Method for producing a solution of astatine

Abstract

Provided is a method for producing a solution of atropine with improved recovery. A method for producing a solution of atropine-211, comprising the steps of: irradiating bismuth with alpha rays, generating atropine-211 in the bismuth, and distilling the bismuth irradiated with the alpha rays, separating and purifying atropine-211, and dissolving it in an aqueous sodium bicarbonate solution.

Description

Technical Field

[0001] This invention relates to a method for producing astatine solutions with improved recovery rates. Background Technology

[0002] Astatine-211 ( 211 Alpha-rays (A) are alpha-ray emitting isotopes, belonging to the halogen group along with iodine. Alpha rays release enormous energy within a short range equivalent to a few cells, thus, by selectively accumulating them at lesion sites such as cancer cells, it is hoped that significant therapeutic effects can be achieved while suppressing the impact on surrounding tissues. In recent years, the use of... 211 Nuclear medicine therapy using sodium astatine has attracted much attention, and publicly available literature has disclosed: sodium astatine ([ 211 Like iodine, NaAt is taken up by cancer cells via a sodium-iodine cotransporter expressed in differentiated thyroid cancer, showing a dose-dependent tumor proliferation inhibition effect and improved survival (Non-Patent Literature 1 & 2, Patent Literature 1).

[0003] 211 At uses bismuth (Bi) as the target material, through... 209 Bi ( 4 He, 2n) 211 At nuclear reactions produce, and contain 211 At was obtained in the form of Bi plates. The purified Bi plates were then isolated from these plates. 211 The method of At is known to include dry distillation (e.g., Patent Document 1, Patent Document 2). This method utilizes... 211 At and 209 The technique for separating Bi based on boiling point differences involves heating the Bi plates in an electric furnace to approximately 850°C, causing only the lower boiling point Bi plates to separate. 211 At (boiling point approximately 330°C) vaporizes and is captured by a cold trap tube located downstream of the electric furnace.

[0004] Collected in the cold trap tube 211 At, good recovery can be achieved mainly through the use of chloroform (non-patent literature 3). After recovery, it is removed and reacted with precursors containing tributyltin groups as leaving groups in the presence of appropriate organic solvents and oxidants to synthesize astatine-labeled drugs. However, chloroform is highly toxic and is considered to pose significant problems in the manufacture of drugs for intravenous administration to humans. On the other hand, methods for capturing at... 211 At, when recovered with water, exhibits a good labeling reaction in aqueous solution with a precursor containing boric acid as a leaving group in the presence of sodium bicarbonate and potassium iodide (Non-Patent Literature 4). However, water recovery... 211The recovery rate of At is lower than that of chloroform, with a recovery rate of only about 30% when using 0.5 mL of water (see Comparative Example 1 of Test Example 1 described later). To obtain high yields of radioactivity in the labeling reaction using boric acid precursors, it is necessary to improve the recovery rate.

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: WO2019 / 131998

[0008] Patent Document 2: WO2019 / 112034

[0009] Non-patent literature

[0010] [Non-Patent Literature 1] Watabe et al., J Nucl Med 2019, volume 60, issue 9, pages 1301-1307; doi.10.2967 / jnumed.118.222638

[0011] [Non-Patent Literature 2] Watabe et al., Int J Mol Sci 2022, volume 23, issue 16, 9434; doi.org / 10.3390 / ijms23169434 (Watabe et al., International Journal of Molecular Sciences, 2022, Vol. 23, No. 16, Document No.: 9434; DOI: 10.3390 / ijms23169434)

[0012] [Non-Patent Literature 3] Lindegren et al., Applied Radiation and Isotopes, volume 55, issue 2, 2001, pages 157-160.

[0013] [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 the Invention

[0014] The technical problem that the invention aims to solve

[0015] The purpose of this invention is to provide a method for manufacturing an astatine solution with improved recovery rate.

[0016] Technical solutions to solve technical problems

[0017] Through in-depth research, the inventors discovered that when recovering purified material from a cold trap tube... 211 At, using an aqueous solution of sodium bicarbonate can improve... 211 The recovery rate of At. Furthermore, the inventors have also discovered that when recovering purified At from the cold trap tube... 211 At this time, the sodium bicarbonate aqueous solution is stopped from being transported in the cold trap tube for a certain period of time, allowed to stand, and then recovered (i.e., the separated and purified sodium bicarbonate is recovered). 211 (Prolonged contact time between At and sodium bicarbonate aqueous solution) can further improve 211 At recovery rate.

