Method for producing high-purity, high-specific-activity radionuclides

Abstract

The present invention relates to a method for producing radionuclides of high specific activity comprising the steps of: a) irradiating a target of interest with a particle beam to obtain an irradiated target comprising a radionuclide of interest; b) chemically extracting a batch of the radionuclide of interest from said irradiated target; c) mass separating the batch of the radionuclide of interest to obtain a radionuclide of high specific activity.

Description

Technical Field

[0001] The present invention relates to the field of production of high purity and high specific activity radionuclides for, for example, medical use on an industrial scale.

Background Art

[0002] Radioisotopes, or radionuclides, are widely used in the fields of life sciences, research, and medicine, such as in nuclear medicine.

[0003] In nuclear medicine, they are used particularly for diagnostic imaging and radiotherapy for cancer diseases. To reach the target, the radioisotope can be added to a molecule / media and injected either in solution (e.g., citrate) or independently (Zimmermann, Nuclear Medicine: Radioactivity for Diagnosis and Therapy - 2017 - EDP Science Edition). Radionuclides can be bound to a medium using chelating agents and linkers. A chelating agent is a substance that can form several bonds to a single atom or ion and is also defined as a polydentate ligand. When using a medium, it is necessary to find a suitable biological target that attaches to tumor cells without harming normal cells. This is made possible by using peptides or antibodies that are preferentially taken up by specific receptors and selecting those target receptors that are more frequently present in tumor cells than in normal cells. A radioisotope labeled with the same medium, preferably a peptide or an antibody, that ensures imaging and therapy is defined as a seranostic (or seragnostic) radioisotope (Langbein et al: J Nucl Med. 2019 Sep;60(Suppl 2):13S-19S).

[0004] One such important application of radioisotopes is the diagnosis and treatment of diseases, such as cancer. For example, there has been considerable progress in the use of radiolabeled tumor-selective peptides and monoclonal antibodies in the diagnosis and treatment of several types of cancer over the past 20 years. The concept of localizing cytotoxic radionuclides to cancer cells is an important complement to conventional forms of radiotherapy. Theoretically, the interaction of radiopharmaceuticals with target cells can concentrate the absorbed radiation dose on the cancer cell site, minimizing damage to normal surrounding cells and tissues (Zhejiang et al. Univ Sci B. 2014 Oct; 15(10): 845-863; Zukotynski et al. Biomark Cancer. 2016; 8(Suppl 2): ​​35-38). The selection of radioisotopes is based on the nature of the emitted radiation, its physical properties (e.g., energy, half-life, and decay series), as well as its chemical properties. Based on the radiation they emit, radioactive isotopes can be further divided into gamma (γ) ray emitters, beta (positron β+ or electron β-) particle emitters, and alpha (α) particle emitters, Auger emitters, or combinations thereof. Further advances in the field of nuclear medicine will require investigations into the use of new isotopes, new sources, and methods for producing isotopes.

