Method and system for producing isotopes

Abstract

A method for producing Pb-212 and Ac-225 isotopes is disclosed. The method comprises irradiating a target comprising Ra-226 with charged particles and / or photons to produce at least Ac-225 isotopes and Ac-224 isotopes. The method further comprises, after a cooling time, applying chromatography to separate actinium from the remaining radium-containing fraction. The method also comprises, after a first further waiting time, applying extraction chromatography using a resin with 18-crown-6 ether or an equivalent of 18-crown-6 ether as extractant in HNO3 and / or HCl to separate Pb from the remaining radium-containing fraction.

Description

Technical Field

[0001] This invention relates to the field of nuclear medical science. More specifically, this invention relates to methods and systems for producing isotopes and the isotopes obtained therefrom. Background Technology

[0002] Ac-225 is well known to have clinical applications in nuclear medicine, such as radiotherapy for malignant tumors. One method of producing Ac-225 is by irradiating a Ra-226 target (e.g., RaCl2) with protons. When Ra-226 (Tl / 2: 1600y) is irradiated with low-energy (10-25 MeV) protons, Ac-225 (Tl / 2: 10d) is formed in the Ra-226(p,2n)Ac-225 nuclear reaction. Around 14 MeV, the threshold energy for the (p,3n) reaction is reached, resulting in the production of Ac-224 (Tl / 2: 2.9h), which rapidly decays into Ra-224 (Tl / 2: 3.66d).

[0003] After irradiation, Ac-225 must be purified from Ra and its progeny (e.g., Pb, Po, and Bi) before it is used.

[0004] However, Pb-212, which decays into Bi-212 (Tl / 2: 10.64h), is also an isotope of interest suitable for targeted alpha therapy (TAT). Due to the difference in half-life and the shorter decay chain, Pb-212 is not considered a direct competitor to Ac-225, but rather a competitor to At-211 (Tl / 2: 7.22h).

[0005] Because the sources for producing medical isotopes are limited, there is a need for efficient methods and systems for producing medical isotopes. Summary of the Invention

[0006] The purpose of embodiments of the present invention is to provide a good system and method for producing medical isotopes and to provide the isotopes obtained therefrom.

[0007] An advantage of the embodiments of the present invention is that the associated production of the Pb-212 isotope is obtained as a byproduct of the production of the Ac-225 isotope, an important isotope for targeted alpha therapy. The Pb-212 isotope is also such an important isotope for targeted alpha therapy. An advantage of the embodiments of the present invention is that the Ac-224 produced during the production of the Ac-225 isotope is advantageously used to derive the Pb-212 isotope therefrom, rather than ignoring this portion and treating it as an undesirable byproduct.

[0008] This invention relates to a method for producing Pb-212 and Ac-225 isotopes, the method comprising:

[0009] A target containing Ra-226 is irradiated with charged particles and / or photons to produce at least Ac-225 and Ac-224 isotopes.

[0010] After the cooling time, chromatography was used to separate actinium from the remaining radium-containing fraction, and

[0011] After the first further waiting time, extraction chromatography using a resin with 18-crown-6 ether or an equivalent of 18-crown-6 ether as an extractant in HNO3 and / or HCl is applied to separate Pb from the remaining radium-containing fraction.

[0012] Separating actinium from the remaining radium-containing fraction can be done by applying extraction chromatography.

[0013] Alternatively, the separation of actinium from the remaining radium-containing fraction can be performed using ion-exchange chromatography with a cation-exchange column. In ion-exchange chromatography, these elements are separated by utilizing the charge difference between Ra(2+) and Ac(3+).

[0014] Targets containing Ra-226 include any one of RaCl2, Ra(NO3)2, Ra(OH)2, or RaCO3. An advantage of the embodiments of the present invention is that different types of targets containing Ra-226 can be used.

[0015] The use of charged particles for radiation includes radiation with protons and / or radiation with deuterium nuclei. An advantage of the various embodiments of the invention is that both proton radiation and / or deuterium radiation can be used.

[0016] The method may further include, when using deuterium radiation, producing Ra-225 isotope in addition to producing at least Ac-225 and Ac-224 isotopes.

[0017] In some embodiments, radiation with charged particles may include or be radiation with protons having an incident beam energy of at least 15 MeV (e.g., between 15 MeV and 30 MeV, such as about 22 MeV, such as between 18 MeV and 30 MeV, such as between 18 MeV and 25 MeV)).

[0018] In some embodiments, radiation with charged particles may include or be radiation with deuterium nuclei. Radiation with deuterium nuclei may be radiation with deuterium nuclei having an incident beam energy of at least 20 MeV (e.g., between 20 MeV and 60 MeV, e.g., between 20 MeV and 50 MeV, e.g., about 27 MeV)).

[0019] The advantage of the various embodiments of the present invention is that, during the production of Ac-225 isotopes, the co-production of Ac-224 isotopes can be maximized, thereby providing a maximization of the possibility of producing Pb-212 isotopes while maintaining efficient Ac-225 isotope production.

[0020] Radiation using photons can include radiation with high-energy photons such as gamma photons (e.g., photons with energies >6.4 MeV). An advantage of the embodiments of the invention is that the production of Ac-225 is relatively clean, as only small amounts of other Ac isotopes are produced, or even none at all. In the embodiments, the photons have energies >12 MeV, where 12 MeV is the threshold for producing Ra-224 / Pb-212.

[0021] After a second further waiting time applied after the first further waiting time, the method may include applying further extraction chromatography to further separate Pb from the remaining radium-containing fraction.

[0022] An advantage of the various embodiments of the present invention is that additional Pb-212 isotopes can be generated due to the further decay of radium. This process can be repeated until the amount of Pb-212 is no longer sufficient to cover the processing costs.