[0018] Based on this new discovery, the inventors conducted further in-depth research, thereby completing this invention.

[0019] That is, the present invention provides the following content.

[0020] [1] A method for manufacturing an astatine-211 solution, comprising:

[0021] The steps of irradiating bismuth with alpha rays to generate astatine-211 in the bismuth, and

[0022] The steps of distilling the bismuth irradiated with the α-ray, separating and purifying astatine-211, and dissolving it in an aqueous sodium bicarbonate solution (also described in this specification as the manufacturing method of the present invention) are also described.

[0023] [2] The manufacturing method described in [1] above, wherein the sodium bicarbonate aqueous solution does not contain either or both of the reducing agent and the oxidizing agent.

[0024] [3] The manufacturing method described in [1] above, wherein the purified astatine-211 is dissolved by contacting an aqueous sodium bicarbonate solution for more than 10 seconds.

[0025] [4] The manufacturing method described in [1] above, wherein the carrier gas used for distillation contains an inert gas and O2.

[0026] [5] The manufacturing method described in [4] above, wherein the carrier gas further contains H2O.

[0027] [6] A method for recovering astatine-211, comprising:

[0028] The steps of irradiating bismuth with alpha rays to generate astatine-211 in the bismuth, and

[0029] The steps include distilling the bismuth irradiated by the α-rays to separate and purify astatine-211, and dissolving it in an aqueous sodium bicarbonate solution.

[0030] [7] The recovery method described in [6] above, wherein the sodium bicarbonate aqueous solution does not contain either or both of the reducing agent and the oxidizing agent.

[0031] [8] The recovery method described in [6] above, wherein the separated and purified astatine-211 is dissolved by contacting an aqueous sodium bicarbonate solution for more than 10 seconds.

[0032] [9] The recovery method described in [6] above, wherein the carrier gas used for distillation contains inert gases and O2.

[0033]

[10] The recovery method as described in [9] above, wherein the carrier gas further contains H2O.

[0034] Invention Effects

[0035] According to the manufacturing method of the present invention, it is possible to manufacture with a high recovery rate. 211 At solution.

[0036] The manufacturing method of the present invention can be carried out without using highly toxic organic solvents such as chloroform and methanol. Therefore, the product obtained by the manufacturing method of the present invention... 211 At solutions do not require distillation to remove organic solvents and can be widely used in astatination reactions in aqueous solutions, primarily in labeling reactions using boric acid precursors or tributyltin-modified precursors.

[0037] Obtained by the manufacturing method of the present invention 211 At solutions do not contain organic solvents such as chloroform and methanol, therefore they can be used as pharmaceutical raw materials.

[0038] Furthermore, the manufacturing method of the present invention can be carried out without the use of reducing agents or oxidizing agents. Therefore, the product obtained by the manufacturing method of the present invention...211 At solutions contain neither reducing agents nor oxidizing agents and can be used for any labeling reaction.

[0039] Brief description of the attached diagram

[0040] Figure 1 This is a schematic diagram illustrating an example of an apparatus for implementing step (2) of the present invention. Detailed Implementation

[0041] The present invention will now be described in detail.

[0042] The present invention 211 The method for manufacturing At solution includes the following steps (1) and (2).

[0043] Step (1): Irradiate bismuth with alpha rays to generate bismuth. 211 The steps of At.

[0044] Step (2): Distill the bismuth irradiated with the α-ray. 211 At is used to separate and purify the substance, and then dissolve it in an aqueous solution of sodium bicarbonate.

[0045] In step (1), bismuth is subjected to alpha rays using an accelerator (e.g., a cyclotron). As the accelerator, any accelerator capable of accelerating alpha rays to 30 MeV can be used.

[0046] Step (1) can be performed, for example, by the following method.

[0047] Target material is prepared by thinly coating bismuth onto an aluminum plate (e.g., approximately 30 mm wide × 70 mm long × 2 mm) using a vapor deposition method. The target material is then irradiated with helium ions (1–50 μA) to approximately 28 MeV using a cyclotron for 10 minutes–24 hours. 209 Bi ( 4 He, 2n) 211 At nuclear reactions produce 211 At. 211 At is in a state where it is embedded in the target material bismuth.

