Method for producing astatine solution

Abstract

The present invention aims to provide a method for producing an astatine solution with an improved recovery rate. A method for producing an astatine-211 solution, including a step of irradiating bismuth with α rays to generate astatine-211 in the bismuth, and a step of distilling the bismuth irradiated with α rays to separate and purify the astatine-211 and dissolving the astatine-211 in an aqueous sodium hydrogen carbonate solution.

Description

[Technical Field]

[0001] The present invention relates to a method for producing an astatine solution with an improved recovery rate.[Background Art]

[0002] Astatine-211 ( 211< At) is an α-emitting radionuclide belonging to the same halogen group as iodine. Because α rays deliver high energy with a short range of only several cells, it is expected that a marked therapeutic effect can be obtained while suppressing the influence on surrounding tissues, by selectively accumulating 211< At at lesion sites such as cancer cells. In recent years, nuclear medicine therapy using 211< At has attracted attention, and it has been disclosed that sodium astatinate ([ 211< At]NaAt) is taken up by cancer cells via the sodium-iodine cotransporter expressed in differentiated thyroid cancer, like iodine, and shows dose-dependent tumor growth suppressive effects and improved survival rates (Non Patent Literatures 1 and 2, Patent Literature 1).

[0003] 211< At is produced by the nuclear reaction of 209< Bi( 4< He,2n) 211< At using bismuth (Bi) as the target material, and is obtained in the form of a Bi plate containing 211< At. Dry distillation is known as a method for separating and purifying 211< At contained in this Bi plate (e.g., Patent Literature 1, Patent Literature 2). This method is a separation technique that utilizes the difference in the boiling point between 211< At and 209< Bi. By heating the electric furnace containing the Bi plate to about 850°C, only the 211< At with a lower boiling point (boiling point around 330°C) is vaporized and captured in a cooling trap tube installed downstream of the electric furnace.

[0004] The 211< At captured in the trap tube can be recovered with good recovery rate by mainly using chloroform (Non Patent Literature 3). After recovery, it is removed and reacted with a precursor with a tributyltin group or the like as a leaving group, under appropriate organic solvents and oxidizing agents to synthesize astatine-labeled drugs. However, chloroform is highly toxic, and its use in the manufacturing process of drugs to be administered intravenously to humans is considered a major problem. On the other hand, it has already been reported that trapped 211< At can be recovered with water and exhibits a good labeling reaction with a precursor having boronic acid as a leaving group in aqueous solution in the presence of sodium hydrogen carbonate and potassium iodide (Non Patent Literature 4). However, the recovery rate of 211< At in water was not high compared to chloroform, and was about 30% using 0.5 mL of water (see Comparative Example 1 in Experimental Example 1 described later). In order to obtain a high yield of radioactivity in the labeling reaction using a boronic acid precursor, improvement in the recovery rate was necessary.[Citation List][Patent Literature]

[0005] [Patent Literature 1] WO2019 / 131998 [Patent Literature 2] WO2019 / 112034 [Non Patent Literature]

[0006] [Non Patent Literature 1] Watabe et al., J Nucl Med 2019, volume 60, issue 9, pages 1301-1307; doi.10.2967 / jnumed.118.222638 [Non Patent Literature 2] Watabe et al., Int J Mol Sci 2022, volume 23, issue 16, 9434; doi.org / 10.3390 / ijms23169434 [Non Patent Literature 3] Lindegren et al., Applied Radiation and Isotopes, volume 55, issue 2, 2001, pages. 157-160 [Non Patent Literature 4] Shirakami et al., Scientific Reports volume 11, Article number: 12982, 2021; doi.org / 10.1038 / s41598-021-92476-6 [Summary of Invention][Technical Problem]

[0007] The present invention aims to provide a method for producing an astatine solution with an improved recovery rate.[Solution to Problem]

[0008] The present inventors have conducted intensive studies and found that the recovery rate of 211< At can be improved by using an aqueous sodium hydrogen carbonate solution when recovering the separated and purified 211< At from a trap tube. Furthermore, the present inventors have found that, when recovering the separated and purified 211< At from a trap tube, the recovery rate of 211< At can be further increased by stopping the flow of the aqueous sodium hydrogen carbonate solution in the trap tube for a certain period of time, allowing the solution to stand, and then recovering 211< At (i.e., increasing the contact time between the separated and purified 211< At and the aqueous sodium hydrogen carbonate solution).

[0009] Based on the new finding, the present inventors further conducted intensive studies and completed the present invention.

