Method for producing radioactively labeled substances, apparatus for producing radioactively labeled substances, and method for evaporating and concentrating radioactive metal nuclides

Abstract

The present invention is a method for evaporating and concentrating a radioactive metal nuclide, the method comprising: a first evaporating and concentrating step for heating a radioactive solution obtained by dissolving a radioactive metal nuclide in an acidic aqueous solution, and evaporating a solvent from the radioactive solution to obtain a concentrated liquid of the radioactive metal nuclide; and a second evaporating and concentrating step for adding a low-boiling-point organic solvent having a lower boiling point than water to the concentrated liquid, and azeotroping the low-boiling-point organic solvent and the concentrated liquid through heating to obtain an evaporative concentrate of the radioactive metal nuclide. According to the present invention, the processing for separating a radioactive metal nuclide from a radioactive solution obtained by dissolving the radioactive metal nuclide in an acidic aqueous solution, and reacting the radioactive metal nuclide with a compound to be labeled to produce a radioactive labeled substance can be performed without requiring manual operation.

Description

[Technical Field]

[0001] The present invention relates to a method for producing a radiolabeled substance obtained by labeling a compound or the like with a radioactive metal nuclide, an apparatus for producing a radiolabeled substance, and a method for evaporating and concentrating a radioactive metal nuclide. [Background technology]

[0002] Beta (β) rays, a type of radiation, have the property of having low material penetration and therefore delivering a large amount of energy per unit length of passage. Utilizing this property of β rays, radioactive therapeutic drugs have been developed in which a radioactive metal nuclide that emits β rays is bound to a compound that has the property of concentrating in cells at the site of a disease. When administered into the body, radioactive therapeutic drugs concentrate at the site of the disease, and by emitting β rays there, they selectively destroy the cells at the site of the disease, thereby treating the disease.

[0003] One of the radioactive metal nuclides that emits beta rays 64 There is Cu. 64 In addition to beta rays, Cu emits special electrons (Auger electrons) that effectively damage the DNA of cancer cells, making it a promising candidate for use in cancer treatment drugs.

[0004] 64 Cu is produced by irradiating a target such as a gold plate plated with metallic nickel (Ni) with a proton beam. 64 Ni(p,n) 64 It is produced by causing a Cu nuclear reaction. It is produced on the target. 64 Cu is dissolved and recovered using an acidic solution such as hydrochloric acid or nitric acid. 64 Not only Cu but also Ni and other products are included, so among these 64 Cu needs to be separated and purified.

[0005] Generally, 64 From a solution containing Cu, Ni, etc. 64 Cu is separated and purified using the following method. first, 64A solution containing Cu, Ni, etc. is passed through a column filled with anion exchange resin. 64 Cu is adsorbed onto the anion exchange resin. Then, an acidic separation solution such as hydrochloric acid is passed through the column to adsorb Cu onto the anion exchange resin. 64 Cu is released from the resin and collected together with the separation solution ( 64 Cu separation process).

[0006] Next, 64 The separation solution containing Cu is placed in a flask, and the flask is heated with a heater while rotating to evaporate the separation solution. This concentrates the separation solution, 64 Cu precipitates ( 64 Cu concentration process). Obtained in the concentration process 64 Cu is dissolved in an appropriate solvent and then mixed with a reaction solution containing the compound to be labeled (therapeutic drug). 64 Cu and the compound bond, 64 A Cu-labeled radiotherapeutic agent is obtained ( 64 Cu labeling process). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2009-84246 Summary of the Invention [Problem to be solved by the invention]

[0008] Conventionally, the above-mentioned 64 From the Cu separation process 64 The series of operations up to the Cu labeling process are performed manually. However, manual work inevitably exposes workers to radiation. Therefore, machines have been developed to automatically perform some of the processes and some of the processing within each process (Patent Document 1).

[0009] However, due to the following circumstances, 64It was difficult to automate the Cu concentration process. 64 Radioactive metal nuclides such as Cu are dissolved in acidic solutions such as hydrochloric acid and nitric acid. 64 Cu separation process and 64 Each treatment in the Cu concentration process is carried out. 64 The separated solution obtained in the Cu separation process 64 Even if the acid solution contained in the separated solution is heated in the Cu concentration step, it is not possible to sufficiently evaporate the acid solution, and therefore a portion of the acid solution remains in the flask. 64 The material recovered in the Cu concentration process becomes acidic.