[0048] exist Figure 1 A schematic diagram of an example of a device for implementing step (2) is shown below. Hereinafter, refer to... Figure 1 Step (2) will be explained.

[0049] (Based on dry distillation apparatus) 211 (Isolation / purification of At)

[0050] The target material (containing) after being irradiated by the accelerator 211 At) is separated and purified by dry distillation.

[0051] Specifically, the target material (bismuth-coated side up), placed on a high-boiling-point metal (target boat) such as nickel (Ni) or copper (Cu), is placed into a quartz tube, and the material is introduced from the inlet of the quartz tube. Figure 1 A carrier gas (e.g., a mixture of O2, He, and H2O) is introduced into the quartz tube (left side). When the quartz tube is heated to the distillation temperature (e.g., 850°C) using an electric furnace, the bismuth of the target material melts, and simultaneously... 211 At sublimates and flows out of the quartz tube outlet with the carrier gas. Figure 1 The quartz tube (right side) is fed to the cooling tube via a three-way valve. 211 At is captured in the cooling tube. For the piping from the quartz tube outlet to the cooling tube via a three-way valve, to prevent the deposition of volatile astatine oxides, it is heated to approximately 130°C using a heater. From the start of heating the quartz tube to... 211 The sublimation and capture of At typically lasts about 1 hour.

[0052] ( 211 At recycling)

[0053] make Figure 1 The cooling pipe is kept cooled, or after returning to room temperature, the inlet on the side of the pipe opposite to the carrier gas delivery side ( Figure 1 The right side of the intermediate cooling pipe will be used for recycling. 211 The liquid at (hereinafter also referred to as the recovery liquid), namely an aqueous solution of sodium bicarbonate, is supplied to the cooling pipes, where it will be collected. 211 The solution is dissolved and recovered into the reaction vessel. The recovered liquid is injected manually by loading it into a syringe, or delivered via a compressed air device or vacuum pump (negative pressure) attached to the separation and purification system.

[0054] The invention is characterized in that, in step (2), an aqueous solution of sodium bicarbonate is used as the solvent for the irradiated target material (containing...) by dry distillation. 211 The liquid recovered during the separation and purification process using At).

[0055] In this invention, the concentration of the sodium bicarbonate aqueous solution used as the recovery liquid is, for example, 0.1 to 30 wt / volume%, preferably 0.5 to 10 wt / volume%, more preferably 2 to 8 wt / volume%, and even more preferably 3 to 8 wt / volume.

[0056] Sodium bicarbonate aqueous solution can be commercially available, such as Meylon intravenous injection 7% (trade name) (Otsuka Pharmaceutical Co., Ltd.).

[0057] In this invention, the amount of sodium bicarbonate aqueous solution used as the recovery liquid is, for example, 0.01 to 100 mL, preferably 0.1 to 30 mL, and more preferably 0.3 to 15 mL. When supplying the recovery liquid to the cooling pipe, the above-mentioned amount can be used in multiple applications.

[0058] In step (2) of the present invention, in addition to using an aqueous solution of sodium bicarbonate as the recovery liquid, 211 In addition to At recovery, liquids other than sodium bicarbonate aqueous solution (such as water) can also be used as recovery liquids. 211 At's recovery, but at least for the first time. 211 At recovery (i.e., the initial delivery of the recovery liquid to the cooling pipe) uses an aqueous solution of sodium bicarbonate as the recovery liquid.

[0059] In step (2) of the present invention, 211 For the recovery of At, it is preferable to use only an aqueous solution of sodium bicarbonate as the recovery liquid.

[0060] In this invention, the sodium bicarbonate aqueous solution used as the recovery liquid preferably does not contain any 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 alter... 211 The redox state of At may affect subsequent labeling reactions.

[0061] According to the manufacturing method of the present invention, high recovery rates can be achieved even without the use of reducing agents or oxidizing agents. 211 The At solution, therefore, is obtained by the manufacturing method of the present invention without containing either or both of a reducing agent and an oxidizing agent (preferably without both reducing agent and oxidizing agent). 211 At solutions can be used not only for labeling reactions of boric acid-modified precursors and tributyltin-modified precursors, but also for arbitrary astatinization reactions in aqueous solutions.