[0010] That is, the present invention provides the following. [1] A method for producing an astatine-211 solution, comprising a step of irradiating bismuth with α rays to generate astatine-211 in the bismuth, and a step of distilling the bismuth irradiated with α rays to separate and purify the astatine-211 and dissolving the astatine-211 in an aqueous sodium hydrogen carbonate solution (also referred to as the production method of the present invention in the present specification). [2] The production method of the above-mentioned [1], wherein the aqueous sodium hydrogen carbonate solution does not comprise either a reducing agent or an oxidizing agent, or both. [3] The production method of the above-mentioned [1], wherein the separated and purified astatine-211 is dissolved by contacting the astatine-211 with the aqueous sodium hydrogen carbonate solution for 10 seconds or more. [4] The production method of the above-mentioned [1], wherein a carrier gas used for the distillation comprises an inert gas and O 2 . [5] The production method of the above-mentioned [4], wherein the carrier gas further comprises H 2 O. [6] A method for recovering astatine-211, comprising a step of irradiating bismuth with α rays to generate astatine-211 in the bismuth, and a step of distilling the bismuth irradiated with α rays to separate and purify the astatine-211 and dissolving the astatine-211 in an aqueous sodium hydrogen carbonate solution. [7] The recovery method of the above-mentioned [6], wherein the aqueous sodium hydrogen carbonate solution does not comprise either a reducing agent or an oxidizing agent, or both. [8] The recovery method of the above-mentioned [6], wherein the separated and purified astatine-211 is dissolved by contacting the astatine-211 with the aqueous sodium hydrogen carbonate solution for 10 seconds or more. [9] The recovery method of the above-mentioned [6], wherein a carrier gas used for the distillation comprises an inert gas and O 2 .

[10] The recovery method of the above-mentioned [9], wherein the carrier gas further comprises H 2 O. [Advantageous Effects of Invention]

[0011] According to the production method of the present invention, a 211< At solution can be produced with a high recovery rate.

[0012] The production method of the present invention can be performed without using highly toxic organic solvents such as chloroform and methanol. Therefore, the 211< At solution obtained by the production method of the present invention does not require a distillation step of organic solvents and can be widely used in astatination reactions in aqueous solutions, including labeling reactions using boronic acid precursors or tributyltin group-modified precursors.

[0013] The 211< At solution obtained by the production method of the present invention does not contain organic solvents such as chloroform and methanol, and is therefore useful as a raw material of pharmaceutical products.

[0014] In addition, the production method of the present invention can be performed without using reducing agents or oxidizing agents. Therefore, the 211< At solution obtained by the production method of the present invention does not contain reducing agents or oxidizing agents and can be used in any labeling reaction.[Brief Description of Drawings]

[0015] [Fig. 1] Fig. 1 is a schematic diagram showing one embodiment of an apparatus for carrying out step (2) of the present invention.[Description of Embodiments]

[0016] The present invention is described in detail below.

[0017] The method for producing a 211< At solution of the present invention includes the following steps (1) and (2): step (1): a step of irradiating bismuth with α rays to generate 211< At in the bismuth, and step (2): a step of distilling the bismuth irradiated with α rays to separate and purify the 211< At and dissolving the 211< At in an aqueous sodium hydrogen carbonate solution.

[0018] In step (1), irradiation of bismuth with α rays is performed using an accelerator (e.g., a cyclotron). Any accelerator capable of accelerating α rays to 30 MeV can be used.

[0019] Step (1) can be performed, for example, by the following method.

[0020] A target material is prepared by thinly coating an aluminum plate (e.g., about 30 mm wide x 70 mm high x 2 mm) with bismuth using a vapor deposition method. Helium ions (1-50 µA) are accelerated to about 28 MeV using a cyclotron and irradiated onto the aforementioned target material for 10 min to 24 hr to generate 211< At through the nuclear reaction of 209< Bi( 4< He,2n) 211< At. 211< At is embedded within the bismuth of the target material.

[0021] Fig. 1 shows a schematic diagram illustrating one embodiment of an apparatus for carrying out step (2). Step (2) is described below with reference to Fig. 1.(Separation and purification of 211< At by dry distillation apparatus)

[0022] The target material (including 211< At) irradiated by an accelerator is separated and purified by dry distillation method.