[0005] Three main direct or indirect nuclear processes can be defined and identified as methods for producing radionuclides, leading to the intended production of radioactive isotopes: nuclear reactions carried out using particle accelerators, such as cyclotrons, linear accelerators, and electron accelerators; nuclear reactions carried out within a nuclear reactor, and the production of optimal radioactive isotopes obtained through chemical elution processes inside so-called generators. Furthermore, the above production methods can be combined with other techniques to improve the quality of the products. Radioactive isotopes can be produced by transmuting radionuclides by colliding charged particles (mainly protons, deuterons, or alpha particles) with a target nucleus. These charged particles need to be accelerated to at least a few MeV of energy to overcome the Coulomb barrier of the target nucleus and enable nuclear reactions. As a result, particle accelerators are required. Due to their practical properties and high current performance across the entire desired energy range (10 to 100 MeV), cyclotrons have almost without exception been chosen as the most convenient option for radioactive isotope production since the 1950s, with the exception of a few therapeutic radionuclides that can be produced more conveniently in nuclear reactors. However, only a few radioactive isotopes can be produced in cyclotrons with high radionuclide purity and high production yield. To improve the availability of several other radionuclides, for example, U.S. Patent Application Publication No. 20170169908 describes the use of a 70 MeV cyclotron with an online mass separation system, which means simultaneous or pseudo-simultaneous irradiation of a target by the cyclotron and separation thereof by online mass separation for the production of radionuclides. However, these methods impose constraints on the target to be irradiated, which must have determined properties, and this can potentially reduce the overall yield (e.g., porosity, evaporation temperature, etc.) and limit the radioisotopes that can be produced efficiently. Another example is U.S. Patent No. 9202600 (US9202600B2) (Canadian Patent No. 2594829 (CA2594829C) and British Patent No. 2436508 (GB2436508B)), which describes the production of radionuclides by high-energy accelerators and mass separation. The main problem, again, is the availability of high-yield produced radionuclides that would enable their industrial applications. [Overview of the project]

[0006] However, the methods currently used in the production of radioactive isotopes have reached their limits, and there is a strong need for new and improved methods to enhance the availability of new isotopes and the isotopes currently in use. This applies particularly to isotopic purity, yield, specific activity, and the range of available radionuclides.

[0007] The increasing diffusion of positron emission tomography (PET) / single-photon emission computed tomography (SPECT) imaging, and the development of whole-body radionuclide therapy, are creating an ever-growing need to prepare radioisotopes with previously unattainable higher radiochemical and radionuclide purities, ensuring adequate production yields for industrial commercialization.

[0008] Furthermore, achieving breakthroughs in the development of drug-targeted delivery systems for novel cancer treatment is limited by the lack of availability of existing radionuclides with optimal decay characteristics for such applications. For radioligand therapy (RLT), it is essential that the purity of the radionuclide is high enough to ensure patient safety and minimize the risks associated with potential hazardous contaminants, both from a toxicity and radioactive waste perspective.

[0009] Furthermore, radionuclides can sometimes be produced only in research facilities, and the production of radionuclides for medical applications in particular corresponds to a small portion of the available time. Consequently, these radionuclides are not routinely available for distribution and use, which undermines their potential use, for example, in nuclear medicine applications and research. Given the growing demand for specific radionuclides and the difficulties faced in providing those specific radionuclides through commercial accelerators, it is important to provide methods that enable the optimization of the use of commercial accelerators, especially during the time dedicated to medical applications.

[0010] This can be achieved by using commercial accelerators and / or nuclear reactors for the production of desired radionuclides. However, sometimes the purity and specific activity of the produced batch of radionuclides are not high enough for receptor target applications. Therefore, the produced batch may require further processing to meet those requirements; for example, chemical separation can increase the purity of the batch, and mass separation can increase the purity of the radionuclides.

[0011] Notably, the inventors have found that a combined method of radionuclide production, chemical extraction, and mass separation provides cost-effective, flexible, and efficient production of a wide variety of radionuclides on a large scale, with high radionuclide purity and specific activity that enables their use in receptor target applications.

[0012] Therefore, an object of the present invention is to provide a method for producing radionuclides with high purity and high specific activity. The specific activity is understood as the ratio of the radioactivity of the produced radionuclide to the total mass of all nuclides belonging to the same element as the produced radionuclide. [Modes for carrying out the invention]

[0013] In that respect, a) A step of irradiating the target with a particle beam to obtain an irradiation target containing the target radionuclide, b) A step of chemically extracting the radioactive nuclide for the above purpose from the irradiation target and increasing its chemical purity. c) A method is provided for producing a high specific activity radionuclide, comprising the step of mass-separating the radionuclide for the above purpose to obtain a high specific activity radionuclide. The particles in the beam described above can be protons, neutrons, photons, deuterons, or alpha particles. A proton beam is preferred for particle beams when considering accelerator-based manufacturing, while a neutron beam is preferred when considering reactor-based manufacturing. The particles in the beam can trigger nuclear reactions, allowing for the production of an irradiation target containing the desired radioactive nuclide. The main objective of process b) is to increase batch purity and significantly improve the efficiency of process c) by removing a large proportion of major impurities.