[0023] In various embodiments, the equivalent of 18-crown-6 ether can be any compound having extraction chromatographic functionality equivalent to that of 18-crown-6 ether for Pb. In various embodiments, the equivalent of 18-crown-6 ether can be any compound comprising a cyclic chain of carbon and oxygen atoms, the cyclic chain of carbon and oxygen atoms being equivalent to the cyclic chain of carbon and oxygen atoms included in 18-crown-6 ether. In various embodiments, the equivalent of 18-crown-6 ether can differ from 18-crown-6 ether because the equivalent includes one or more substituents on the cyclic chain, the substituents comprising a saturated or unsaturated hydrocarbon, possibly containing heteroatoms, on one or more carbon atoms, i.e., replacing one or more hydrogen atoms of 18-crown-6 ether. In various embodiments, the equivalent includes at least one π bond between two adjacent carbon atoms of the cyclic chain. In various embodiments, the equivalent of 18-crown-6 ether includes benzo-18-crown-6 ether or dibenzo-18-crown-6 ether, or equivalents thereof.

[0024] Separating Pb from the remaining radium-containing fraction can be based on extraction chromatography using a Sr or Pb resin in HNO3 and / or HCl. This resin can alternatively be any other resin with an 18-crown 6-ether.

[0025] The advantage of the various embodiments of the present invention is that Pb-212 can be generated in a relatively easy manner.

[0026] Radiation using charged particles can include radiation with deuterium nuclei, and the method further includes separating Ac-225 from the remaining radium-containing fraction based on extraction chromatography using DGA.

[0027] The target containing Ra-226 is radiated using a stack of targets with a single radiation beam. The stack of targets includes a first target for radiating with charged particles having a first incident beam energy and a second target for radiating with charged particles having a second incident beam energy higher than the second beam energy. The first and second targets are stacked and arranged such that a single radiation beam first enters the first target and then enters the second target after leaving the first target.

[0028] The advantage of the various embodiments of the present invention is that, by using stacked targets, one target can be optimized for producing Ac-225, and another target can be optimized for jointly producing Ac-225 and Pb-212.

[0029] The extraction chromatography method can be used to separate Pb from the remaining radium-containing fraction, and this can be performed on the first target rather than the second target.

[0030] The advantage of the various embodiments of the present invention is that the second target will have a lower amount of Ac-224, so that there is less contamination of Ac-225 isotope and Ac-225 isotope is available after a shorter cooling time.

[0031] The product of the thickness and density of the first target is higher than that of the second target.

[0032] The present invention also relates to compounds comprising the Pb-212 isotope obtained using the above method.

[0033] The compound may include traces of Pb-210. The concentration relative to the activity of Pb-212, as determined by its activity, may be in the range of 0.00001% to 0.01%, for example, in the range of 0.00005% to 0.01%.

[0034] The present invention also relates to the use of the above-described compounds in targeted alpha therapy.

[0035] The present invention also relates to a target assembly for producing Ac-225 and Pb-212 isotopes, the target assembly comprising a stack of a first radium-containing target and a second radium-containing target.

[0036] The present invention also relates to a chromatographic system for separating Pb from radium-containing fractions, the chromatographic system being an extraction chromatography system using a resin having an 18-crown 6-ether as an extractant in HNO3 and / or HCl. The chromatographic system may use Sr or Pb resin. The chromatographic system may include a DGA resin located below the resin having an 18-crown 6-ether as an extractant. The present invention further relates to a method for separating Pb from radium-containing fractions.

[0037] Specific and preferred aspects of the invention are set forth in the appended independent and dependent claims. Features from the dependent claims may be suitably combined with features of the independent claims and other dependent claims, and not merely as expressly set forth in the claims.

[0038] These and other aspects of the invention will be apparent from the embodiments described herein, and are illustrated with reference to these embodiments.

[0039] Brief description of the attached figures

[0040] Figure 1 The Ra-226 proton reaction cross section and information, which can be used as in various embodiments of the present invention, are explained.

[0041] Figure 2 The Ra-226 deuterium nucleus reaction cross section and information, as can be used in various embodiments of the present invention, are explained.

[0042] Figure 3 A flowchart illustrating the separation of Pb-212 from proton radiation according to an embodiment of the present invention is shown.

[0043] Figure 4 A flowchart illustrating the separation of Pb-212 from deuterium radiation according to an embodiment of the present invention is shown.

[0044] Figure 5 The acid dependence k' of actinides and other selected ions at 23 to 25 °C for loaded Sr resins with particle sizes between 50 and 100 μm is shown, as can be used in various embodiments of the invention.

[0045] Figure 6 The acid dependence k' of alkaline earth metal ions at 23 to 25 °C for loaded resins with particle sizes between 50 and 100 μm is shown, as can be used in various embodiments according to the invention.

[0046] Figure 7The retention factors k' for Ra(ll) and Pb(ll) in HCl for loaded Sr resin, as can be used in various embodiments according to the invention, are shown.

[0047] Figure 8 The factor k' for the selected transition and post-transition elements on HNO3 for TODGA resins (50 and 100 μm) during a 1-hour equilibration time at 22°C is shown, as can be used in various embodiments of the invention.

[0048] Figure 9 The Kd value of Ac, which is dependent on acid concentration, is explained in various Sr resin / acid systems that can be used in the embodiments of the present invention.

[0049] Figure 10 The k' factor for AC-225 relative to [HNO3] or HCl on DGA resin, as can be used in various embodiments of the invention, is explained.

[0050] Figure 11 Examples of stacked target components according to various embodiments of the present invention have been explained.

[0051] Figure 12 The PB-212, which varies with decay time, has been explained, thereby providing information that can be used as in various embodiments of the invention.