[0023] Specifically, the target material, placed on a high-boiling-point metal such as nickel (Ni) or copper (Cu) (target boat), is placed in a quartz tube (with the bismuth-coated surface facing upwards), and a carrier gas (for example, a mixed gas of O 2 gas, He gas, and H 2 O) is introduced into the quartz tube from the inlet of the quartz tube (left side of the quartz tube in Fig. 1). When the quartz tube is heated to the distillation temperature (for example, 850°C) in an electric furnace, the bismuth of the target material melts and the 211< At sublimes. The 211< At is then transported by the carrier gas flow from the outlet of the quartz tube (right side of the quartz tube in Fig. 1) through a three-way cock to a cooling tube, and captured in the quartz tube. The piping from the outlet of the quartz tube, through the three-way active, to the cooling tube is heated to about 130°C using a heater to prevent the deposition of volatile astatine oxides. It is generally about 1 hr from the start of heating the quartz tube to the sublimation and completion of capture of 211< At.(Recovery of 211< At)

[0024] While still cooling the cooling tube shown in Fig. 1 or after returning the cooling tube to room temperature, an aqueous sodium hydrogen carbonate solution for the recovery of 211< At (hereinafter also referred to as the recovery liquid) is transferred into the cooling tube from the inlet on the side (the right side of the cooling tube in Fig. 1) opposite to the carrier gas transfer side of the tube. The 211< At captured in the cooling tube is dissolved therein and recovered into the reaction vessel. The recovery liquid is injected manually using a syringe, or transferred using an air compressor or vacuum pump (negative pressure) attached to the separation and purification system.

[0025] The present invention is characterized in that an aqueous sodium hydrogen carbonate solution is used as the recovery liquid when separating and purifying the irradiated target material (including 211< At) by dry distillation method in step (2).

[0026] In the present invention, the concentration of the aqueous sodium hydrogen carbonate solution used as the recovery liquid is, for example, 0.1 to 30% by weight / volume, preferably 0.5 to 10% by weight / volume, more preferably 2 to 8% by weight / volume, further preferably 3 to 8% by weight / volume.

[0027] The aqueous sodium hydrogen carbonate solution can also be a commercially available product, for example, Meylon Injection 7% (trade name) (Otsuka Pharmaceutical Factory, Inc.).

[0028] In the present invention, the amount of aqueous sodium hydrogen carbonate solution used as the recovery liquid is, for example, 0.01 to 100 mL, preferably 0.1 to 30 mL, more preferably 0.3 to 15 mL. The above-mentioned amount of the recovery liquid in multiple portions may be transferred to the cooling tube.

[0029] In step (2) of the present invention, in addition to the recovery of 211< At using an aqueous sodium hydrogen carbonate solution as the recovery liquid, the recovery of 211< At using a liquid other than an aqueous sodium hydrogen carbonate solution (e.g., water) as the recovery liquid may be combined. However, an aqueous sodium hydrogen carbonate solution is preferably used as the recovery liquid at least for the initial recovery of 211< At (i.e., the first transfer of the recovery liquid to the cooling tube).

[0030] In step (2) of the present invention, 211< At is preferably recovered using only an aqueous sodium hydrogen carbonate solution as the recovery liquid.

[0031] In the present invention, the aqueous sodium hydrogen carbonate solution used as the recovery liquid preferably does not contain either or both of a reducing agent (e.g., ascorbic acid) and an oxidizing agent (e.g., N-chlorosuccinimide), and particularly preferably does not contain both a reducing agent and an oxidizing agent. This is because reducing agents and oxidizing agents can change the oxidation-reduction state of 211< At and affect the subsequent labeling reaction.

[0032] According to the production method of the present invention, a 211< At solution can be produced with a high recovery rate even without using a reducing agent or an oxidizing agent. Therefore, the 211< At solution obtained by the production method of the present invention, which does not contain either or both of a reducing agent and an oxidizing agent (preferably, which does not contain a reducing agent or an oxidizing agent), can be widely used not only for labeling reactions of boronic acid-modified precursors and tributyltin group-modified precursors, but also for any astatinization reaction in aqueous solution.

[0033] In the present invention, after transferring the aqueous sodium hydrogen carbonate solution, which is the recovery liquid, to the cooling tube, the recovery liquid is preferably left in the cooling tube for a certain period of time (for example, 1 second or more, preferably 10 seconds or more, more preferably 30 seconds or more, further preferably 1 min or 5 min or more) (in other words, the recovery liquid and the 211< At trapped in the cooling tube are in contact for a certain period of time (for example, 1 second or more, preferably 10 seconds or more, more preferably 30 seconds or more, further preferably 1 min or 5 min or more)).

[0034] By prolonging the contact time between the recovery liquid and the 211< At trapped in the cooling tube, the recovery rate of 211< At can be increased.

[0035] The above-mentioned retention time (contact time) is 7 hr or less, preferably 1 hr or less, more preferably 10 min or less, because the half-life of 211< At is 7.2 hr, and it gradually decays and disappears.

