge upon the window foil and water target to produce fluorine- 18 in the water target, and avoid producing neutrons in the beryllium target. In some embodiments, this may be accomplished via gravity, by rotating, withdrawing or sliding using a motorized attachment or pneumatic attachment, or the like, to avoid placing the beryllium target in the path of the proton beam. In some embodiments, the18O water in the water target may be pumped out of the water target after fluorine- 18 production is finished, to separate out the fluorine- 18 from the18O water, and recycle the unused18O water. In some embodiments, after pumping the18O water out, heavy water may be pumped back into the water target, to both cool the beryllium target and / or window foil, as well as to produce additional neutron flux from protons irradiation of the heavy water target as described above. In some embodiments, at a later time, the heavy water may be pumped out of the water target, and18O water may be pumped back in, to resume production of fluorine- 18. In this way, one target as described in FIG. 5 may be used to alternate between producing fluorine- 18 alone, producing radium-225 and / or actinium-225 alone, producing a subset of the radionuclides listed in Table 1 alone, or some combination thereof, based on the insertion of a beryllium target, and the selection of which water target and / or neutron targets are loaded.

[0045] Turning back to FIG. 5, in some embodiments, the target assembly 560 may be surrounded by supplemental neutron shielding 590. This shielding may be composed of a plurality of polyethylene, borated polyethylene, water-extended polyester (WEP) resin, paraffin, concrete, high density concrete, lead, or hydrogenous polymers. In some embodiments, this shielding may range from 1 cm to 50 cm in thickness, or 10 cm to 100 cm in thickness, or approximately 20 cm. This supplemental neutron shielding may be placed surrounding the target assembly, to reduce the dose field generated during irradiation of the target assembly, to levels within the cyclotron manufacturer’s advertised dose fields, i.e., producing no higher radiation fields than those already present during routine operation of the cyclotron using commercial18O water targets. In some embodiments, the neutron targets (including a radium-226 target) selected from a subset of those listed in Table 1, maybe loaded upwards out of a shielded shipping container 550, using pneumatic arms, motorized attachments, or the like. In some embodiments, this shielded shipping container may be made from lead or tungsten. In some embodiments, this shielded shipping container may have wall thicknesses and lid thickness of 0.5 cm to 8 cm, or approximately 3 cm. In some embodiments, following the end of irradiation of the neutron target(s), the loading system may return the irradiated neutron targets back into the shielded shipping container and close the lid, making it safe for workers to handle the irradiated neutron targets either by hand, or using remote handling systems.

[0046] Turning back to FIG. 1 and FIG. 3, the design of the proton target 215 is crucial to obtaining a sufficiently high neutron flux to meet the required production rate of actinium-225 or a subset of the radionuclides listed in Table 1. Namely, this design represents a balancing between providing sufficient cooling of the heat deposited by the proton beam in the proton target, while accomplishing this in a compact design. While the cooling challenge can be trivially mitigated through large amounts of cooling channels or convective heat transfer interfaces, this increases the size of the target assembly, lowering the neutron flux received by the neutron target, and reducing production rates. Tn some embodiments, FIG. 6 shows an example of a cross-sectional schematic design of the proton target used for producing a beam of neutrons in the above embodiments. In FIG. 6, the proton beam 605 is incident upon the proton target assembly 610, to generate the forward- focused neutron beam described in FIG. 1, to be used to irradiate neutron target 650. In some embodiments, the proton target is disposed proximate to the neutron target. In some embodiments, the proton target is positioned about 0.5 millimeters to 1 millimeter from the neutron target. In some embodiments, the proton target is positioned about 0.5 millimeters to 10 millimeters from the neutron target. In some embodiments, the proton target is positioned about 10 millimeters from the neutron target. In some embodiments, the proton target and the neutron target are not in contact.

[0047] Proton target assembly 610 is composed of proton targets 620 and 640. In some embodiments, these targets comprise a beryllium target. In some embodiments, these targets are selected from a group consisting of a beryllium, aluminum, boron, carbon, tantalum, tungsten or a gold target if the goal is to optimize a different radionuclide. In some embodiments, proton target 620 is thicker than proton target640, as the majority of the neutron beam is produced in proton target 620. In some embodiments, the proton target 620 is about 1 millimeter (mm) to 8 mm thick, based on the energy of the proton beam, or about 3 mm thick. In some embodiments, the proton target 640 is about 0.1 millimeter (mm) to 4 mm thick, based on the material of the target, or about 1 mm thick. These proton targets are supported in proton target assembly 610 by target body 615. In some embodiments, this target body is selected from a group consisting of a beryllium, aluminum, copper, OFHC copper, stainless steel, or carbon fiber target body. The space between proton target 620 and proton target 640 is coolant channel 630, through which flows coolant to remove the heat deposited by proton beam 605 in proton target 620. In some embodiments, this coolant is selected from a group consisting of a water, a low-conductivity water, a nitrogen, a helium, or a chilled helium coolant. In some embodiments, the coolant flows at a flow rate of approximately 1 to 10 gallons / minute, or about 5 gallons / minute. Tn some embodiments, the coolant flows at a linear velocity of approximately 1 to 20 meters per second, or about 10 meters per second. In some embodiments, the coolant has an inlet temperature of approximately 5 to 30 degrees Celsius, or about 25 degrees Celsius. In some embodiments, the coolant has an outlet temperature of approximately 25 to 60 degrees Celsius, or about 42 degrees Celsius. In some embodiments, the coolant has a pressure drop (from inlet to outlet) of approximately 5 to 25 psi, or about 11 psi. In some embodiments, proton targets 620 and 640 form a seal around coolant channel 630 by mounting into target body 615 using methods selected from a group consisting of o-ring seals, brazing to target body 615, or flanges.