[0014] Another object of the present invention is the high specific activity radionuclides that can be obtained by the method of the present invention. A further object of the present invention is the medical use of the high specific activity radionuclides of the present invention. The present invention relates to the high specific activity radionuclides of the present invention for use in methods of therapeutic treatment of the human or animal body, or in diagnostic methods performed on the human or animal body.

[0015] The target radionuclide is defined as a known radionuclide, preferably an α- emitter, a β(-) emitter, a β(+) emitter, a γ- emitter, or an Auger emitter. Preferably, the known radionuclides mentioned above are the radionuclides listed below in this specification: F-18, Sc-43, Sc-44, Sc-47, Cr-51, Mn-52m, Fe-52, Co-55, Cu-61, Cu-62, Cu-64, Ga-66, Cu-67, Ga-67, Ga-68, As-72, As-76, Rb-82, Y-86, Zr-89, Y-90, Ru-97, Tc-99m, Rh-105, In-111, Ag111, Sn-117m, Sn-121, I-123, I-124, I-131, Pr-142, Pr-143, Tb-149, Pm-149, Pm-151, Tb-152, Sm Belonging to -153, Tb-155, Gd-157, Gd-159, Tb-161, Er-165, Dy-166, Ho-166, Tm-167, Er-169, Yb-169, Tm-172, Yb-175, Lu-177, Re-186, Re-188, Au-198, Au-199, Pb-203, At-211, Pb-212, Bi-212, Bi-213, Ac-225, Ac-227, and Th-229, preferably selected from Sc-43, Sc-44, Sc-47, Tb-149, Tb-152, Tb-155, Tb-161, Lu-177, other lanthanides, and Ac-225.

[0016] This invention makes it possible to produce batches of radionuclides that are difficult or impossible to produce with sufficient purity by other means. These radionuclides are produced with high purity and high specific activity, enabling a wide variety of applications, such as imaging and therapeutic protocols in the medical field. The radionuclides are available to hospitals and research centers for, for example, in-vivo and in-vitro research. Preferably, the radionuclides for the above purposes are selected from radionuclides that enable theranostic therapy. The theranostic approach in nuclear medicine combines imaging and therapy using the same molecule or at least very similar molecules, which are differently radiolabeled or given in different doses. For example, copper-67, iodine-131, and lutetium-177 are both γ- and β-emitting, and therefore these substances can be used for both imaging and therapy. Furthermore, different isotopes of the same element, such as iodine-123 (γ-emitting) and iodine-131 (γ- and β-emitting), can also be used for theranostic purposes. More recent examples include yttrium-86 / yttrium-90, or terbium isotopes (Tb): Tb-152 (β+ emitting), Tb-155 (γ-emitting), Tb-149 (α-emitting), and Tb-161 (β-emitting) [Table 1]. Furthermore, different isotopes of different chemical elements, such as radioactive lanthanides, e.g., Lu-177 (a γ and β emitter for therapeutic purposes), and radionuclides with similar chemical properties, e.g., Ga-68 (a β+ emitter), can also be used for theranostic purposes.

[0017] [Table 1]

[0018] Preferably, the high specific activity radionuclide is selected from isotopes of terbium. In this case, the target for the above purpose preferably comprises natural or enriched gadolinium, preferably a metal, oxide, or chloride, and is preferably irradiated with an accelerator proton beam.

[0019] In fact, for terbium isotopes in the medical industry, there are increasing potential demands that are difficult to meet with current manufacturing means. For example, natural gadolinium in the form of metal or oxide can be a good compromise between the availability of raw materials and the radionuclide production yield of terbium. The above chemical separation mainly involves the terbium element and the gadolinium element, and the above mass separation will mainly involve the above terbium nuclides.