[0036] In another embodiment of the present invention, instead of the above-mentioned sodium hydrogen carbonate, hydrogen carbonate salts such as potassium hydrogen carbonate, calcium hydrogen carbonate, cesium hydrogen carbonate, and the like; carbonate salts such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, and the like; or a carbonate buffer solution may be used as the recovery liquid.

[0037] In the present invention, the carrier gas used in distillation (step (2)) preferably contains an inert gas and O 2 .

[0038] In the present invention, the carrier gas used in distillation (step (2)) more preferably contains H 2 O in addition to the inert gas and O 2 .

[0039] Examples of inert gas in the carrier gas include He, Ne, Ar, Kr, Xe, N 2 , and the like, preferably He or N 2 .

[0040] The flow rate of the inert gas in the carrier gas is preferably 1 to 300 mL / min, more preferably 3 to 100 mL / min, further preferably 6 to 30 mL / min. The flow rate of O 2 in the carrier gas is preferably 1 to 300 mL / min, more preferably 3 to 100 mL / min, further preferably 6 to 10 mL / min. The flow rate ratio of inert gas:O 2 in the carrier gas is preferably 99:1 to 1:99, more preferably 90:10 to 10:90, further preferably 80:20 to 30:70. If the flow rate ratio of inert gas:O 2 in the carrier gas or the flow rate ratio is outside the above-mentioned range, astatine oxide is not generated and problems such as a decrease in the yield of 211< At and the like occur.

[0041] In the present invention, when the carrier gas contains H 2 O, the content of H 2 O in the carrier gas is preferably 1 to 15 µg / cm 3< , more preferably 1 to 10 µg / cm 3< , further preferably 2 to 5 µg / cm 3< . If the H 2 O content of the carrier gas is outside the above-mentioned range, problems such as a decrease in the yield of 211< At and the like occur.

[0042] In a preferred embodiment of the present invention, the flow rate of the inert gas in the carrier gas is 1 to 300 mL / min, the flow rate of O 2 in the carrier gas is 1 to 300 mL / min, the flow rate ratio of inert gas:O 2 in the carrier gas is 99:1 to 1:99, and the H 2 O content is 1 to 15 µg / cm 3< .

[0043] In a more preferred embodiment of the present invention, the flow rate of the inert gas in the carrier gas is 3 to 100 mL / min, the flow rate of O 2 in the carrier gas is 3 to 100 mL / min, the flow rate ratio of inert gas:O 2 in the carrier gas is 90:10 to 10:90, and the H 2 O content is 1 to 10 µg / cm 3< .

[0044] In a more preferred embodiment of the present invention, the flow rate of the inert gas in the carrier gas is 6 to 30 mL / min, the flow rate of O 2 in the carrier gas is 6 to 10 mL / min, the flow rate ratio of inert gas:O 2 in the carrier gas is 80:20 to 30:70, and the H 2 O content is 2 to 5 µg / cm 3< .

[0045] From the viewpoint of improving the recovery rate of 211< At, it is preferable that both the inert gas and O 2 have high purity (for example, 99.999% or higher, preferably 99.9999% or higher).

[0046] In the present invention, the temperature of the quartz tube for distillation (i.e., the distillation temperature) is preferably 500 to 850°C, more preferably 650 to 850°C, further preferably 800 to 850°C. Where the temperature of the quartz tube is outside the above-mentioned range, problems such as a decrease in the yield of 211< At and the like occur.

[0047] In the present invention, the target boat for carrying the target material is used to prevent the target material from contacting and damaging the above-mentioned quartz tube. The target boat is made of a material superior in heat resistance and corrosion resistance, such as nickel, copper, titanium, quartz, or the like, and nickel and copper are preferred.

[0048] In the present invention, the temperature of the cooling tube is, for example, -80 to 100°C, preferably -10 to 60°C, further preferably -3 to 25°C.

[0049] In the present invention, the material of the cooling tube may be, for example, a fluororesin (e.g., Teflon (registered trademark)) or a polyetheretherketone resin (e.g., PEEK). The inner diameter of the cooling tube is, for example, 1 to 3 mm. The length of the cooling tube is, for example, 1 to 100 cm.

[0050] According to the production method of the present invention, a 211< At solution can be produced with a high recovery rate. The recovery rate of 211< At by the production method of the present invention is, for example, 60% or more, preferably 70% or more, further preferably 80% or more.

[0051] The recovery rate in the present invention can be measured and calculated by the methods described in the below-mentioned Experimental Examples 1 to 3 or a method analogous thereto.