[0010] Included in the collected items 64 Because the reaction between Cu and the target compound for labeling occurs under neutral conditions, the pH value is adjusted by adding an appropriate dissolving solution to the recovered material before mixing it with the reaction solution containing the target compound. The pH value of the recovered material depends on the amount of residual acidic solution contained in the recovered material, which varies depending on various factors. In addition, because the recovered material is small in volume, it is difficult to measure the pH value of the recovered material, and workers must measure the pH value while adding the dissolving solution to the recovered material.

[0011] The problem to be solved by the present invention is to make it possible to separate radioactive metal nuclides from a radioactive solution obtained by dissolving radioactive metal nuclides in an acidic aqueous solution, and to react the separated radioactive metal nuclides with a compound to be labeled to produce a radioactively labeled product, all without human intervention. [Means for solving the problem]

[0012] A first aspect of the present invention, which has been made to solve the above problems, is a method for evaporatively concentrating radioactive metal nuclides, comprising: a first evaporation concentration step of heating a radioactive solution in which at least a radioactive metal nuclide is dissolved in an acidic aqueous solution to evaporate the solvent in the radioactive solution, thereby obtaining a concentrated solution of the radioactive metal nuclide; a second evaporation and concentration step of adding a low-boiling organic solvent having a boiling point lower than that of water to the concentrated solution, and heating the mixture to form an azeotropic mixture between the low-boiling organic solvent and the concentrated solution, thereby obtaining an evaporated concentrate of the radioactive metal nuclide; It has the following characteristics.

[0013] In the above method, in the first evaporation and concentration step, when the radioactive solution is heated, the water solvent in the radioactive solution mainly evaporates, resulting in a concentrated solution having higher dissolved concentrations of radioactive metal nuclides and higher acid concentrations than the radioactive solution. Subsequently, in the second evaporation and concentration step, when a low-boiling organic solvent is added to the concentrated solution and heated, the concentrated solution (contained in the concentrated acidic aqueous solution) and the low-boiling organic solvent form an azeotrope, evaporating the low-boiling organic solvent and the acidic aqueous solution, thereby obtaining an evaporated concentrate of radioactive metal nuclides. Because the acidic aqueous solution contained in the concentrated solution evaporates, the evaporated concentrate tends to be more neutral than the concentrated solution.

[0014] In the method for evaporatively concentrating radioactive metal nuclides, The second evaporation and concentration step may be performed by adding the low-boiling point organic solvent to the concentrated liquid, heating the mixture, and then adding a low-boiling point organic solvent of the same type as the low-boiling point organic solvent or a different type, and heating the mixture to obtain the evaporation and concentration product. According to the above method, a larger amount of the acidic aqueous solution can be removed from the evaporated concentrate.

[0015] Here, the acidic aqueous solution may be an acidic aqueous solution containing one selected from acids that can be evaporated and concentrated, such as hydrochloric acid, nitric acid, and phosphoric acid. Examples of the low-boiling organic solvent include ethanol (boiling point: about 78.5°C), acetonitrile (boiling point: about 82°C), and acetone (boiling point: about 56°C). The radioactive metal nuclides are adsorbed on an ion exchange resin and can be eluted with an acidic eluent. 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 28 Mg, 43 Sc, and 68 It is a type selected from Ga.

[0016] A second aspect of the present invention, which has been made to solve the above-mentioned problems, is a method for producing a radiolabeled substance by labeling a compound with a radioactive metal nuclide, comprising the steps of: an adsorption step of passing a radioactive solution obtained by dissolving radioactive metal nuclides in an acidic solution through an ion exchange resin to adsorb the radioactive metal nuclides onto the ion exchange resin; an elution step of passing an acidic eluate through the ion exchange resin to ion-exchange the radioactive metal nuclides adsorbed on the ion exchange resin with the eluate, thereby recovering the radioactive metal nuclides as a radioactive solution; a first evaporation concentration step of heating the radioactive solution recovered in the elution step to evaporate the solvent in the radioactive solution to obtain a concentrated solution of the radioactive metal nuclide; a second evaporation and concentration step of adding a low-boiling organic solvent having a boiling point lower than that of water to the concentrated solution, and heating the mixture to form an azeotropic mixture of the low-boiling organic solvent and the concentrated solution, thereby obtaining an evaporated concentrate of the radioactive metal nuclide; a labeling step in which the radioactive metal nuclide contained in the evaporated concentrate is reacted with a compound to be labeled to obtain a radioactively labeled product; It has the following characteristics.