[0052] Figure 13 The decay of 5kBq Ra-224 is explained, thereby providing information that can be used as in various embodiments of the invention.

[0053] Figure 14 The decay of 1.5 MBq Ra-225 is explained, thereby providing information that can be used as in various embodiments of the invention.

[0054] Figure 15 The Ra-226 proton reaction cross section and information, which can be used as in various embodiments of the present invention, are explained.

[0055] The accompanying drawings are illustrative only and not restrictive. In the drawings, some elements may be enlarged and not drawn to scale for illustrative purposes.

[0056] Any reference numerals in the claims should not be construed as limiting the scope.

[0057] In different accompanying drawings, the same reference numerals refer to the same or similar elements. Detailed Implementation

[0058] The invention will be described with reference to specific embodiments and certain accompanying drawings, but the invention is not limited thereto but is defined solely by the claims. The described drawings are illustrative only and not restrictive. In the drawings, some elements may be enlarged and not drawn to scale for illustrative purposes. Dimensions and relative dimensions do not correspond to an actual reduction in the implementation of the invention.

[0059] Furthermore, the terms first, second, etc., used in the specification and claims are used to distinguish between similar elements and are not necessarily used to describe an order in time, space, rank, or any other way. It should be understood that the terms thus used are interchangeable where appropriate, and the embodiments of the invention described herein can be operated in a different order than that described or illustrated herein.

[0060] Furthermore, the terms "top," "below," etc., used in the specification and claims are for descriptive purposes and are not necessarily used to describe relative positions. It should be understood that such terms are interchangeable where appropriate, and embodiments of the invention described herein can operate in orientations different from those described or illustrated herein.

[0061] It should be noted that the term "comprising" as used in the claims should not be construed as limiting oneself to the means listed thereafter; it does not exclude other elements or steps. Therefore, the term should be interpreted as specifying the presence of the features, integers, steps, or components stated as mentioned, but does not exclude the presence or addition of one or more other features, integers, steps, or components, or groups thereof. Thus, the scope of the statement "device comprising means A and B" should not be limited to a device consisting solely of components A and B. It means that for the purposes of this invention, the only relevant components of the device are A and B.

[0062] Throughout this specification, the reference to "an embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrase "in an embodiment" or "in one embodiment" appearing in various places throughout this specification does not necessarily refer to all of the same embodiment, but may refer to the same embodiment. Furthermore, in one or more embodiments, particular features, structures, or characteristics that will be obvious to those skilled in the art from this disclosure can be combined in any suitable manner.

[0063] Similarly, it should be understood that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, drawing, or description for the purpose of simplifying the disclosure and aiding in the understanding of one or more inventive aspects. However, this method of disclosure should not be construed as reflecting an intention to claim more features than are expressly recited in each claim. Rather, as reflected in the appended claims, inventive aspects exist in fewer features than all the features of a single foregoing disclosed embodiment. Therefore, the claims appended following the detailed description are thus explicitly incorporated into this detailed description, wherein each claim itself represents a separate embodiment of the invention.

[0064] Furthermore, while some embodiments described herein include features that are included in other embodiments but not others, it will be understood by those skilled in the art that combinations of features from different embodiments are intended to fall within the scope of the invention and form different embodiments. For example, any embodiment of the claimed embodiments in the appended claims can be used in any combination.

[0065] In embodiments of the present invention, when target thickness is mentioned, it is typically expressed not only by the physical thickness itself, but also by the product of the physical thickness and the density. Therefore, the thickness can be expressed in g / cm³. 2 To express.

[0066] Numerous specific details are set forth in the description provided herein. However, it should be understood that embodiments of the invention may be practiced without these specific details. In other instances, well-known methods, structures, and techniques have not been shown in detail so as not to obscure the understanding of this description. A method for producing Pb-212 and Ac-225 isotopes is described. In addition to these isotopes and depending on the charged particles and / or photons used, the production of Ra-225 isotope is also contemplated. These isotopes can be advantageously used for medical applications. The method comprises irradiating a target containing Ra-226 with charged particles and / or photons to produce at least Ac-225 and Ac-224 isotopes, and optionally Ra-225. The target containing Ra-226 may, for example, include any of RaCl2, Ra(NO3)2, Ra(OH)2, or RaCO3.

[0067] In some embodiments, irradiation with charged particles can be proton irradiation. When Ra-226 (with a half-life of 1600 y) is irradiated with low-energy (10-25 MeV) protons, Ac-225 (with a half-life of 10 d Tl / 2) is formed in the Ra-226(p,2n)Ac-225 nuclear reaction. Near 14 MeV, a threshold energy for another reaction (i.e., (p,3n)) is reached, resulting in the production of Ac-224 (with a half-life of 2.9 h Tl / 2), which rapidly decays into Ra-224 (with a half-life of 3.66 d Tl / 2). Above 17 MeV, the (p,3n) reaction becomes dominant, while Ac-225 is still produced in large quantities. Figure 1 The Ra-226 proton reaction cross section has been explained. Depending on the type of proton accelerator used and the maximum proton energy it can deliver, the beam through the target can be shaped for different optimizations: In one embodiment, the Ac-224 (Ra-224 / Pb-212) yield can be optimized, for example, by selecting an energy range of 25 MeV → 15 MeV. In another embodiment, an Ac-225 yield with minimal Ac-224 / Ra-224 can be obtained, for example, by selecting an energy range of 17 MeV → 10 MeV. In yet another embodiment, high yields of both Ac-225 and Ac-224 / Ra-224 can be obtained, for example, by selecting an energy range of 25 MeV → 10 MeV.