[0020] Preferably, the selected high-specific-activity therapeutic radionuclide is erbium Er-169. In that case, the target for the above purpose preferably contains natural or (in the case of Er-168) enriched erbium, preferably metal, oxide, nitrate or chloride, and is preferably irradiated with neutrons in a nuclear reactor.

[0021] In fact, for high-specific-activity erbium in the medical industry, there are potential demands that cannot be achieved with current manufacturing means. For example, highly enriched Er-168 in the form of nitrate and oxide is a good target material that is considered to achieve a high production yield. The above chemical separation mainly involves the ytterbium element and the erbium element, and the above mass separation will mainly involve the above erbium nuclides.

[0022] Other preferred high-specific-activity radionuclides may be selected from scandium isotopes. In that case, the target for the above purpose preferably contains metallic titanium, more preferably natural metallic titanium that is widely available and enables a high scandium radionuclide production yield.

[0023] In fact, for scandium isotopes in the medical industry, there are increasing demands that are difficult to meet with current manufacturing means. Metallic titanium is a good compromise between the availability of raw materials and the scandium radionuclide production yield. The above chemical separation mainly involves the scandium element and the titanium element, and the above mass separation will mainly involve the above scandium nuclides.

[0024] The above high specific activity radionuclide may also be selected from actinium isotopes, and the target for the above purpose preferably contains natural thorium.

[0025] In fact, for actinium isotopes in the medical industry, there are increasing requirements that are difficult to meet with current manufacturing means. Natural thorium is a good compromise between the availability of raw materials and the production yield of actinium radionuclides. The above chemical separation mainly involves thorium and actinium elements, and the above mass separation will mainly involve the above actinium nuclides.

[0026] The above high specific activity radionuclide may also be selected from lutetium isotopes, and the target for the above purpose preferably contains metallic ytterbium.

[0027] In fact, for lutetium isotopes in the medical industry, there are increasing requirements that are difficult to meet with current manufacturing means. Metallic ytterbium is a good compromise between the availability of raw materials and the production yield of lutetium radionuclides. The above chemical separation mainly involves lutetium and ytterbium elements, and the above mass separation will mainly involve the above lutetium nuclides.

[0028] The main steps of the present invention are described below. The above steps can also be carried out in a different order or repeated several times to ensure the production of high-quality products.

[0029] Step a): Target irradiation The method for producing the high specific activity radionuclide described above includes step a) irradiating a target of interest with a particle beam, preferably a proton beam, to obtain an irradiated target containing the radionuclide of interest. The proton beam in step a) can exhibit an energy between 18 and 200 MeV, preferably between 30 and 70 MeV. Such an energy provides an interesting compromise between the difficulty of producing such a beam and the yield of radionuclide production. This proton beam can be supplied by a commercial cyclotron, for example, the Arronax IBA C70 cyclotron located in Nantes, France.

[0030] Step b): Chemical extraction The method for producing the high specific activity radionuclide described above includes step b) chemically extracting a batch of the desired radionuclide from the irradiation target.

[0031] The target for the above purpose in step b may be dissolved in an acid solution.

[0032] This dissolution results in a solution of the target material and the radionuclide, which becomes an input for a chemical separation process for the production of a specific radionuclide. Preferably, the chemical separation process is chromatography.

[0033] Step b) above may include, for example, dissolving the target object in an acid solution containing nitric acid (HNO3). The resulting solution can then be passed through a resin.

[0034] Step b) above may include liquid-liquid extraction.

[0035] Liquid-liquid extraction allows for a good compromise between the cost of materials required for chemical separation and the volume of experimental setup needed for advanced target mass separation.

[0036] Step b) described above may also include liquid-solid extraction.