[0017] A third aspect of the present invention, which has been made to solve the above problems, is an evaporation and concentration apparatus for radioactive metal nuclides, a concentration container; a heater for heating the concentration vessel; an organic solvent tank for storing a low-boiling organic solvent having a boiling point lower than that of water; an introduction section that introduces the low-boiling point organic solvent contained in the organic solvent tank into the concentration vessel through an introduction path; a temperature sensor for detecting the temperature of the concentration vessel; a control unit; a first evaporation concentration step in which the control unit drives the heater to heat the concentration container while a radioactive solution obtained by dissolving radioactive metal nuclides in an acidic aqueous solution is contained in the concentration container, and evaporates a solvent contained in the radioactive solution to obtain a concentrated solution of the radioactive metal nuclides; a second evaporation and concentration step in which the low-boiling organic solvent in the organic solvent tank is introduced into the concentration vessel through the introduction part, and then the heater is driven to heat the concentration vessel, and the concentrated liquid and the low-boiling organic solvent are subjected to azeotropy to obtain an evaporation and concentration of the radioactive metal nuclide; It is configured to be executed in order.

[0018] Furthermore, a fourth aspect of the present invention, which has been made to solve the above-mentioned problems, is a radiolabeled substance manufacturing apparatus, comprising: a separation and recovery unit that separates the radioactive metal nuclides from a radioactive solution obtained by dissolving the radioactive metal nuclides and impurities in an acidic solution, and recovers the radioactive metal nuclides as a radioactive solution; an evaporation and concentration unit that heats the radioactive solution recovered in the separation and recovery unit to evaporate the solvent in the radioactive solution, thereby evaporating and concentrating radioactive metal nuclides; a labeling unit that reacts the evaporated and concentrated radioactive metal nuclide with a compound to be labeled to produce a radioactively labeled substance; The evaporation concentration section a concentration container; a heater for heating the concentration vessel; an organic solvent tank for storing a low-boiling organic solvent having a boiling point lower than that of water; an introduction section that introduces the low-boiling organic solvent in the organic solvent tank into the concentration vessel through an introduction path; a temperature sensor for detecting the temperature of the concentration vessel; a control unit; a first evaporation concentration step in which the control unit drives the heater to heat the concentration container while a radioactive solution obtained by dissolving radioactive metal nuclides in an acidic aqueous solution is contained in the concentration container, and evaporates a solvent contained in the radioactive solution to obtain a concentrated solution of the radioactive metal nuclides; a second evaporation and concentration step in which the low-boiling organic solvent in the organic solvent tank is introduced into the concentration vessel through the introduction part, and then the heater is driven to heat the concentration vessel, and the concentrated liquid and the low-boiling organic solvent are subjected to azeotropy to obtain an evaporation and concentration of the radioactive metal nuclide; It is configured to run. [Effects of the Invention]

[0019] In the present invention, in the process of concentrating radioactive metal nuclides, a low-boiling organic solvent is added to a radioactive solution obtained by dissolving the radioactive metal nuclides in an acidic aqueous solution and heated, so that the acidic aqueous solution contained in the radioactive solution is removed by azeotropy with the low-boiling organic solvent. As a result, the evaporated concentrate of the radioactive metal nuclides becomes neutral. Therefore, unlike conventional methods, there is no need to neutralize the evaporated concentrate before reacting the radioactive metal nuclides with the compound to be labeled. Therefore, the process of recovering the radioactive metal nuclides from a radioactive solution obtained by dissolving the radioactive metal nuclides in an acidic aqueous solution such as hydrochloric acid, and reacting the radioactive metal nuclides with the compound to be labeled to produce a radiolabeled product can be performed without human intervention. [Brief explanation of the drawings]