[0068] In some embodiments, the radiation with charged particles can be deuterium radiation. Replacing protons (H) with deuterium (D) radiation in Ra-226 can produce even greater amounts of Ac-225 and Pb-212. The Ra-226 deuterium reaction cross-section is... Figure 2 The diagram shows the advantages of using deuterium nuclei instead of protons. The production capacity can be significantly increased due to the higher cross-section, extended range in the target at higher energies, and a considerably large combined yield of Ra-225 and Ra-224. Depending on the type of deuterium accelerator used and the maximum deuterium energy it can deliver, the beam through the target can be shaped in different ways. In one embodiment, the Ac-224 (Ra-224 / Pb-212) yield can be optimized, for example, by selecting an energy range of 60 MeV → 15 MeV. In another embodiment, the Ac-225 yield with minimal Ac-227 / Ac-224 / Ra-224 can be obtained, for example, by selecting an energy range of 20 MeV → 10 MeV. In yet another embodiment, high yields of both Ac-225 and Ac-224 / Ra-224 can be obtained, for example, by selecting an energy range of 60 MeV → 10 MeV.

[0069] One aspect of deuterium radiation is the significantly higher yield of Ac-226 (Tl / 2:29h) compared to protons. Ac-226 also possesses properties of interest for TAT, with 83% β-decay to Th-226 (a short-lived alpha emitter (4α)) and 17% electron-capture decay to Ra-226. For a hypothetical therapeutic dose of Ac-225 of 200 μCi, combined with 10% active Ac-226 (20 μCi), a total of 0.25 Bq Ra-226 and 93 Bq Pb-210 are produced from Ac-226 decay. Given the annual intake limits (ALI) of 71 kBq for Ra-226 and 29 kBq for Pb-210 (source: nucleonica.com), the combined production of Ra-226 and Pb-210 is not expected to pose a problem for clinical application.

[0070] In various embodiments, photon radiation can include radiation with high-energy photons (such as gamma photons, for example, with an energy of at least 6 MeV). In some embodiments, photons with an energy of at least 6 MeV preferably convert Ra-226 into Ra-225, which then decays into Ac-225. In various embodiments, the advantage of using photons is that it is likely the cleanest way to produce Ac-225 because no other Ac isotopes are produced. In various embodiments, the production of Ra-224 can become significant when photons with energies higher than 12 MeV are used.

[0071] In various embodiments, the photonic reaction cross-section for the (γ,n) reaction used to generate Ra-225 is relatively low. In cases where, for example, 1 Ci or higher of Ac-225 is preferred, this problem can be addressed by using a high photon flux: for example, an electron accelerator of 20-40 MeV can be used in conjunction with a high-power electron converter target to generate the bremsstrahlung photons required for the reaction. Advantageously, because photons lack charge, the range (i.e., the depth to which photons penetrate the target) can be much greater than that of charged particles. Therefore, advantageously, when using photons, the target mass can be up to 10 g of Ra-226 or higher. In various embodiments, the higher the energy of the electron-impact converter, the more photons above the 12 MeV threshold for generating Ra-224 / Pb-212 are produced. The electron energy of the impact converter (which determines a photon flux above 12 MeV) can be fine-tuned to increase or decrease the co-generated Ra-224.

[0072] Liquid targets can also be used in the Ra-226(γ,n)Ra-225 generation pathway because the flux of high-energy photons is not significantly affected by the presence of H2O. In various embodiments, the characteristics of the photon beam (e.g., shape and / or flux) can be largely determined by the electron converter, which will specify the optimal Ra-226 target.

[0073] The method further includes, after a cooling time, applying chromatography to separate actinium from the remaining radium-containing fraction. This chromatographic step can be extraction chromatography, but alternatively, it can be ion-exchange chromatography using a cation-exchange column. In ion-exchange chromatography, these elements are separated using the charge difference between Ra(2+) and Ac(3+). The method further includes, after a first further waiting time, applying extraction chromatography to separate Pb from the remaining radium-containing fraction. In this method, a resin having an 18-crown-6 ether or an equivalent of an 18-crown-6 ether is used as the extractant in HNO3 and / or HCl.

[0074] As a commentator, in Figure 3 An exemplary flowchart for separating Pb-212 using proton irradiation is shown. As a simplified theoretical example, a single 100 mCi Ra-226 target is irradiated with protons ranging from 22 MeV to 10 MeV, producing 100 mCi Ac-225 and 8276 mCi Ac-224 at EOB (End of Bombardment), which is equivalent to Ac-224 and Ac-225 atoms. Based on the calculated yield of Ac-225 and... Figure 1Comparing the cross-sectional data, this starting point seems realistic. In this example, after a 24-hour cooling time, 93.3 mCi Ac-225 is ready to be separated from Ra. 20.8 mCi Ac-224 remains after 24 hours, which is 1 / 400th of its original activity. The isotopic purity of Ac-225 is >99.7% based on atoms. Nevertheless, waiting more time to purify Ac-225 until the Ac-225 / Ac-224 activity ratio is sufficiently high seems reasonable. At 36 hours, it will be 90.1 mCi Ac-225 and 1 mCi Ac-224 (for an Ac-225 / Ac-224 ratio of 90.1). After 24 hours of cooling, Ac-224 decays to form 204 mCi Ra-224 in the target. The target is opened, and the contents are separated into Ac and Ra fractions by prior application of extraction chromatography and an optional precipitation step. The Ac fraction is removed from the hot chamber. The Ra fraction, containing 204 mCi Ra-224 and 100 mCi Ra-226, was stored again for 24 hours. After another 24 hours (i.e., 48 hours after EOB), the Ra fraction contained 0.169 Ci Ra-224 and 0.143 Ci Pb-212. The decay of Ra-226 produced 0.66 μCi Pb-210 (Tl / 2: 22.2 μy) and 16.1 mCi Pb-214 (Tl / 2: 26.8 m). Pb was separated from Ra using extraction chromatography. After 12 hours (e.g., dispersion, transport to a hospital), the total activity associated with Pb-214 was converted to 40.4 nCi Pb-210, while 65.4 mCi Pb-212 remained available, including the presence of 0.66 μCi Pb-210. For reference, a Phase 1 study of Pb-212-TCMC-trastuzumab tested up to 21.1 MBq / m 2 The dosage. At an average body surface area of ​​1.7 m². 2 In this case, 67 patient doses can be prepared from the 65.4 mCi Pb-212. The Ra fraction is then stored again for 24 hours. Next (72 hours after EOB), 0.140 Ci Ra-224 is still present, and 119 mCi Pb-212 can be isolated. Following the same pathway, this will yield 56 patient doses. This process can be repeated until the amount of Pb-212 is no longer sufficient to cover the processing costs.