[0052] The 211< At solution obtained by the production method of the present invention can be used, for example, as a raw material for therapeutic drugs for prostate cancer, [ 211< At]PSMA-5. Conventionally, [ 211< At]PSMA-5 was produced by adding a 211< At aqueous solution (pure water or distilled water for injection) to an aqueous solution of a labeling precursor (PSMA-5 solution), then adding a 7% aqueous sodium hydrogen carbonate solution and a 0.1 mol / L aqueous potassium iodide solution, and reacting the mixture by heating at 80°C for 45 min (WO2023 / 008556). The 211< At solution obtained by the production method of the present invention shows a high recovery rate. Therefore, the raw material costs are expected to be reduced by using the 211< At solution obtained by the production method of the present invention instead of the 211< At aqueous solution (pure water or distilled water for injection) used as a raw material in the above-mentioned method.

[0053] Furthermore, the 211< At solution obtained by the production method of the present invention is, in principle, also applicable to the production of pharmaceutical products other than the aforementioned PSMA-5, except for compounds that are unstable in the presence of sodium hydrogen carbonate (pH 8-9). PSMA-5 contains a boronic acid group within the molecule, and the boronic acid group undergoes a substitution reaction with astatine. Therefore, the 211< At solution obtained by the production method of the present invention is particularly useful in the astatination reaction of compounds containing a boronic acid group. In addition, the 211< At solution obtained by the production method of the present invention can also be used in the astatination reaction of compounds containing alkyltin group or alkylsilyl group, in addition to boronic acid group.

[0054] The present invention also relates to a method for recovering astatine-211, including a step of irradiating bismuth with α rays to generate astatine-211 in the bismuth (step (1)), and a step of distilling the bismuth irradiated with α rays to separate and purify the astatine-211 and dissolving the astatine-211 in an aqueous sodium hydrogen carbonate solution (step (2)) (also referred to as the recovery method of the present invention in the present specification).

[0055] In the recovery method of the present invention, step (1) and step (2) can be performed in the same manner as step (1) and step (2) of the aforementioned production method of the present invention.[Example]

[0056] The present invention is described in more detail in the following based on Examples and Experimental Examples, but the present invention is not limited thereto.[Experimental Example 1](Example 1)

[0057] A bismuth target material was irradiated with helium ions accelerated to 28 MeV using a cyclotron, and 211< At was produced by the 209< Bi( 4< He,2n) 211< At nuclear reaction.

[0058] This target material (containing 211< At, using Ni boat) was separated and purified by dry distillation method. Specifically, the irradiated target material was placed in a quartz tube, and the target material was heated to 850°C under a stream of a mixed gas (carrier gas) of helium (6 mL / min) and oxygen (10 mL / min), to which water (3000-4000 ppm (adjusted as needed during the process to stay within this range)) was added, and then captured in a cooling tube (temperature: -3°C, made of Teflon (registered trademark), inner diameter 2 mm x length 600 mm) connected to the downstream side of the quartz tube.

[0059] Then, 0.1 mL of a recovery liquid (7% aqueous sodium hydrogen carbonate solution (Meylon Injection 7% (trade name) (Otsuka Pharmaceutical Factory, Inc.) was injected into the cooling tube from the downstream side. The recovery liquid was left in the tube for 5 min, and then transferred to a reaction vessel to obtain 211< At solution (fraction 1). The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution), leaving same in the tube for 5 min, and transferring same to the reaction vessel was repeated four more times to obtain 211< At solution (fractions 2-5).

[0060] Furthermore, 5 mL of ethanol as a washing solution and 30 mL of distilled water for injection were sequentially injected into the cooling tube, and the remaining 211< At was recovered into a vial for the washing solution.

[0061] The radioactivity in the recovery liquid ( 211< At solution of each fraction) transferred to the above-mentioned reaction vessel and in the washing solution recovered in the vial for the washing solution was measured using an RI dose calibrator (Capintec). The recovery rate of the 211< At solution (all fractions) was calculated according to the following calculation formula 1. The results are shown in Table 1. [Math. 1] recovery rate % in 211 At solution all fractions = total radioactivity MBq of recovery liquid each fraction transferred to reaction vessel total radioactivity MBq of recovery liquid each fraction transferred to reaction vessel + radioactivity MBq of washing solution recovered in vial for washing solution × 100 (Example 2)

[0062] Using the same method as in Example 1, the 211< At solution (fractions 1-5) of Example 2 were obtained.