[0020] [Figure 1] 1 is a diagram showing a schematic overall configuration of a radiolabeled substance production system according to one embodiment of the present invention. [Figure 2] FIG. 1 is a diagram showing the overall configuration of a dissolution apparatus. [Figure 3] FIG. 2 is a diagram showing the overall configuration of a separation and purification section. [Figure 4] FIG. 2 is a diagram showing the overall configuration of an evaporation concentration section. [Figure 5] FIG. 2 is a diagram showing the overall configuration of a sign unit. [Figure 6] FIG. 1 is a schematic block diagram of a manufacturing system. [Figure 7] FIG. 2 is a diagram for explaining the flow of operations of each part of the dissolving device and radioactively labeled substance manufacturing device in the manufacturing system. DETAILED DESCRIPTION OF THE INVENTION

[0021] Hereinafter, embodiments of the present invention will be described with reference to the drawings.

[0022] [System Configuration of This Embodiment] FIG. 1 shows a schematic overall configuration of a radiolabeled substance manufacturing system 100. Here, the radiolabeled substance is one of the radioactive metal nuclides.64 An example of a radioactively labeled compound obtained by labeling a compound with Cu will be described below. The production system 100 includes a dissolving apparatus 1, a radiolabeled substance production apparatus 2, and a gas supply apparatus 10. The radiolabeled substance production apparatus 2 includes a separation and purification section 3, an evaporation and concentration section 4, and a labeling section 5. The dissolving apparatus 1, the radiolabeled substance production apparatus 2, and the gas supply apparatus 10 are all arranged in a single hot cell 6.

[0023] 2 shows a schematic overall configuration of the melting apparatus 1 and the gas supply device 10. As shown in FIGS. 1 and 2, the melting apparatus 1 and the gas supply device 10 are arranged vertically in the hot cell 6.

[0024] The dissolving apparatus 1 has a dissolving tank 11, a dissolving liquid tank 14, a diluting water tank 12, and a cleaning water tank 13. The dissolving tank 11 is irradiated with a proton beam. 64 This is a tank for dissolving nickel plating (gold plate) on which Cu has been produced to produce a radioactive solution. The solution tank 14 contains an acidic solution such as a nitric acid solution or a hydrochloric acid solution. In the following explanation, the solution containing radioactive metal nuclides obtained in the dissolving apparatus 1, i.e., the solution obtained by dissolving the raw metal from which radioactive metal nuclides have been produced in the acidic solution, is referred to as the radioactive solution. The radioactive solution is the solution before the radioactive metal nuclides are separated in the separation and purification section, which will be described later.

[0025] The dilution water tank 12 stores dilution water that is added to the radioactive dissolved solution produced in the dissolution tank 11 to adjust the concentration (nitric acid concentration, hydrochloric acid concentration) of the dissolved solution. The cleaning water tank 13 stores cleaning water for cleaning the flow path R1 that runs from the dissolution device 1 to the radiolabeled substance production device 2 (evaporation concentration section 4).

[0026] The gas supply device 10 has a nitrogen gas supply unit 101 and an air supply unit 102. The nitrogen gas supply unit 101 supplies nitrogen gas, which is an inert gas, to each part of the dissolving apparatus 1 and the radiolabeled substance manufacturing apparatus 2 through a gas supply line G1. The air supply unit 102 supplies air to each part of the dissolving apparatus 1 and the radiolabeled substance manufacturing apparatus 2 through a gas supply line G2. Valves are provided in the middle of the gas supply lines G1 and G2, and the supply destinations of the nitrogen gas and air are switched by opening and closing the valves.

[0027] 3 shows a schematic overall configuration of the separation and purification section 3. The separation and purification section 3 corresponds to the separation and recovery section of the present invention. As shown in this figure, the separation and purification section 3 has a buffer tank 31, a column 32, a column wash water tank 33, a column wash solution tank 34, a first eluate tank 35, a second eluate tank 36, a third eluate tank 37, and a waste liquid tank 38.

[0028] The column 32 is filled with an ion exchange resin for separating Ni and other components from 64Cu. A flow path R1 is connected to the inlet of the buffer tank 31, and the radioactive dissolution solution sent from the dissolution device 1 is introduced into the buffer tank 31. The radioactive dissolution solution introduced into the buffer tank 31 is pumped by a tube pump (peristaltic pump) 323 The liquid passes through a flow path formed by the column 32 and other components and is collected in a waste liquid tank 38. In this process, Ni and other components as well as 64Cu are adsorbed onto the column 32. 323 The outlet of the column 32 is connected to the evaporation concentration section 4 via a flow path R2. A flow rate sensor 321 is provided in the flow path R1 near the inlet of the column 32, and a radioactivity (RI) sensor 322 is provided between the column 32 and the tube pump 323.