[0075] The same method can be applied to deuterium radiation. The first target in the beam can be used to primarily produce Ac-224, while the second target primarily produces Ac-225. However, the complexity of the separation process increases because the cross-sections for Ra-224 and Ra-225 production are more pronounced compared to proton radiation, and Ac-225 can be produced from Ra-225. As an explanation, in Figure 4 An exemplary flowchart for separating Pb-212 using deuterium irradiation is shown. As a simplified theoretical example, a single 500 mCi Ra-226 target is irradiated with deuterium nuclei at a rate of 50 MeV → 10 MeV, producing 1 Ci Ac-225 and 165.52 Ci Ac-224 at the end of bombardment (EOB), which is more than twice the number of Ac-224 and Ac-225 atoms. 338 mCi Ra-225 (half the atomic mass of Ac-225) and 683 mCi Ra-224 (half the atomic mass of Ra-225) are produced. After a 24-hour cooling time, 933 mCi Ac-225 + 22.1 mCi Ac-225 from Ra-225 decay is ready to be separated from Ra. 417 mCi Ac-224 remains after 24 hours, which is 1 / 400th of its original activity. The isotopic purity of Ac-225 based on atoms is >99.5%. Nevertheless, it seems reasonable to wait longer to purify Ac-225 until the Ac-225 / Ac-224 activity ratio is sufficiently high. At 36 hours, it would be 923 mCi Ac-225 and 20.9 mCi Ac-224 (for an Ac-225 / Ac-224 ratio of 44.2).

[0076] After cooling for 24 hours, the decay of Ac-224 forms 4.08 Ci of Ra-224 in the target, and 0.565 Ci of Ra-224 remains from the direct production. The target is opened, and the contents are separated into Ac and Ra fractions by prior application of extraction chromatography and an optional precipitation step. The Ac fraction is removed from the hot chamber. The Ra fraction, containing 4.645 Ci Ra-224, 323 mCi Ra-225, and 500 mCi Ra-226, is stored again for 24 hours. After 24 hours (i.e., 48 hours after EOB), the Ra fraction contains 3.84 Ci Ra-224 and 3.26 Ci Pb-212. The decay of Ra-225 produces 21.1 mCi Ac-225. The decay of Ra-226 yields 3.3 μCi Pb-210 (Tl / 2: 22.2 μg) and 80.5 mCi Pb-214 (Tl / 2: 26.8 m). Pb was separated from Ac and Ra using extraction chromatography. After 12 hours (e.g., dispersion, delivery to the hospital), the total activity associated with Pb-214 was converted to 202 nCi Pb-210, while 1.49 Ci Pb-212 remained available, including the presence of 3.3 μCi Pb-210. For reference, a Phase 1 study of Pb-212-TCMC-trastuzumab tested up to 21.1 MBq / m³. 2 The dosage. At an average body surface area of ​​1.7 m². 2In this case, approximately 1500 patient doses can be prepared from the 1.49Ci Pb-212. The Ra fraction is then stored again for 24 hours. Next (72 hours after EOB), 3.17Ci Ra-224 is still present, and 2.7Ci Pb-212 can be isolated. Following the same pathway, this will yield approximately 1250 patient doses. Similarly, 20.1mCi Ac-225 is also produced from the decay of Ra-225. This process can be repeated until the amount of Pb-212 is no longer sufficient to cover the processing costs. It can then remain an option to store the Ra fraction for eventual Ac-225 recovery, for example, two to three weeks after EOB. A major advantage of obtaining Ac-225 from the Ra-225 fraction is the absence of contaminants such as Ac-224, Ac-226, and Ac-227.

[0077] By explaining an embodiment in which radiation is performed using photons, see reference. Figure 15 The diagram illustrates the photonic reaction cross-sections of Ra-226 for the formation of Ra-225, Ra-224, and Ra-223, varying with photon energy. For photon energies between 6 MeV and 12 MeV, Ra-225 is primarily produced. 12 MeV is the threshold for producing Ra-224. 19 MeV is the threshold for producing Ra-223. In the example, 1 gram of Ra-226 is irradiated with photons for 48 hours. In this example, it is assumed that for every 10 Ac-225 atoms produced, one Ra-224 atom is produced simultaneously, corresponding to photon energies between 11 MeV and 12 MeV. According to embodiments of this method, after the end of irradiation (EOI), a one-day cooling period is performed before the first separation, i.e., separating Ra, Ac, and Pb from each other. In various embodiments, the same separation method as for deuterium irradiation targets can be followed. In this example, a further separation is performed 48 hours after each previous separation. Table 1 summarizes the activity of different isotopes before and after subsequent separation: five separations were performed, and the time in days after EOI was mentioned for each separation.