[0062] In this invention, after the sodium bicarbonate aqueous solution used as the recovery liquid is supplied to the cooling pipe, it is preferable to retain the recovery liquid in the cooling pipe for a certain period of time (e.g., more than 1 second, preferably more than 10 seconds, more preferably more than 30 seconds, and even more preferably more than 1 minute or 5 minutes) (in other words, to allow the recovery liquid to react with the sodium bicarbonate solution trapped in the cooling pipe). 211 At contact time (e.g., more than 1 second, preferably more than 10 seconds, more preferably more than 30 seconds, and even more preferably more than 1 minute or 5 minutes)).

[0063] By extending the time between the recovered liquid and the liquid trapped in the cooling pipes... 211 The contact time of At can improve 211At recovery rate.

[0064] The above-mentioned detention time (contact time) is due to 211 At has a half-life of 7.2 hours and gradually decays and disappears, so it is less than 7 hours, preferably less than 1 hour, and more preferably less than 10 minutes.

[0065] In this invention, as other methods, the following substances can be used instead of sodium bicarbonate as the recovery liquid: bicarbonates such as potassium bicarbonate, calcium bicarbonate, and cesium bicarbonate; carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, and cesium carbonate; and carbonate buffer solution.

[0066] In this invention, the carrier gas used in distillation (step (2)) preferably contains an inert gas and O2.

[0067] In this invention, the carrier gas used in distillation (step (2)) is more preferably H2O in addition to inert gases and O2.

[0068] Examples of inert gases in the carrier gas include He, Ne, Ar, Kr, Xe, and N2, with He or N2 being preferred.

[0069] The flow rate of the inert gas in the carrier gas is preferably 1–300 mL / min, more preferably 3–100 mL / min, and even more preferably 6–30 mL / min. The flow rate of O2 in the carrier gas is preferably 1–300 mL / min, more preferably 3–100 mL / min, and even more preferably 6–10 mL / min. The flow rate ratio of the inert gas to O2 in the carrier gas is preferably 99:1–1:99, more preferably 90:10–10:90, and even more preferably 80:20–30:70. If the flow rate ratio of the inert gas to O2 in the carrier gas is outside the above ranges, astatine oxides cannot be formed. 211 Issues such as reduced At yield.

[0070] In this invention, when the carrier gas contains H2O, the H2O content in the carrier gas is preferably 1–15 μg / cm³. 3 More preferably 1–10 μg / cm 3 More preferably 2–5 μg / cm 3 If the H2O content in the carrier gas is outside the above range, it will produce... 211 Issues such as reduced At yield.

[0071] In a preferred embodiment of the present invention, the flow rate of the inert gas in the carrier gas is 1–300 mL / min, the flow rate of O2 in the carrier gas is 1–300 mL / min, the flow rate ratio of the inert gas to O2 in the carrier gas is 99:1 to 1:99, and the H2O content is 1–15 μg / cm³. 3 .

[0072] In a more preferred embodiment of the present invention, the flow rate of the inert gas in the carrier gas is 3–100 mL / min, the flow rate of O2 in the carrier gas is 3–100 mL / min, the flow rate ratio of the inert gas to O2 in the carrier gas is 90:10–10:90, and the H2O content is 1–10 μg / cm³. 3 .

[0073] In a further preferred embodiment of the present invention, the flow rate of the inert gas in the carrier gas is 6–30 mL / min, the flow rate of O2 in the carrier gas is 6–10 mL / min, the flow rate ratio of the inert gas to O2 in the carrier gas is 80:20–30:70, and the H2O content is 2–5 μg / cm³. 3 .

[0074] From improving 211 From the perspective of At recovery rate, both inert gases and O2 are preferably of high purity (e.g., 99.999% or higher, preferably 99.9999% or higher).

[0075] In this invention, the temperature of the quartz tube used for distillation (i.e., the distillation temperature) is preferably 500–850°C, more preferably 650–850°C, and even more preferably 800–850°C. If the temperature of the quartz tube is not within the above range, it will produce… 211 Issues such as reduced At yield.

[0076] In this invention, the target boat used to hold the target material is intended to prevent the quartz tube from being damaged due to contact with the target material. The target boat is made of a material with excellent heat resistance and corrosion resistance, such as nickel, copper, titanium, quartz, etc., with nickel and copper being preferred.