[0037] Liquid-solid extraction can offer a good compromise between the cost of materials required for chemical separation and the volume of experimental setup needed for advanced target mass separation.

[0038] This chemical separation step provides an improvement in radiochemical purity. Therefore, by removing the target material compared to the desired radionuclides, the efficiency of the mass separation in step c) is increased, and the yield obtained from the present invention is increased.

[0039] A method for producing high specific activity radionuclides according to any embodiment is: Step b) A step of pouring the liquid solution obtained in step b) onto a support, preferably a metal support, A step of heating and concentrating the liquid solution on the support and depositing the radioactive nuclide on the support, Steps to insert the support containing the radioactive nuclide for the above purpose into a mass separation system. The process may further include a target coupling step b2) which includes the above.

[0040] If gadolinium is the target for the above purpose, step b) may include dissolving metallic gadolinium in an acidic solution, preferably containing nitric acid. The resulting solution may then be passed through a resin. This step will be described in more detail in Example 2.

[0041] This process reduces the gadolinium content, which can then be converted into an improved efficiency for subsequent mass separation.

[0042] If a high specific activity radionuclide is selected from scandium isotopes, step b) may include dissolving metallic titanium in an acidic solution, preferably a hydrobromic acid (HBr) solution. This process may require a potential difference to be imparted to the metal to facilitate dissolution. The resulting solution is then dissolved in the acid and passed through the resin.

[0043] This process reduces the titanium content, which can then be converted into an improved efficiency in the subsequent mass separation.

[0044] Step c): Mass separation Contaminants belonging to the same element cannot be separated by chemical separation. Therefore, a physical separation process, preferably mass separation, is considered. The mass separation process can achieve higher specific activity and higher radionuclide purity.

[0045] The above method for producing high specific activity radionuclides includes step c) mass-separating a batch of radionuclides of interest to obtain high specific activity radionuclides, wherein the mass separation uses a conventionally used target oven for evaporating atoms, an ionizer for ionizing the atoms, an extraction electrode for further accelerating the ions, a magnet for enabling the mass separation, and a recovery support.

[0046] The ionization of the atoms in the mass separation process described above can be achieved using a conventional ion source. Ultimately, laser ionization may be considered to improve ionization efficiency.

[0047] Step d): Second chemical separation (optional) The method for producing the above-mentioned high specific activity radionuclide may further include step d), which consists of a second chemical separation and purification performed after the mass separation step.

[0048] This is an optional step and unlikely to be performed due to the very pure product extracted after mass separation. However, interest is shown whenever there is interest in defining a compromise between the time required for a very good first chemical separation before mass separation and the final product. In those cases, the above chemical separation can be divided into two steps: a first chemical separation before mass separation and a second chemical separation after mass separation. Furthermore, this second purification may be required depending on how the radionuclide is recovered after mass separation. In fact, various methods can be used to recover the radionuclide. For example, if the radionuclide is deposited on a metal plate, this second chemical separation step is required to recover the prepared radionuclide.

[0049] Further features, details, and advantages are shown in the following detailed description and drawings. [Brief explanation of the drawing]

[0050] [Figure 1] This flowchart shows the radionuclides predicted to be generated during irradiation of a natural titanium target, depending on the energy of the irradiation beam. [Figure 2] A flowchart showing the theoretical scandium yields obtained starting from various targets is shown. [Examples]

[0051] [Example 1] Manufacturing of Scandium-47 preface Determining the best starting materials is extremely important.

[0052] For the production of scandium-47, natural titanium has been found to be a good compromise between availability, cost, and properties, and alternatively, concentrated titanium or concentrated calcium can also be used. As shown in Figure 1, the production of Sc-47 from natural titanium is possible at proton beam energies lower than 70 MeV. However, other impurities are also produced, most importantly Sc-46, which has a considerably longer lifetime and is undesirable when considering Sc-47 for medical applications. This is why appropriate purification and mass separation steps, as described in this invention, are essential to obtain a product usable for medical applications, such as a radionuclide with high production yield, high purity, and high specific activity.