[0048] FIG. 7 shows an example of a complete model of one embodiment of the proton target described schematically in FIG. 6. In some embodiments, target assembly 700 shows the coolant connections 710, where coolant flows in and out of the target assembly through coolant channel 630. In some embodiments, these connections may be selected from a group consisting of Swagelok fittings, friction- fit connections, soldered fittings, or hose clamp fittings. In some embodiments, view 720 shows a cutaway viewpoint of target assembly 700, revealing the internal structure 740 of target assembly, as depicted schematically in FIG. 6. Target flange 730 allows the target assembly 700 to be mounted on the beamline of a cyclotron or accelerator for use in producing radionuclides using the methods described herein. In someembodiments, this flange may be selec ted from a group consisting of KF flanges, CF flanges, ISO flanges, or ASA flanges. In some embodiments, the dimensions of this flange are approximately 1 to 6 inches in internal diameter, or about 4 inches in internal diameter, based on the beamline dimensions to be mounted onto.

[0049] In the foregoing a method for producing a radioisotope and a target assembly in accordance with the present disclosure has been described with reference to specific embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

Claims

Claims1. A method of producing a radioisotope, comprising: irradiating a proton target with a beam of protons to produce a beam of neutrons; irradiating at least one neutron target with the beam of neutrons to produce a specified radioisotope.

2. The method of claim 1, wherein the specified radioisotope is radium-225.

3. The method of claim 2, wherein the radium-225 decays to actinium-225 and further comprising separating the actinium-225 from unreacted radium-226 and radium-2254. The method of claim 1, wherein the proton target is a beryllium target.

5. The method of claim 1, wherein the neutron target is a radium-226 target.

6. The method of claim 1, where the proton beam is not incident upon the neutron target.

7. The method of claim 1 , where the neutron target does not receive more than 0.1 mW of heat while being irradiated by neutrons.

8. The method of claim 1, further comprising producing the proton beam with a charged particle accelerator selected from the group consisting of a cyclotron, a Van de Graff accelerator, a pelletron, a radio frequency quadrupole (RFQ) linear accelerator (linac), a tandem linac, or a synchrotron.

9. The method of claim 1, further comprising producing the proton beam with a medical cyclotron that produces medical isotopes.

10. The method of claim 1, wherein the neutron target is selected from the group consisting of a sulfur target, a zinc target, a yttrium target, etc.

11. The method of claim 1, further comprising irradiating a water target with the proton beam such that the proton beam irradiates the proton target before irradiating the water target.

12. The method of claim 11, wherein the water target includes18O- water.

13. The method of claim 11, wherein the water target includes heavy water.

14. The method of claim 11, wherein the water target generates a second beam of neutrons and Fluorine- 18, and further comprising irradiating a secondary target with the second beam of neutrons.

15. The method of claim 14, wherein the secondary target is the neutron target.

16. The method of claim 14, wherein the secondary target is selected from the group consisting of a sulfur target, a zinc target, a yttrium target, etc.

17. A target assembly, comprising: a proton target for producing a first neutron beam when irradiated with a proton beam;, the proton target being selectively movable into and out of the proton beam; a water target aligned with the neutron target such that the water target is irradiated with by the proton beam after traversing the proton target to produce a second neutron beam; and at least one neutron target arranged to receive the first neutron beam.

18. The target assembly of claim 17, wherein the neutron target is further arranged to receive the second neutron beam.

19. The target assembly of claim 17, further comprising a window foil disposed before or between the proton target and the water target such that the window foil produces a neutron flux that contributes to the first beam of neutrons.

20. The target assembly of claim 17, wherein at least one neutron target includes a plurality of neutron sources, the plurality of neutron sources being arranged so that neutrons traverse a first of the neutron sources irradiates a second of the neutron sources.

21. The target assembly of claim 17, wherein at least one neutron target may be remotely transferred to or from a shielded transport container during operation.

22. A supplementary radiation shield surrounding the target assembly of claim 15, wherein a radiation dose during irradiation is reduced to be no higher than during operation of existing water targets for flourine-18 production.

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