[0077] In this invention, the temperature of the cooling pipe is, for example, -80 to 100°C, preferably -10 to 60°C, and more preferably -3 to 25°C.

[0078] In this invention, the material of the cooling pipe may include, for example, fluoropolymers (e.g., Teflon, a registered trademark) and polyetheretherketone resins (e.g., PEEK). The inner diameter of the cooling pipe is, for example, 1 to 3 mm. The length of the cooling pipe is, for example, 1 to 100 cm.

[0079] According to the manufacturing method of the present invention, it is possible to manufacture with a high recovery rate. 211 At solution. Based on the manufacturing method of the present invention.211 The recovery rate of At is, for example, 60% or more, preferably 70% or more, and even more preferably 80% or more.

[0080] The recovery rate in this invention can be calculated by the method described in or based on the test examples 1 to 3 described later.

[0081] Obtained by the manufacturing method of the present invention 211 At solutions, for example, can be used as a treatment for prostate cancer. 211 At]PSMA-5 raw material. Previously, it was added to an aqueous solution of the labeling precursor (PSMA-5 solution). 211 An aqueous solution of At (pure water or distilled water for injection) is added, followed by the addition of a 7% sodium bicarbonate aqueous solution and a 0.1 mol / L potassium iodide aqueous solution. The mixture is then heated at 80°C for 45 minutes to produce […]. 211 At]PSMA-5 (WO2023 / 008556). Due to the manufacturing method of the present invention, it is obtained... 211 At solutions can be obtained with high recovery rates, therefore, solutions obtained using the manufacturing method of the present invention... 211 At solution can be used as a raw material in the above methods. 211 Aqueous solutions of At (pure water or distilled water for injection) can be expected to reduce raw material costs.

[0082] Furthermore, the manufacturing method of the present invention yields... 211 In addition to PSMA-5, the At solution can, in principle, be used in the manufacture of other pharmaceutical products, except for compounds that are unstable in the presence of sodium bicarbonate (pH 8-9). PSMA-5 contains a borate group, which can undergo a substitution reaction with astatine. Therefore, the method of this invention yields… 211 At solutions are particularly useful in the astatidization reactions of compounds containing boric acid groups. Furthermore, the method of manufacture of the present invention yields… 211 At solution can also be used for the astatinization reaction of compounds containing alkyltin or alkylsilane groups other than borate groups.

[0083] The present invention also relates to a method for recovering astatine-211 (also referred to in this specification as the recovery method of the present invention), comprising: irradiating bismuth with α rays to generate astatine-211 in the bismuth (step (1)), and distilling the bismuth irradiated with the α rays to separate and purify the astatine-211 and dissolve it in an aqueous sodium bicarbonate solution (step (2)).

[0084] In the recycling method of the present invention, steps (1) and (2) can be performed in the same way as steps (1) and (2) of the manufacturing method of the present invention described above.

[0085]

Example

[0086] The present invention will now be described in more detail based on embodiments and test examples, but the present invention is not limited thereto.

[0087] [Experimental Example 1]

[0088] (Example 1)

[0089] The bismuth target material was irradiated with helium ions accelerated to 28 MeV using a cyclotron, and then... 209 Bi ( 4 He, 2n) 211 At is produced by nuclear reaction. 211 At.

[0090] The target material (containing) was subjected to dry distillation. 211 At, separation and purification are performed using a Ni boat. That is, the irradiated target material is placed in a quartz tube, and the target material is heated to 850°C under a mixed gas flow (carrier gas) of helium (6 mL / min) and oxygen (10 mL / min) with added water (3000-4000 ppm (adjusted during operation to maintain within this range)). The target material is then trapped in a cooling tube (temperature: -3°C, material: Teflon (registered trademark), inner diameter 2 mm × length 600 mm) connected to the downstream side of the quartz tube.

[0091] Next, 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution (Meylon intravenous injection 7% (trade name), Otsuka Pharmaceutical Co., Ltd.)) was injected into the cooling tube from the downstream side. After the recovery liquid was left in the tube for 5 minutes, it was transferred to the reaction vessel to obtain... 211 At solution (fraction 1). The process of injecting 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution), allowing it to remain in the tube for 5 minutes, and then transferring it to the reaction vessel was repeated four times to obtain… 211 At solution (fraction 2-5).