[0063] Using the same method as in Example 1, the remaining 211< At was recovered using a washing solution into a vial for washing solution, the radioactivity in the recovery liquid (each fraction) transferred to the reaction vessel and in the washing solution recovered in the vial for washing solution was measured, and the recovery rate of the 211< At solution (all fractions) was calculated. The results are shown in Table 1.(Examples 3 - 6)

[0064] Using the same method as in Example 1 except that "The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution), leaving same in the tube for 5 min, and transferring same to the reaction vessel was repeated four more times to obtain 211< At solution (fractions 2-5)" in Example 1 was changed to "The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution), leaving same in the tube for 5 min, and transferring same to the reaction vessel was repeated six more times to obtain 211< At solution (fractions 2-7)", each of the 211< At solutions (fractions 1-7) of Examples 3 - 6 was obtained.

[0065] Using the same method as in Example 1, the remaining 211< At was recovered using a washing solution into a vial for washing solution, the radioactivity in the recovery liquid (each fraction) transferred to the reaction vessel and in the washing solution recovered in the vial for washing solution was measured, and the recovery rate of each 211< At solution (all fractions) was calculated. The results are shown in Table 1.(Example 7)

[0066] Using the same method as in Example 1 except that "leaving the recovery liquid in the tube for 5 min" in Example 1 was changed to "leaving the recovery liquid in the tube for 1 min", and "The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution), leaving same in the tube for 5 min, and transferring same to the reaction vessel was repeated four more times to obtain 211< At solution (fractions 2-5)" in Example 1 was changed to "The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution), leaving same in the tube for 1 min, and transferring same to the reaction vessel was repeated nine more times to obtain 211< At solution (fractions 2-10)", the 211< At solution (fractions 1-10) of Example 7 was obtained.

[0067] Using the same method as in Example 1, the remaining 211< At was recovered using a washing solution into a vial for washing solution, the radioactivity in the recovery liquid (each fraction) transferred to the reaction vessel and in the washing solution recovered in the vial for washing solution was measured, and the recovery rate of the 211< At solution (all fractions) was calculated. The results are shown in Table 1.(Example 8)

[0068] Using the same method as in Example 1 except that "leaving the recovery liquid in the tube for 5 min" in Example 1 was not performed, and "The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution), leaving same in the tube for 5 min, and transferring same to the reaction vessel was repeated four more times to obtain 211< At solution (fractions 2-5)" in Example 1 was changed to "The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution), and transferring same to the reaction vessel was repeated nine more times to obtain 211< At solution (fractions 2-10)", the 211< At solution (fractions 1-10) of Example 8 was obtained.

[0069] Using the same method as in Example 1, the remaining 211< At was recovered using a washing solution into a vial for washing solution, the radioactivity in the recovery liquid (each fraction) transferred to the reaction vessel and in the washing solution recovered in the vial for washing solution was measured, and the recovery rate of the 211< At solution (all fractions) was calculated. The results are shown in Table 1.(Comparative Example 1)

[0070] Using the same method as in Example 1 except that the 7% aqueous sodium hydrogen carbonate solution as the recovery liquid in Example 1 was changed to distilled water, and "leaving the recovery liquid in the tube for 5 min" in Example 1 was not performed, the 211< At solution (fractions 1-5) of Comparative Example 1 was obtained.

[0071] Using the same method as in Example 1, the remaining 211< At was recovered using a washing solution into a vial for washing solution, the radioactivity in the recovery liquid (each fraction) transferred to the reaction vessel and in the washing solution recovered in the vial for washing solution was measured, and the recovery rate of the 211< At solution (all fractions) was calculated. The results are shown in Table 1.

[0072] The recovery rate when 211< At was recovered using distilled water (water for injection) as the recovery liquid was only 33% (Comparative Example 1).

[0073] On the other hand, when 211< At was recovered using 0.5 or 0.7 mL of a 7% aqueous sodium hydrogen carbonate solution as the recovery liquid and leaving same for 5 min, the recovery rate was highest and 90.7-94.4% (Examples 1-6). The volume of the 7% aqueous sodium hydrogen carbonate solution was not particularly different and was 0.5 mL or 0.7 mL.

[0074] Even when the leaving time of the 7% aqueous sodium hydrogen carbonate solution was shortened to 1 min, the recovery rate remained high at 91.2% (Example 7).