[0029] The buffer tank 31 also collects, via the flow path R1, the cleaning water flowing from the cleaning water tank 13 for cleaning the dissolution tank 11 and the flow path R1. The first eluate tank 35 64 Contains an eluent for Cu elution. 64The eluent for eluting Cu is an acidic aqueous solution. The second and third eluent tanks 36 and 37 contain eluents for recovering Ni. The eluents contained in the second and third eluent tanks 36 and 37 may be the same or different. In the following description, 64 The eluate for eluting Cu is passed through the column 32 and discharged from the column 32. 64 The eluate containing Cu is referred to as a radioactive solution. That is, the solution containing radioactive metal nuclides separated in the separation and purification unit 3 is referred to as a radioactive solution to distinguish it from the radioactive dissolution solution described above. In the following explanation, the acidic aqueous solution used to elute radioactive metal nuclides in the separation and purification unit 3 is referred to as an acidic aqueous solution to distinguish it from the acidic dissolution solution described above.

[0030] The column washing water tank 33 and the column washing liquid tank 34 respectively store washing water and washing liquid for washing the ion exchange resin in the column 32. The waste liquid tank 38 is used to collect the washing water and washing liquid that have flowed into the column 32, or the eluate containing Ni and the like.

[0031] FIG. 4 shows a schematic overall configuration of the evaporation concentration section 4. As shown in this figure, the evaporation concentration section 4 includes an evaporator unit 41, an organic solvent tank 42, a syringe pump 43, a vacuum pump 44, and a Dewar vessel 45. The organic solvent tank 42 contains an organic solvent with a boiling point lower than that of water (a low-boiling organic solvent). The syringe pump 43 operates a syringe (not shown) attached thereto to supply the low-boiling organic solvent contained in the syringe to the evaporator unit 41. The evaporator unit 41 includes a flask 411 serving as a concentration container, a heater 412 for heating the flask 411, and a rotary holder 413 for holding the flask 411. The flask 411 is a round-bottom flask or an eggplant-shaped flask with a hemispherical bottom. The flask 411 held by the rotary holder 413 is rotated by the rotary holder 413.

[0032] The mouth of flask 411 is sealed with lid 414. Lid 414 has a decompression tube 415 for reducing the pressure inside flask 411 and a pressurization tube 416 for increasing the pressure inside flask 411. Decompression tube 415 is connected to vacuum pump 44 via Dewar vessel 45, and pressurization tube 416 is connected to nitrogen gas supply unit 101 (see FIG. 2) through a gas flow path.

[0033] The lid 414 also has an inlet tube 417 and an outlet tube 418. The inlet tube 417 is used to introduce the radioactive solution sent from the separation and purification section 3 and the low-boiling organic solvent supplied from the syringe pump 43 into the flask 411. The outlet tube 418 is used to discharge the contents of the flask 411 to the labeling section 5. The inlet tube 417 and the flow path from the syringe pump 43 to the inlet tube 417, and the flow path from the organic solvent tank 42 to the flask 411 correspond to the inlet path of the present invention. The inlet path, the syringe pump 43, the vacuum pump 44, and the control section 200 constitute an inlet section.

[0034] 5 shows a schematic overall configuration of the labeling unit 5. The labeling unit 5 has a reaction liquid tank 51, a dissolving liquid tank 52, and an additive liquid tank 53, and is disposed above the separation and purification unit 3 in the hot cell 6. The reaction liquid tank 51 contains a reaction liquid containing a compound to be labeled. The dissolving liquid tank 52 stores an appropriate dissolving liquid used to dissolve the radioactive metal nuclide, and the additive liquid tank 53 stores an additive liquid necessary for the reaction between the radioactive metal nuclide and the compound.

[0035] In this embodiment, the reaction liquid tank 51, the dissolving liquid tank 52, and the additive liquid tank 53 are all containers with a V-shaped bottom cross section, in order to make it easy to take out the entire amount of liquid contained in each tank, regardless of the amount of the liquid.