[0078]

[0079] Table 1

[0080] Here, each box in the table corresponding to one of the separations includes two rows for each isotope included in the target: the top row corresponds to the isotope included in the target before the corresponding separation, and the bottom row corresponds to the isotope included in the target after the corresponding separation (i.e., after the corresponding amounts of Ac and Pb have been extracted from the target). In this example, the first Ac fraction extracted during the first separation is likely to be contaminated with a small amount of Ac-227 (i.e., 0.1 mCi of Ac-227 in this example). It is possible that the first Ac fraction may only be available with an Ac-225 / Bi-213 generator. In the second separation, 589 mCi of Ac-225 can be extracted, in the third separation 759 mCi, in the fourth separation 1220 mCi, and in the fifth separation 1010 mCi. Although five separations are performed in this example, more separations can be performed to collect more Ac-225.

[0081] Compared to the continuous Pb fraction, the first Pb fraction in this example may also contain elevated amounts of Pb-210 and Pb-214 (not shown in Table 1). However, as shown by this example, 1200 mCi of Pb-212 can be extracted in the second separation, 823 mCi in the third separation, and 232 mCi in the fourth separation. Therefore, even if the first fraction is ignored, a Ci amount of Pb-212 can be obtained in this example.

[0082] Examples of the chemical separation of Pb from Ra are further discussed. Separating Pb from Ra using, for example, Sr (or Pb) resin is direct. Because Pb has a high affinity for the 18-crown-6 ether in Sr resin in HNO3, the Ra moiety can be separated over a wide concentration range (from dilution to 2-4 M HNO3 (see [link to HNO3]). Figure 5 The loading of Sr resin is mainly limited by the solubility of Ra(NO3)2. Sr resin has no affinity for Ra in HNO3 (see [link to Sr resin description]). Figure 6 Loading Sr resin into an HCl matrix is ​​also feasible. In one embodiment, the HCl matrix can be 1 to 2 M HCl (e.g., ...). Figure 7 (See image). No affinity for Ra was found across the entire concentration range. Stripping Pb from Sr resin by forming a Pb chloride compound can be efficiently performed using 8M HCl, which will also leave Po-210 on the resin. Alternatively, Pb can be recovered from Sr resin using 0.1M ammonium citrate, 0.1M ammonium oxalate, or 0.1M glycine.

[0083] An example of chemically separating Ac from Pb / Ra using a string with DGA is also discussed.

[0084] In cases where Ra-225 is present when Ra-226 is irradiated with deuterium nuclei, DGA resin and Sr resin can be placed in series, and Ac-225 can be grown from DGA. This is because Pb is retained to some extent by DGA (see...). Figure 8 Ac was not retained by the Sr resin in the HNO3 or HCl matrix (see [reference]). Figure 9 Therefore, DGA should be placed below Sr. Ac-225 can be eluted using diluted HCl or HNO3.

[0085] According to embodiments of the invention, the method described above can utilize stacked target assemblies. In such stacked target assemblies, two or optionally more targets are stacked such that these targets can be used simultaneously in a single radiation session to produce Ac-225 and Pb-212 isotopes. The target assembly comprises a stack of a first radium-containing target and a second radium-containing target. The first target in the beam can be adapted to primarily produce Ac-224→Ra-224, while the second target, which enters after the first target has been irradiated by the beam, primarily produces Ac-225. As an example, using a RaCI2 target and an incident beam energy of 25 MeV, (1.51–0.793)0.717 g / cm³ 2 The target is placed in the beam as the first target, with the beam exiting the target at 17 MeV. Next, (0.793–0.332)0.461 g / cm³ is applied. 2 The targets are stacked directly behind it, with the beam exiting at 10 MeV. This achieves optimization of isotope production. Figure 11 An example of stacked targets is shown in the figure.

[0086] A similar example can be given for deuterium radiation. The first target in this beam can be used to primarily produce Ac-224, while the second target primarily produces Ac-225. For deuterium radiation, the cross-sections produced by Ra-224 and Ra-225 are more prominent compared to proton radiation. Based on Figure 2 The data shown, in this example, indicate that deuterium nuclei at 50 MeV on the first target will primarily produce Ac-224 until approximately 22 MeV (where Ac-225 production becomes dominant). Ra-225 and Ra-224 are primarily produced in the first target. As an example, using a RaCI2 target and an incident beam energy of 50 MeV, the (3.062–0.97)2.092 g / cm³ 2 The target is placed in the beam as the first target, with the beam exiting the target at 25 MeV. Next, (0.97–0.224)0.746 g / cm³ is applied. 2The targets are stacked directly behind it, with the beam exiting at 10 MeV. This allows for optimization of isotope production. Ac-225 produced from the first target has a higher amount of Ac-227 and may only be suitable for producing Ac-225 / Bi-213 generators.

[0087]

[0088]

[0089] Table 2

[0090] By way of explanation, the present invention is not limited thereto. Examples of experimental results will now be discussed below to illustrate the features and advantages of embodiments of the present invention.

[0091] In the first example, proton radiation of RaCl2 is considered. The projected range of the protons was theoretically evaluated using modeling software, and the results are shown in Table 2.

[0092] The thickness of the target is expressed in g / cm 2 It is expressed as (thickness multiplied by density). In the case of RaCl2 with a density of 2 g / cc, the projected range of 25 MeV protons in RaCl2 is 1.51 g / cm³. 2 / 2g / cm 3 =0.755cm. From Figure 1 As can be seen, there is no more significant Ac-225 yield below 10 MeV, and protons still release their energy in the target as heat (1.6 x 10⁻¹² J / proton). Therefore, according to an embodiment of the invention, the target is adjusted to the correct energy range so that protons leave the target material at approximately 10 MeV. For a 25 MeV RaCl₂ target, this would be 1.51–0.332 = 1.178 g / cm³. 2 Or, for a 2g / cc target, it is 0.589cm.