[0092] Next, 5 mL of cleaning solution ethanol and 30 mL of distilled water for injection were sequentially injected into the cooling tube to remove any remaining residue. 211 At is recovered into a small vial of cleaning fluid.

[0093] The recovery liquid (each fraction) transferred to the above reaction vessel was measured using an RI dosimeter (manufactured by Capintec). 211 The radioactivity of the At solution and the cleaning solution recovered in the cleaning solution vial is calculated according to the following formula 1. 211 Recovery of At solution (all fractions). Results are shown in Table 1.

[0094]

Number 1

[0095] (Calculation Formula 1)

[0096]

[0097] (Example 2)

[0098] Using the same method as in Example 1, Example 2 was obtained. 211 At solution (fractions 1-5).

[0099] Using the same method as in Example 1, the residual [substance / material] was removed with a cleaning solution. 211 At was recovered into a vial for cleaning solution. The radioactivity of the recovered liquid (each fraction) transferred to the reaction vessel and the cleaning solution recovered into the vial for cleaning solution was measured, and the results were calculated. 211 Recovery of At solution (all fractions). Results are shown in Table 1.

[0100] (Examples 3-6)

[0101] The procedure of "injecting 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution), leaving it in the tube for 5 minutes, and transferring it to the reaction vessel" in Example 1 was repeated 4 times to obtain... 211 The procedure “At solution (fractions 2-5)” is changed to “injecting 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution), leaving it in the tube for 5 minutes, and then transferring it to the reaction vessel is repeated 6 times to obtain…” 211 "At solution (fractions 2-7)", except that, the same method as in Example 1 was used to obtain the products of Examples 3-6. 211 At solution (fractions 1-7).

[0102] Using the same method as in Example 1, the residual [substance / material] was removed with a cleaning solution. 211 At, the radioactivity of the recovered liquid (each fraction) transferred to the reaction vessel and the recovered cleaning solution in the vial was measured, and the radioactivity of each fraction was calculated. 211 Recovery of At solution (all fractions). Results are shown in Table 1.

[0103] (Example 7)

[0104] In Example 1, the step of "retaining the recovered liquid in the tube for 5 minutes" was changed to "retaining the recovered liquid in the tube for 1 minute." Furthermore, the steps of "injecting 0.1 mL of the recovered liquid (7% sodium bicarbonate aqueous solution), retaining it in the tube for 5 minutes, and transferring it to the reaction vessel" in Example 1 were repeated four more times to obtain... 211The procedure “At solution (fractions 2-5)” is changed to “injecting 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution), leaving it in the tube for 1 minute, and then transferring it to the reaction vessel is repeated 9 times to obtain…” 211 "At solution (fraction 2-10)", except that, the same method as in Example 1 was used to obtain Example 7. 211 At solution (fractions 1-10).

[0105] Using the same method as in Example 1, the residual [substance / material] was removed with a cleaning solution. 211 At was recovered into a vial for cleaning solution. The radioactivity of the recovered liquid (each fraction) transferred to the reaction vessel and the cleaning solution recovered into the vial for cleaning solution was measured, and the results were calculated. 211 Recovery of At solution (all fractions). Results are shown in Table 1.

[0106] (Example 8)

[0107] Instead of performing the step of "retaining the recovered liquid in the tube for 5 minutes" as in Example 1, the procedure of "injecting 0.1 mL of the recovered liquid (7% sodium bicarbonate aqueous solution), retaining it in the tube for 5 minutes, and transferring it to the reaction vessel" as in Example 1 was repeated 4 times to obtain... 211 The phrase "At solution (fractions 2-5)" is changed to "the operation of injecting 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution) and transferring it to the reaction vessel is repeated 9 times to obtain..." 211 "At solution (fraction 2-10)", except that, the same method as in Example 1 was used to obtain Example 8. 211 At solution (fractions 1-10).

[0108] Using the same method as in Example 1, the residual [substance / material] was removed with a cleaning solution. 211 At was recovered into a vial for cleaning solution. The radioactivity of the recovered liquid (each fraction) transferred to the reaction vessel and the cleaning solution recovered into the vial for cleaning solution was measured, and the results were calculated. 211 Recovery of At solution (all fractions). Results are shown in Table 1.