[0036] Although detailed explanations are omitted, the dissolving apparatus 1, and the separation and purification section 3, evaporation and concentration section 4, and labeling section 5 of the radiolabeled substance production apparatus 2 have, in addition to the flow paths R1 to R3, liquid flow paths for the flow of various liquids such as cleaning water and cleaning liquid, and gas flow paths for the flow of nitrogen gas and air sent through the gas flow paths G1 and G2. These liquid flow paths and gas flow paths are provided with valves, and the flow of liquid and gas can be switched by opening and closing the valves.

[0037] 6 is a schematic block diagram of the manufacturing system 100. As shown in this figure, the manufacturing system 100 includes a control unit 200, which includes a flow rate sensor 321 , temperature sensor 201, RI sensor 322, pressure sensor 202, flow meter 203, heater 412, tube pump 323 , rotary holder 413, syringe pump 43, vacuum pump 44, gas supply device 10 (nitrogen gas supply unit 101, air supply unit 102), solenoid valve 204 for the liquid flow path, solenoid valve 205 for the gas flow path, and operation unit 206 are connected. Temperature sensor 201 detects the temperature of flask 411. Pressure sensor 202 detects the pressure of the gas supplied from gas supply device 10.

[0038] The control unit 200 is 321 , temperature sensor 201, RI sensor 322 Based on signals input from the pressure sensor 202 and the flow meter 203, the heater 412 and the tube pump 413 are controlled in accordance with a program pre-stored in the control unit 200. 323 , rotary holder 413, syringe pump 43, vacuum pump 44, solenoid valve 204 for the liquid flow path, and solenoid valve 205 for the gas flow path.

[0039] [Overview of Operation of Each Device in the Manufacturing System of the Present Embodiment] Next, with reference to FIG. 7, the operation of each part of the dissolving apparatus 1 and the radiolabeled substance manufacturing apparatus 2 in the above-described manufacturing system 100 will be roughly described.

[0040] In the melting apparatus 1, a process of melting the nickel-plated (gold plate) on which 64Cu has been generated by irradiation with a proton beam is carried out. In the 64Cu melting process, the nickel-plated (gold plate) on which 64Cu has been generated is placed in a melting tank 11, and a nitrogen gas supply unit 101 The process begins by supplying a predetermined amount of nitrogen gas to the dissolving solution tank 14 from the dissolving tank 11, and then pumping the acidic dissolving solution, such as nitric acid solution or hydrochloric acid solution, from the dissolving solution tank 14 into the dissolving tank 11. As a result, 64Cu, Ni (including 64Ni), and other products dissolve in the dissolving solution, producing a radioactive dissolving solution. Ni (including 64Ni) and other products correspond to impurities in this invention.

[0041] When a predetermined time has elapsed since the dissolving solution was pumped into the dissolving tank 11, the control unit 200 controls the gas supply device 10 to supply a predetermined amount of nitrogen gas from the nitrogen gas supply unit 101 to the dissolving tank 11. As a result, the radioactive dissolving solution in the dissolving tank 11 is pumped through the flow path R1 to the buffer tank 31 of the separation and purification unit 3. Note that, if necessary, before pumping the radioactive dissolving solution from the dissolving tank 11 to the separation and purification unit 3, dilution water may be pumped from the dilution water tank 12 to the dissolving tank 11 to adjust the acid concentration of the radioactive dissolving solution.

[0042] In the separation and purification section 3, 64 A step of separating and purifying Cu is carried out. 64 The Cu separation and purification process is started by introducing the radioactive solution in the buffer tank 31 sent from the dissolution tank 11 into the column 32. When the separation and purification process is started, the control unit 200 controls the tube pump 323 As a result, the radioactive solution introduced into the column 32 passes through the ion exchange resin, and at this time, the radioactive solution present as anions is 64 Cu and Ni are adsorbed onto the ion exchange resin ( 64 Cu adsorption process).