[0093] In the second example, deuterium radiation from RaCl2 is considered. The projected range of the deuterium was theoretically evaluated using modeling software, and the results are shown in Table 3.

[0094]

[0095]

[0096] Table 3

[0097] Comparing the range data for protons (Table 2) and deuterons (Table 3), it is clear that the range of deuterons at a certain energy is much shorter than that of the corresponding protons, but the cross-section is higher at higher energies (see Table 3). Figure 2This leads to higher available production, which compensates for the aforementioned effects.

[0098] In the third example, proton radiation for alternative targets was investigated, including radiation from Ra(NO3)2, (electroplated) Ra(OH)2, and RaCO3. The proton ranges of these compounds are shown in Table 4.

[0099] Range (g / cm) 2 )

[0100]

[0101] Table 4

[0102] The range differences among these compounds are quite limited. Similarly, for deuterium nuclei, there are no significant differences among these compounds.

[0103] The following example discusses the complete experiment used to derive the isotope. A source of isolated and purified Th-229, from historical Th-228 (Tl / 2: 1.913y) containing a small amount (approximately 15 kBq) of pristine Th-228, was used to produce Ac-225. Ra-225 was also collected separately during this separation process. As Th-228 decays via Ra-224, the Ra-224 activity balances with the Th-228 activity at the Th / Ac / Ra separation point and is collected in the same fraction as Ra-225. This radium fraction is the starting solution for the experiment.

[0104] After separating the approximately 6.3 MBq Th-229 source into Th-229 / Ra-225 / Ac-225 fractions, the Ra fraction in the 4 M HNO3 matrix was further processed by extraction chromatography using a Trishelm vacuum chamber (approximately 40-45 ml).

[0105] In the first step, the initial recovery of Pb-212 and Ac-225 was performed. Approximately 24 hours later, a 1 ml sample from the Ra fraction was analyzed using HPGe to verify Ra-225 activity and obtain the Ra-225 / Ac-225 and Ra-224 / Pb-212 equilibrium parameters (Pb S1). A tandem 2 ml Sr and 2 ml DGA (DGA below Sr) container was pretreated with 10 ml of 4M HNO3. Next, 10 ml (5 BV) of the Ra fraction was loaded onto the column. Pb-212 was retained by the Sr resin. Ac-225 passed through Sr but was retained by the DGA resin. Ra-225 / Ra-224 passed through both resins. The Sr resin was washed with 10 ml (5 BV) of 1M HNO3. Pb and Ac were quantitatively retained by the Sr and DGA resins, respectively. 1M HNO3 was chosen instead of 4M because the k' values ​​for Ac and Pb on DGA and Sr resins, respectively, are still high enough, and the lower HNO3 concentration allows the fraction to be evaporated / distilled back to its original volume (or close to it) without significantly increasing the acid concentration. This may be important when the solubility of Ra in HNO3 solution comes into play. A total of 20 ml (Pb S2) was collected. DGA was removed from below the Sr resin. Pb-212 (Pb S3) was eluted from the Sr resin using 10 ml of 8M HCl. Another 10 ml of 8M HCl was added to the Sr resin to verify the tail (Pb S4). Ac-225 (Pb S5) was eluted from the DGA using 10 ml of 0.1M HCl.

[0106] In the second step, a second recovery of Pb-212 and Ac-225 was performed. 24 hours after the first Pb / Ac / Ra separation, the above process was repeated, starting directly from the Ra fraction of Pb S2 in the first part (10 ml 4M HNO3 + 10 ml 1M HNO3). A tandem 2 ml Sr container and a 2 ml DGA container (DGA below Sr) were pretreated with 10 ml 4M HNO3. Next, 20 ml (10 BV) of Pb S2 was loaded onto the column. Pb-212 was retained through the Sr resin. Ac-225 passed through Sr but was retained by the DGA resin. Ra-225 / Ra-224 passed through both resins. The Sr resin was washed with 10 ml (5 BV) 1M HNO3. Pb and Ac were quantitatively retained by the Sr and DGA resins. A total of 30 ml was collected. DGA was removed from below the Sr resin. Pb-212 (Pb S6) was eluted from the Sr resin using 10 ml of 8M HCl. Another 10 ml of 8M HCl was added to the Sr resin to verify the tail (Pb S7). Ac-225 (Pb S8) was eluted from the DGA using 10 ml of 0.1M HCl.

[0107] To explain the above example, the time-dependent decay of Pb-212 activity must be taken into account. When Pb-212 separates from Ra-224 and Ac-225, no more Pb-212 is generated from Ra-224, and the decay of Pb-212 reduces its activity. For example, 5 hours after the measurement, the remaining Pb-212 activity is only 72% of what it was at the start of the measurement. Figure 12 The decay factor is shown to be determined by the decay time.

[0108] Further growth of Pb-212 and AC-225 into the Ra(224+225) region must also be taken into account. Once Pb / Ac / Ra separation is performed and the Ra region is collected, Pb-212 and Ac-225 / Bi-213 begin to grow. Figure 13 and Figure 14 The rate of inward growth was explained. Therefore, trace amounts of Pb-212 and Ac-225 penetrating the Sr and DGA resins cannot be detected because they will be immediately masked by the newly generated Pb-212 and Ac-225.

[0109] The table below shows the results from the gamma spectrum without corrections for decay and inward growth.