[0109] (Comparative Example 1)

[0110] The recovery liquid in Example 1 was changed from a 7% sodium bicarbonate aqueous solution to distilled water, and the step of "retaining the recovery liquid in the tube for 5 minutes" as in Example 1 was omitted. Otherwise, the same method as in Example 1 was used to obtain Comparative Example 1. 211 At solution (fractions 1-5).

[0111] Using the same method as in Example 1, the residual [substance / material] was removed with a cleaning solution. 211At was recovered into a vial for cleaning solution. The radioactivity of the recovered liquid (each fraction) transferred to the reaction vessel and the cleaning solution recovered into the vial for cleaning solution was measured, and the results were calculated. 211 Recovery of At solution (all fractions). Results are shown in Table 1.

[0112] Distilled water (water for injection) is used as the recovery liquid. 211 The recovery rate at At was only 33% (Comparative Example 1).

[0113] On the other hand, use 0.5 or 0.7 mL of a 7% sodium bicarbonate aqueous solution as the recovery liquid, let it stand for 5 minutes, and then recover it. 211 The highest recovery rate was observed at At, reaching 90.7–94.4% (Examples 1–6). There was no significant difference between 0.5 mL and 0.7 mL of 7% sodium bicarbonate aqueous solution.

[0114] Even when the retention time of the 7% sodium bicarbonate aqueous solution was shortened to 1 minute, the recovery rate was as high as 91.2% (Example 7).

[0115] In Examples 1-8, the recovery rate was significantly improved compared to Comparative Example 1.

[0116] Table 1

[0117]

[0118] ※1: Total of 0.1mL of recycled liquid × 5 times

[0119] ※2: Total of 0.1mL of recycled liquid × 7 times

[0120] ※3: Total of 0.1mL of recycled liquid × 10 times

[0121] [Experimental Example 2]

[0122] The carrier gas in Comparative Example 1 of Test Example 1, which was "a mixture of helium (6 mL / min) and oxygen (10 mL / min) with added water (3000-4000 ppm)," was changed to "a mixture of nitrogen (30 mL / min) and oxygen (10 mL / min) with added water (3000-4000 ppm)." Furthermore, the number of injections of 0.1 mL of the recovery liquid and the number of transfer operations to the reaction vessel were changed so that the total volume of the recovery liquid reached the total volume of the recovery liquid listed in Table 2. Otherwise, Comparative Example 2 was obtained using the same method as Comparative Example 1. 211 At solution (fractions 1-4), Comparative Example 3 211 At solution (fractions 1-3), Comparative Example 4 211 At solution (fractions 1-4).

[0123] The recovery liquid (each fraction) transferred to the above reaction vessel was monitored using a Ge semiconductor detector (manufactured by Canberra). 211 The radioactivity of the solution was measured. After the procedure, the cooling tube was removed, and the radioactivity was measured directly using a Ge semiconductor detector (manufactured by Canberra). 211 The recovery rate of the At solution (all fractions) was calculated according to the following formula 2. 211 The recovery rate of the At solution (fraction 1) was calculated according to the following formula 3. The results are shown in Table 2.

[0124]

Number 2

[0125] (Calculation formula 2)

[0126]

Number 3

[0127] (Calculation formula 3)

[0128] Recover with 0.3–0.4 mL of distilled water (water for injection). 211 The average recovery rate at At was 71% (the average of Comparative Examples 2-4), but the recovery rates were uneven (57.5%-78.5%).

[0129] Table 2

[0130]

[0131] ※1: Total of 0.1mL of recycled liquid × 4 times

[0132] ※2: Total of 0.1mL of liquid for recycling × 3 times

[0133] [Experimental Example 3]

[0134] (Example 9)

[0135] The bismuth target material was irradiated with helium ions accelerated to 28 MeV using a cyclotron, and then... 209 Bi ( 4 He, 2n) 211 At is produced by nuclear reaction. 211 At.

[0136] The target material (containing) was subjected to dry distillation. 211At, separation and purification are performed using a Cu boat. That is, the irradiated target material is placed in a quartz tube, and under a mixed gas flow (carrier gas) of nitrogen (30 mL / min) and oxygen (10 mL / min) with added water (3000-4000 ppm, which is adjusted during operation to maintain within this range), the target material is heated to 850°C and trapped in a cooling tube (temperature: -3°C, material: Teflon (registered trademark), inner diameter 2 mm × length 600 mm) connected to the downstream side of the quartz tube.