[0053] The production yield evaluated and shown in Figure 2 should be determined. Table 2 below shows theoretical calculations of potential contaminants produced by irradiation of natural titanium targets. The calculations were performed using the software MCNPx. Most of the listed contaminants can be removed by chemical separation. The main concern is Sc-46, which requires supplemental separation, such as mass separation. The yield ratio of Sc-46 to Sc-47 is approximately 10% at impact termination (EOB), which is too high for medical applications, especially RTL applications.

[0054] [Table 2]

[0055] A theoretical calculation can be performed assuming that one titanium disc has a thickness of 4 mm and a diameter of 26 mm. The metal disc is subjected to a 70 MeV, 25 μA proton beam for 3 days (3 days corresponds to the half-life of Sc-47).

[0056] After irradiation, a batch of the target radionuclides is chemically separated and purified from the irradiation target. A potential difference is applied to the irradiation target to facilitate its dissolution in diluted HBr. Subsequently, the acid solution is modified with diluted HNO3 to meet the conditions for incorporation into the resin. After washing with a suitable medium, Sc is eluted from the resin. The eluted solution has a significantly reduced titanium content compared to the initial solution. This greatly reduces Ti-47, which cannot be separated during the mass separation process. This drawback can be overcome using laser ionization.

[0057] The specific activity per unit target mass is 65.8 MBq / mg at this point in the process.

[0058] Next, a batch of radionuclides is separated according to a mass separation process, in which atoms and, consequently molecules, having a mass of Sc-47 can be selectively extracted and recovered onto a dedicated foil, such as a gold support coated with Zn, which then undergoes a chemical process to recover Sc-47 from the foil material.

[0059] The specific activity per unit target mass is 3.08 x 10⁻¹⁰ of the maximum theoretical specific activity at the end of the process according to the present invention. 4 Approximately 2.8 x 10, close to GBq / mg 3 The concentration is GBq / mg.

[0060] To further enhance radiochemical purity, after mass separation, further chemical separation may be anticipated to remove any remaining titanium content from the batch of radionuclides produced.

[0061] [Example 2] For the production of Tb-155 (this also applies to two other Tb radionuclides, e.g., Tb-149 and Tb-152), three metallic gadolinium foils (25 μm thick) purchased from Goodfellow were used as targets. These were irradiated in an Arronax cyclotron at 30 μA for 12 hours using 55 MeV protons. This energy was selected to yield 33 MeV to the target based on our target design. The Tb-155 / Gd ratio in EBO was 1:2.7E6. The main radioactive contaminants are listed in the table below.

[0062] [Table 3] After irradiation, remove the three targets from the target holder.

[0063] The chemical process consists of two chromatography columns packed with Ln resin (Column 1 (500 mm, V=36.9 mL) and Column 2 (250 mm, V=8.6 mL)). All elution is performed at 1 mL / mn using a high-pressure pump. Gd foil was dissolved in concentrated nitric acid (2M) and then evaporated to dry. The dried residue was collected in 3 mL of dilute nitric acid (0.75M), washed to remove impurities, and placed on column 1 prepared with 0.75 M HNO3. Under these conditions, gadolinium was less likely to be retained by the column than Tb, and most of it could be removed by washing the column with 40 mL of 0.75 M HNO3, followed by 80 mL of 1 M HNO3. Next, terbium was eluted using 45 mL of 1 M HNO3, followed by 40 mL of 2 M HNO3. Then, 85 mL was evaporated and dried, and recovered in 3 mL of 0.75 M HNO3 for a second purification step using column 2. The solution was poured into column 2, and traces of Gd were eluted using 12 mL of 0.75 M HNO3, followed by 15 mL of 1 M HNO3. Then, Tb was recovered using 10 mL of 1 M HNO3, followed by 15 mL of 2 M HNO3. These 25 mL were evaporated and dried.