[0075] In Examples 1-8, the recovery rate was markedly higher than in Comparative Example 1. [Table 1]carrier gastarget boatkind of recovery liquidretention time of recovery liquid in cooling tubeall fractionsHe gas (mL / min)O 2 gas (mL / min)water (ppm)total liquid volume (mL) of recovery liquidrecovery rate (%) in 211< At solution (all fractions)Example 17% aqueous sodium hydrogen carbonate solution5 min0.5 (*1)94.4Example 20.5 (*1)90.7Example 30.7 (*2)91. 8Example 40.7 (*2)91.9Example 56103000-4000nickel0.7 (*2)91. 7Example 60.7 (*2)93.5Example 71 min1.0 (*3)91.2Example 80 min1.0 (*3)85.9Comparative Example 1distilled water0 min0.5 (*1)33.0*1: total of 0.1 mL of recovery liquid x 5 times *2: total of 0.1 mL of recovery liquid x 7 times *3: total of 0.1 mL of recovery liquid x 10 times [Experimental Example 2]

[0076] Using the same method as in Comparative Example 1 in Experimental Example 1 except that the carrier gas "a mixed gas of helium (6 mL / min) and oxygen (10 mL / min), to which water (3000-4000 ppm) was added" was changed to "a mixed gas of nitrogen (30 mL / min) and oxygen (10 mL / min), to which water (3000-4000 ppm) was added" and the number of operations of injecting 0.1 mL of the recovery liquid and transferring to the reaction vessel was changed to make the total volume of the recovery liquid that listed in Table 2, the 211< At solution (fractions 1-4) of Comparative Example 2, the 211< At solution (fractions 1-3) of Comparative Example 3, and the 211< At solution (fractions 1-4) of Comparative Example 4 were obtained.

[0077] The radioactivity in the recovery liquid ( 211< At solution of each fraction) transferred to the above-mentioned reaction vessel was measured using a Ge semiconductor detector (manufactured by Canberra). Furthermore, the cooling tube was removed after the procedure and the radioactivity was directly measured using a Ge semiconductor detector (manufactured by Canberra). The recovery rate of the 211< At solution (all fractions) was calculated according to the following calculation formula 2, and the recovery rate of the 211< At solution (fraction 1) was calculated according to the following calculation formula 3. The results are shown in Table 2. [Math. 2] recovery rate % in 211 At solution all fractions = total radioactivity MBq of recovery liquid each fraction transferred to reaction vessel total radioactivity MBq of recovery liquid each fraction transferred to reaction vessel + radioactivity MBq of removed cooling tube × 100 [Math. 3] recovery rate % in 211 At solution fraction 1 = radioactivity MBq of recovery liquid fraction 1 transferred to reaction vessel total radioactivity MBq of recovery liquid each fraction transferred to reaction vessel + radioactivity MBq of removed cooling tube × 100

[0078] The recovery rate when 211< At was recovered with 0.3 to 0.4 mL of distilled water (water for injection) was an average of 71% (average of Comparative Examples 2 to 4), but there was some variation in the recovery rate (57.5 - 78.5%). [Table 2]carrier gastarget boatkind of recovery liquidfraction 1all fractionsN 2 gas (mL / min)O 2 gas (mL / min)water (ppm)liquid volume (mL) of recovery liquidrecovery rate (%) in 211< At solution (fraction 1)total liquid volume (mL) of recovery liquidrecovery rate (%) in 211< At solution (all fractions)Comparative Example 251.60.4 (*1)77.6Comparative Example 330103000-4000nickeldistilled water0.164.90.3 (*2)78.5Comparative Example 432.40.4 (*1)57.5*1: total of 0.1 mL of recovery liquid x 4 times *2: total of 0.1 mL of recovery liquid x 3 times [Experimental Example 3](Example 9)

[0079] A bismuth target material was irradiated with helium ions accelerated to 28 MeV using a cyclotron, and 211< At was produced by the 209< Bi( 4< He,2n) 211< At nuclear reaction.

[0080] This target material (containing 211< At, using Cu boat) was separated and purified by dry distillation method. Specifically, the irradiated target material was placed in a quartz tube, and the target material was heated to 850°C under a stream of a mixed gas (carrier gas) of nitrogen (30 mL / min) and oxygen (10 mL / min), to which water (3000-4000 ppm (adjusted as needed during the process to stay within this range)) was added, and then captured in a cooling tube (temperature: -3°C, made of Teflon (registered trademark), inner diameter 2 mm x length 600 mm) connected to the downstream side of the quartz tube.

[0081] Then, 0.1 mL of a recovery liquid (7% aqueous sodium hydrogen carbonate solution (Meylon Injection 7% (trade name) (Otsuka Pharmaceutical Factory, Inc.) was injected into the cooling tube from the downstream side. The recovery liquid was transferred to a reaction vessel to obtain 211< At solution (fraction 1). The operation of injecting 0.1 mL of the recovery liquid (7% aqueous sodium hydrogen carbonate solution) and transferring same to the reaction vessel was repeated two more times to obtain 211< At solution (fractions 2, 3).