[0110] Pb S1-peak 1.5E+05 7.7E+03 5.2E+02 Pb S2-Ra portion 1.5E+06 8.5E+03 8.1E+02 Pb S3-Pb Part 1 1.1E+03 2.6E+01 4.1E+03 Pb S4-Pb Part 2 1.8E+02 6.4E+00 6.1E+00 Pb S5-Ac part 4.9E+02 7.9E+04 <DL

[0111] Table 5

[0112] Pb S6-Pb Part 1 1.2E+03 2.2E+01 2.6E+03 Pb S7-Pb Part 2 1.4E+02 5.1E+00 5.3E+00 Pb S8-Ac part 6.8E+02 7.8E+04 <DL

[0113] Table 6

[0114] The first Pb fractions (S3 and S6) separated from Ra and Ac were collected as Pb-212 in 5 BV 8 M HCl. The feed column and barrel were flushed with only 5 BV 1 M HNO3, so trace amounts of Ra-225 were still visible in the Pb fractions. For both S3 and S6, this was approximately 0.08%, or >10%. 3 DFRa. Due to the very high k' Pb in this acidic matrix (see... Figure 12 It can be inferred that flushing the Sr resin with an additional 5–10 BV of 1–4 M HNO3 without penetrating Pb-212 would further increase DFRa. Although 8 M HCl has been shown to be used to recover Pb from Sr resin, (compound) alternatives such as citrate and oxalate can also be used to achieve this purpose.

[0115] The second Pb fraction (S4 and S7) contained almost no traces of residual Pb-212 and Ra. This indicates that the recovery of Pb-212 (S3 and S6) in 5 BV 8 M HCl was nearly quantitative. The Ra fraction (S2) recovered almost all of Ra. The activity of Ac-225 (Bi-213) and Pb-212 can be explained by inward growth from Ra-225 / Fr-221 and Ra-224.

[0116] Ac portions (S5 and S8) from the DGA were collected and recovered as expected, and no Pb was found in these portions. Similar to the Pb portions, a small amount of BV used to flush the column and barrel resulted in visible traces of Ra in these portions. For S5, this was 0.04%, and for S8, it was 0.05%. It is known empirically that flushing the DGA with 10 BV 1-4 M HNO3 without detectable penetration into Ac will further increase DFRa.

[0117] There are no indications that the process performed in Part 2 is less efficient than that in Part 1. The Ac-225 collection rate is almost identical. After one day, Ra-225 decay is only 4.6%, and Ac-225 decay is less pronounced after collection and during measurement. Pb-212 measurement activity is largely dependent on collection and measurement times. When pursuing Ac-225 yield, the co-produced Ac-224 / Ra-224 / Pb-212 can still be stabilized without significant additional work. Therefore, co-producing Ac-224 should not be considered a disadvantage in Ac-225 production. The proton / deuterium energies entering the target are flexible and can be optimized for maximum Ac-225 yield, minimum Ac-224 yield, or a combination of both. Stacked target designs can improve processing efficiency.

[0118] When the radium fraction is further processed after the initial Ra / Ac separation, Ac-225 and / or Pb-212 can be separated multiple times. Especially in the case of deuterium radiation, Ra-224 and Ra-225 become valuable sources of Pb-212 and NCA Ac-225. Based on the tandem arrangement of Sr resin and DGA, this process can be repeated multiple times to produce nuclides of interest.

Claims

1. A method for deriving Pb-212 isotopes from Ac-224 isotopes produced during Ac-225 isotope production, the method comprising: A target containing Ra-226 is irradiated with charged particles and / or photons to produce at least Ac-225 and Ac-224 isotopes. After the cooling time, chromatography was used to separate actinium from the remaining radium-containing fraction, and After a first further waiting period, extraction chromatography is applied using a resin having an 18-crown-6 ether or an equivalent of an 18-crown-6 ether as an extractant in HNO3 and / or HCl to separate Pb from the remaining radium-containing fraction, thereby obtaining a compound containing the Pb-212 isotope and trace amounts of Pb-210, determined by its activity, with a concentration in the range of 0.00001% to 0.01% compared to the activity of Pb-212.

2. The method according to claim 1, wherein the target containing Ra-226 comprises any one of RaCl2, Ra(NO3)2, Ra(OH)2 or RaCO3.

3. The method according to claim 1 or 2, characterized in that, Radiation using charged particles includes radiation using protons and / or radiation using deuterium nuclei.

4. The method according to claim 3, characterized in that, Radiation using charged particles includes: Radiation is performed using protons with an incident beam energy of at least 18 MeV, or Radiation is performed using deuterium nuclei with an incident beam energy of at least 20 MeV.

5. The method according to claim 1 or 2, characterized in that, After a second further waiting time applied after the first further waiting time, a further extraction chromatography process is applied to further separate Pb from the remaining radium-containing fraction.

6. The method according to claim 1 or 2, characterized in that, The separation of Pb from the remaining radium-containing fraction was based on extraction chromatography using an 18-crown 6-ether as the extractant in HNO3 and / or HCl.

7. The method according to claim 1 or 2, characterized in that, Radiation with charged particles includes radiation with deuterium nuclei, and the method further includes separating Ac-225 from the remaining radium-containing fraction based on extraction chromatography using DGA.

8. The method according to claim 1 or 2, characterized in that, The target containing Ra-226 is radiated using a stack of targets with a single radiation beam. The stacked targets include a first target for radiating with charged particles having a first incident beam energy and a second target for radiating with charged particles having a second incident beam energy, the first incident beam energy being higher than the second incident beam energy. The first and second targets are stacked and arranged such that the single radiation beam first enters the first target and then enters the second target after leaving the first target.

9. The method according to claim 8, characterized in that, The application of extraction chromatography to separate Pb from the remaining radium-containing fraction is performed on the first target, not on the second target.

10. The method according to claim 8, characterized in that, The product of the thickness and density of the first target is higher than that of the second target.

11. A target assembly for the method of claim 1, the target assembly comprising a stack of a first radium-containing target and a second radium-containing target, wherein the product of the thickness and density of the first target is greater than the product of the thickness and density of the second target.

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