[0064] After cooling, the residue is collected in 3 mL of 0.01 M HNO3. The resulting terbium solution is then poured into a rhenium-coated tantalum boat, which is suitable for a mass separation target system, particularly the CERN-MEDICIS target system, as was investigated in this example. The sample is then heated to evaporate the acid and obtain the terbium residue deposited on the rhenium support. The tantalum boat is then loaded onto CERN and inserted into the CERN-MEDICIS target for mass separation. At the end of these chemical steps, Tb155:Gd is lower than 1:20, representing a very significant improvement from the EOB ratio.

[0065] The target system was installed in CERN MEDICIS, and a mass separator was positioned for terbium extraction. The target was heated to 600 A, and a laser with a mass of 159 was optimized. A laser on / off ratio of 620 / 110 pA was measured. The target was heated to 700 A, and optimized at 22.3 kV. A primary current of 726 nA (FC70) was measured. The separation current was 241 pA with the laser on and 245 pA with the laser off. A current of 194 pA was measured in the sample, and 5.8 pA was measured with the collimator. The target was heated to 750 A, and the sample current was set to 600 pA (3.8 pA with the collimator). The maximum current measured in the sample was 900 pA (3 pA with the collimator). The recovery time was 22 hours.

[0066] The target placed on the separator had a radioactivity of 230 MBq, and the recovered Tb-155 amounted to 2.9 MBq, which corresponds to an overall efficiency of 1.3% and a radionuclide purity higher than 99.9%.

[0067] Further chemical purification is required to extract Tb-155 atoms from embedded zinc-coated gold foil.

[0068] [Example 3] A natural Er-2O3 target was irradiated with a 72 MeV proton beam to produce radionuclides Tm-165, 167, and 168. The target, with a total radioactivity of 150 MBq, was transferred to a target ion source unit and connected to the MEDICIS target station; isotope mass separation was performed on the target with mass 167 over 4 days at a beam energy of 60 kV with an ion source temperature between 2100 and 2190 °C, and then steadily increased to 1760 °C to 2300 °C over 4 days. The total ion beam current was between 14 nA and 8 uA. The measured beam intensity during recovery at A=167 varied between 53 pA and 118 nA, and the Gaussian beam profile was σH 1.0 mm x V 0.74 mm. The separated radioactivity was recovered across three metal foils and partially distributed into the chamber. The initial Tm-167 radioactivity in the target before separation was 77 MBq, and the recorded separated radioactivity was 42 MBq at the end of recovery; this provides a separation efficiency of 54%. Radionuclide purity was assessed using a high-purity germanium detector and found to be better than 99.99%, with the radioactivity of Tm-165 and Tm-168 contaminants below the detection threshold.

[0069] conclusion These examples demonstrate that the method of the present invention can yield a target radionuclide with high specific activity, high purity, and potentially high yield. The examples also show how chemical separation prior to mass separation improves its efficiency and how important the mass separation step is for increasing the purity of the radionuclide. Furthermore, the present invention shall encompass the following embodiments. [1] a) A step of irradiating the target with a particle beam to obtain an irradiation target containing the target radionuclide, b) A step of chemically extracting the target radionuclide from the irradiation target, c) A method for producing a high specific activity radionuclide, comprising the step of mass-separating a batch of target radionuclides to obtain a high specific activity radionuclide. [2] A method for producing a high specific activity radionuclide according to [1], wherein the particle beam in step a) is a proton beam exhibiting an energy between 18 and 200 MeV. [3] A method for producing a high specific activity radionuclide according to any one of the above [1] to [2], wherein step b) includes dissolving the target of the objective in an acid solution. [4] A method for producing a high specific activity radionuclide according to any one of the above [1] to [3], wherein the high specific activity radionuclide is selected from isotopes of terbium and the target of interest comprises metallic gadolinium. [5] A method for producing a high specific activity radionuclide according to [4], wherein step b) comprises the steps of dissolving metallic gadolinium in a nitric acid solution and passing the resulting solution through a resin. [6] A method for producing a high specific activity radionuclide according to any one of the above [1] to [3], wherein the high specific activity radionuclide is selected from isotopes of scandium, and the target of interest contains metallic titanium. [7] A method for producing a high specific activity radionuclide according to [6], wherein step b) includes the steps of exposing metallic titanium to an HBr solution while applying a voltage, dissolving the solution in an acid, and passing the resulting solution through a resin. [8] A method for producing a high specific activity radionuclide according to any one of the above [1] to [7], wherein step b) includes liquid-liquid extraction. [9] A method for producing a high specific activity radionuclide according to any one of the above [1] to [7], wherein step b) includes liquid-solid extraction.