[0137] Next, 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution (Meylon intravenous injection 7% (trade name), Otsuka Pharmaceutical Co., Ltd.)) was injected into the cooling tube from the downstream side and transferred to the reaction vessel to obtain... 211 At solution (fraction 1). Repeat the process of adding 0.1 mL of recovery liquid (7% sodium bicarbonate aqueous solution) and transferring to the reaction vessel twice more to obtain... 211 At solution (fractions 2 and 3).

[0138] The recovery liquid (each fraction) transferred to the above reaction vessel was monitored using a Ge semiconductor detector (manufactured by Canberra). 211 The radioactivity of the solution was measured. After the procedure, the cooling tube was removed, and the radioactivity was measured directly using a Ge semiconductor detector (manufactured by Canberra). 211 The recovery rate of the At solution (all fractions) was calculated according to the above formula 2. 211 The recovery rate of At solution (fraction 1) was calculated according to formula 3 above. The results are shown in Table 3.

[0139] (Compare Examples 5, 6, and 9)

[0140] In Example 9, the liquid used for recovery was changed from a 7% sodium bicarbonate aqueous solution to distilled water, and the number of times the 0.1 mL of liquid used for recovery was injected and transferred to the reaction vessel was changed so that the total volume of liquid used for recovery reached the total volume of liquid used for recovery recorded in Table 3. Otherwise, the same method as in Example 9 was used to obtain Comparative Example 5. 211 At solution (fractions 1-4), Comparative Example 6 211 At solution (fractions 1-4), Comparative Example 9 211 At solution (fractions 1-4).

[0141] Using the same method as in Example 9, the recovery liquid (each fraction) transferred to the reaction vessel was... 211 The radioactivity of the At solution and the radioactivity of the disassembled cooling tube were measured and calculated. 211Recovery of At solution (all fractions). Results are shown in Table 3.

[0142] (Compare Examples 7 and 8)

[0143] Comparative Example 7 was obtained by changing the recovery liquid in Example 9 from a 7% sodium bicarbonate aqueous solution to distilled water, except that the same method as in Example 9 was used. 211 At solution (fractions 1-3), Comparative Example 8 211 At solution (fractions 1-3).

[0144] Using the same method as in Example 9, the recovery liquid (each fraction) transferred to the reaction vessel was... 211 The radioactivity of the At solution and the radioactivity of the disassembled cooling tube were measured and calculated. 211 Recovery of At solution (all fractions). Results are shown in Table 3.

[0145] Recover with 0.3–0.4 mL of distilled water (water for injection). 211 The average recovery rate at At was 81.6% (average of all fractions in Comparative Examples 5-9).

[0146] Even when recovered using 0.1 mL of 7% sodium bicarbonate aqueous solution. 211 At, the recovery rate was also 87% (fraction 1 of Example 9), and when a total of 0.3 mL was added for recovery, the highest value of 96.3% (all fractions of Example 9) was obtained.

[0147] Table 3

[0148]

[0149] ※1: Total of 0.1mL of recycled liquid × 4 times

[0150] ※2: Total of 0.1mL of liquid for recycling × 3 times

[0151] Industrial availability

[0152] According to the manufacturing method of the present invention, it is possible to manufacture with a high recovery rate. 211 At solution.

[0153] This application is based on Japanese Patent Application No. 2023-187204, the contents of which are contained in this specification.

Claims

1. A method for manufacturing an astatine-211 solution, comprising: The steps of irradiating bismuth with alpha rays to generate astatine-211 in the bismuth, and The steps include distilling the bismuth irradiated with the α-ray, separating and purifying astatine-211, and dissolving it in an aqueous sodium bicarbonate solution.

2. The manufacturing method as described in claim 1, wherein, Sodium bicarbonate aqueous solution does not contain either or both of the reducing agent and the oxidizing agent.

3. The manufacturing method as described in claim 1, wherein, Dissolve the purified astatine-211 by contacting it with an aqueous sodium bicarbonate solution for more than 10 seconds.

4. The manufacturing method as described in claim 1, wherein, The carrier gas used in distillation contains inert gases and O2.

5. The manufacturing method as described in claim 4, wherein, The carrier gas further contains H2O.

Images