[0043] Next, the control unit 200 controls the solenoid valves 204 and 205 to secure a flow path from the column washing water tank 33 through the column 32 to the waste tank 38, and starts the tube pump 323 to suck column washing water from the column washing water tank 33 and wash the column 32. Next, the control unit 200 secures a flow path from the column washing solution tank 34 through the column 32 to the waste tank 38, and starts the tube pump 323 to suck column washing solution from the column washing solution tank 34 and remove impurities from the column 32. Next, the control unit 200 secures a flow path from the first elution solution tank 35 through the column 32 to the waste tank 38, and starts the tube pump 323 to suck column washing solution from the first elution solution tank 35. 64 An eluent for eluting Cu (hereinafter referred to as a first eluent) is aspirated into the column 32. Here, a hydrochloric acid solution with a pH of about 1 is used as the first eluent. This causes ion exchange. 64 Cu is eluted ( 64 At this time, by monitoring the RI sensor 322 provided on the outlet side of the column 32, the radioactive 64 When the measurement value of the RI sensor 322 rises above the background level, the control unit 200 controls the solenoid valve to switch to the flow path R2 to the evaporation concentration unit 4. 64 The radioactive solution containing Cu is sent to the evaporation concentration unit 4. When the measurement value of the RI sensor falls below the background level, the tube pump 323 is stopped, and the sending of the solution is terminated.

[0044] Next, the control unit 200 controls the solenoid valves 204 and 205 to secure a flow path from the second eluate tank 36 through the column 32 to the waste liquid tank 38, and starts the tube pump 323. As a result, Ni in the column 32 is eluted and collected in the waste liquid tank 38. By flowing the eluate for Ni collection through the column 32 in this manner, it is possible to almost completely discharge Ni remaining in the ion exchange resin. However, the number of times that the eluate for Ni collection is introduced into the column 32 is not limited to two, and it may be once, or three or more times.

[0045] In the evaporation concentration section 4, the radioactive solution is heated to evaporate the solvent in the radioactive solution, 64An evaporation concentration step is carried out to concentrate Cu. The evaporation concentration step is initiated when the radioactive solution sent from the separation and purification unit 3 through the flow path R2 is introduced into the flask 411 via the introduction tube 417. When the evaporation concentration step is initiated, the control unit 200 drives the vacuum pump 44 to reduce the pressure inside the flask 411. In addition, the heater 412 heats the flask 411, and rotates the rotary holder 413. As a result, the radioactive solution inside the flask 411 is heated while the flask 411 is rotating, and the solvent (mainly the first eluate) contained in the radioactive solution evaporates. A part of the evaporated solvent liquefies (condenses) at the top inside the flask 411 and refluxes. As a result, the amount of the radioactive solution 64 Cu is concentrated and a concentrated solution is obtained ( 64 Cu first evaporation concentration process). 64 In the Cu first evaporation concentration step, the water and hydrochloric acid in the first eluate are refluxed in the same manner. Therefore, the hydrochloric acid concentration in the concentrated solution is almost the same as that in the radioactive solution, and the concentrated solution is acidic.

[0046] Next, the control unit 200 stops the rotation of the rotary holder 413 and stops heating by the heater 412. Then, when a predetermined time has elapsed (when the temperature of the concentrated liquid falls below a predetermined value), the vacuum pump 44 is driven to suck a predetermined amount of low-boiling-point organic solvent from the organic solvent tank 42 and add it to the concentrated liquid in the flask 411. Thereafter, the heater 412 heats the flask 411 again, and the rotary holder 413 is rotated. As a result, the concentrated liquid and the low-boiling-point organic solvent in the flask 411 form an azeotrope, and the first eluate and the low-boiling-point organic solvent contained in the concentrated liquid evaporate. As a result, the flask 411 contains 64 Cu and a small amount of hydrochloric acid solution and low-boiling organic solvent that did not evaporate remain.

[0047] Next, the syringe pump 43 is driven to add a predetermined amount of low-boiling-point organic solvent to the residue in the flask 411. Thereafter, the flask 411 is again heated by the heater 412, and the rotary holder 413 is rotated. This causes an azeotropic mixture of the first eluent contained in the residue and the low-boiling-point organic solvent, and almost all of the small amount of eluent contained in the residue evaporates together with the low-boiling-point organic solvent. The control unit 200 stops the heater 412 when a predetermined time has elapsed since the start of heating by the heater 412. As a result, 64 Cu evaporation concentrate is produced ( 64 Cu second evaporation concentration process). 64 The evaporated concentrate of Cu is 64 Dry Cu or a small amount of the first eluate and a low boiling organic solvent 64 Whether the concentrate becomes a dry product or a mixture depends on the conditions such as the heating time and temperature by the heater 412, but in either case, the concentrate contains no or only a small amount of the first eluate, which is an acidic aqueous solution, and therefore the evaporated concentrate is in a neutral region.