[0082] The radioactivity in the recovery liquid ( 211< At solution of each fraction) transferred to the above-mentioned reaction vessel was measured using a Ge semiconductor detector (manufactured by Canberra). Furthermore, the cooling tube was removed after the procedure and the radioactivity was directly measured using a Ge semiconductor detector (manufactured by Canberra). The recovery rate of the 211< At solution (all fractions) was calculated according to the aforementioned calculation formula 2, and the recovery rate of the 211< At solution (fraction 1) was calculated according to the aforementioned calculation formula 3. The results are shown in Table 3.(Comparative Examples 5, 6, 9)

[0083] Using the same method as in Example 9 except that the 7% aqueous sodium hydrogen carbonate solution as the recovery liquid in Example 9 was changed to distilled water, and the number of operations of injecting 0.1 mL of the recovery liquid and transferring to the reaction vessel was changed to make the total volume of the recovery liquid that listed in Table 3, the 211< At solution (fractions 1-4) of Comparative Example 5, the 211< At solution (fractions 1-4) of Comparative Example 6, and the 211< At solution (fractions 1-4) of Comparative Example 9 were obtained.

[0084] Using the same method as in Example 9, the radioactivity in the recovery liquid ( 211< At solution of each fraction) transferred to the reaction vessel and the radioactivity of the removed cooling tube were measured, and the recovery rate of the 211< At solution (all fractions) was calculated. The results are shown in Table 3.(Comparative Examples 7, 8)

[0085] Using the same method as in Example 9 except that the 7% aqueous sodium hydrogen carbonate solution as the recovery liquid in Example 9 was changed to distilled water, the 211< At solution (fractions 1-3) of Comparative Example 7 and the 211< At solution (fractions 1-3) of Comparative Example 8 were obtained.

[0086] Using the same method as in Example 9, the radioactivity in the recovery liquid ( 211< At solution of each fraction) transferred to the reaction vessel and the radioactivity of the removed cooling tube were measured, and the recovery rate of the 211< At solution (all fractions) was calculated. The results are shown in Table 3.

[0087] The recovery rate when 211< At was recovered with 0.3-0.4 mL of distilled water (water for injection) was an average of 81.6% (average of all fractions of Comparative Examples 5-9).

[0088] Even when 211< At was recovered with 0.1 mL of a 7% aqueous sodium hydrogen carbonate solution, the recovery rate was 87% (fraction 1 of Example 9), and the highest value of 96.3% (all fractions of Example 9) was obtained by recovery with an additional total amount of 0.3 mL. [Table 3]carrier gastarget boatkind of recovery liquidfraction 1all fractionsN 2 gas (mL / min)O 2 gas (mL / min)water (ppm)liquid volume (mL) of recovery liquidrecovery rate (%) in 211< At solution (fraction 1)total liquid volume (mL) of recovery liquidrecovery rate (%) in 211< At solution (all fractions)Comparative Example 530103000-4000copperdistilled water0.158.30.4 (*1)82.1Comparative Example 659.10.4 (*1)80.5Comparative Example 751.00.3 (*2)71.1Comparative Example 872.00.3 (*2)87.5Comparative Example 956.90.4 (*1)86.7Example 930103000-4000copper7% aqueous sodium hydrogen carbonate solution0.187.00.3 (*2)96.3*1: total of 0.1 mL of recovery liquid x 4 times *2: total of 0.1 mL of recovery liquid x 3 times [Industrial Applicability]

[0089] According to the production method of the present invention, 211< At solution can be produced with a high recovery rate.

[0090] This application is based on patent application No. 2023-187204 filed in Japan, the contents of which are encompassed in full herein.

Claims

1. A method for producing an astatine-211 solution, comprising a step of irradiating bismuth with α rays to generate astatine-211 in the bismuth, and a step of distilling the bismuth irradiated with α rays to separate and purify the astatine-211 and dissolving the astatine-211 in an aqueous sodium hydrogen carbonate solution.

2. The production method according to claim 1, wherein the aqueous sodium hydrogen carbonate solution does not comprise either a reducing agent or an oxidizing agent, or both.

3. The production method according to claim 1, wherein the separated and purified astatine-211 is dissolved by contacting the astatine-211 with the aqueous sodium hydrogen carbonate solution for 10 seconds or more.

4. The production method according to claim 1, wherein a carrier gas used for the distillation comprises an inert gas and O2.

5. The production method according to claim 4, wherein the carrier gas further comprises H2O.

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