[10] A method for producing the high specific activity radionuclide according to any one of the above [1] to [3], wherein the high specific activity radionuclide is selected from isotopes of actinium, and the target of interest contains natural thorium.

[11] A method for producing a high specific activity radionuclide according to any one of the above [1] to [3], wherein the high specific activity radionuclide is selected from isotopes of erbium and the target of interest includes natural erbium.

[12] A method for producing the high specific activity radionuclide according to any one of the above [1] to [3], wherein the high specific activity radionuclide is selected from isotopes of lutetium and the target of interest includes metallic ytterbium.

[13] Step b) A step of pouring the liquid solution obtained in step b) onto a support, preferably a metal support, A step of heating and concentrating the liquid solution on the support, and depositing the radioactive nuclide on the support, A method for producing a high specific activity radionuclide according to any one of the claims [1] to

[12] , further comprising a target coupling step b2) which includes inserting the support containing the radionuclide of the objective into a mass separator.

[14] A method for producing a high specific activity radionuclide according to any one of the above [1] to

[13] , further comprising a second chemical separation and purification step d2) after the mass separation step.

[15] A radionuclide with high specific activity obtained by the method described in any one of the above [1] to

[14] .

[16] The high specific activity radionuclides described in

[15] above for use in methods of treatment of human or animal bodies, or in diagnostic methods performed on human or animal bodies.

Claims

1. a) A step of irradiating a target with a particle beam to obtain an irradiation target containing the target radionuclide, b) A step of chemically extracting the target radionuclide from the irradiation target, c) A method for producing a high specific activity radionuclide, comprising the step of mass-separating a batch of target radionuclides to obtain a high specific activity radionuclide, If the high specific activity radionuclide is selected from scandium isotopes, the target of the choice includes metallic titanium, and step b) includes the steps of exposing metallic titanium to an HBr solution while applying a voltage, dissolving the solution in an acid, and passing the resulting solution through a resin. A method for producing a high specific activity radionuclide, wherein the target of the choice is selected from isotopes of terbium, and step b) comprises dissolving metallic gadolinium in a nitric acid solution and passing the resulting solution through a resin.

2. A method for producing a high specific activity radionuclide according to claim 1, wherein the particle beam in step a) is a proton beam exhibiting an energy between 18 and 200 MeV.

3. A method for producing a high specific activity radionuclide according to claim 1, wherein step b) includes liquid-liquid extraction.

4. A method for producing a high specific activity radionuclide according to claim 1, wherein step b) includes liquid-solid extraction.

5. Step b) A step of pouring the liquid solution obtained in step b) onto the support, A step of heating and concentrating the liquid solution on the support, and depositing the radioactive nuclide on the support, Steps to insert the support containing the radioactive nuclide for the above purpose into a mass separator. A method for producing a high specific activity radionuclide according to claim 1, further comprising a target coupling step b2) including the above.

6. The method for producing a high specific activity radionuclide according to claim 5, wherein the support in step b2) is a metal support.

7. A method for producing a high specific activity radionuclide according to claim 1, further comprising a second chemical separation and purification step d2) after the mass separation step.

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