[0048] Next, the control unit 200 controls the solenoid valves 204 and 205 to secure a flow path from the dissolving solution tank 52 of the labeling unit 5 through flow path R3 to the flask 411, and drives the vacuum pump 44 to suck the entire amount of the dissolving solution in the dissolving solution tank 52 into the flask 411. Then, the rotary holder 413 is rotated to stir the contents of the flask 411 and dissolve the evaporated concentrate, and then the rotary holder 413 and the vacuum pump 44 are stopped. Thereafter, the control unit 200 controls the solenoid valves 204 and 205 to secure a flow path from the flask 411 to flow path R3, and drives the vacuum pump 44 to suck the entire amount of the dissolving solution in the dissolving solution tank 52 into the flask 411. 411 The entire amount of the dissolving solution in the container is sent to the reaction vessel 51 of the labeling unit 5 through the flow path R3.

[0049] In the labeling section 5, 64 React Cu with the compound to be labeled to obtain a radioactively labeled product 64The Cu labeling process is carried out. The labeling process starts when the dissolving liquid sent from the evaporation concentration unit 4 is introduced into the reaction liquid tank 51. When the labeling process starts, the control unit 200 controls the gas supply device 10 to supply nitrogen gas from the nitrogen gas supply unit 101 to the additive liquid tank 53. As a result, the entire amount of the additive liquid contained in the additive liquid tank 53 is introduced into the reaction liquid tank 51. The reaction liquid tank 51, the dissolving liquid tank 52, and the additive liquid tank 53 are 64 The reaction solution, dissolving solution, and additive solution required for the reaction between Cu and the compound to be labeled are contained in advance. 64 The reaction between Cu and the compound to be labeled proceeds, producing a radioactively labeled product.

[0050] [Example] Next, the production system 100 of the above embodiment is used to produce a radioactively labeled substance. 64 Cu-ATSM[ 64 Cu-diacetyl-bis(N 4 -methylthiosemicarbazone)] will be described below. 64 Cu-ATSM is a radioactive therapeutic agent developed for the treatment of malignant brain tumors.

[0051] In the examples, the dissolving apparatus 1 and the hot cell 6 were both products manufactured by Sumitomo Heavy Industries, Ltd. Furthermore, a cation exchange resin (AG 50W-X8 100-200 H+ manufactured by Bio-Rad Laboratories, Inc.) was used as the ion exchange resin packed in the column 32. The dissolving apparatus 1, the radiolabeled substance manufacturing apparatus 2, and the gas supply apparatus 10 were connected by flow paths, and the dissolving apparatus 1, the radiolabeled substance manufacturing apparatus 2, the gas supply apparatus 10, and the valves provided on each flow path were all controlled by a single control system, whereby 64 From the Cu melting process 64 Cu separation and purification process, 64 Cu evaporation and concentration process, 64 All steps up to the Cu labeling step were carried out automatically.

[0052] 64 Prior to the production of Cu-ATSM,64 A proton beam was irradiated onto a Ni-plated target gold plate using a cyclotron (Sumitomo Heavy Industries, Ltd., HM-12S), and [ 64 Ni(p,n) 64 Cu] by nuclear reaction 64 Cu was produced.

[0053] The types and amounts of the various solutions used in each step are shown in Table 1 below.

[0054] [Table 1]

[0055] In this embodiment, 64 The Cu-ATSM production test was carried out three times, and the results are shown in Table 2. [Table 2]

[0056] As shown in Table 2, in all three trials, the therapeutic dose met quality specifications. 64 Cu-ATSM was successfully produced. In addition, in this example, in the evaporation concentration step, the radioactive solution introduced from the separation and purification section 3 into the flask 411 was 60 mL, and by heating this radioactive solution using the evaporator unit 41, the desired evaporated concentrate could be obtained 30 minutes after the start of the evaporation concentration step.

[0057] On the other hand, as a comparative test, when a radioactive solution was evaporated and concentrated by the conventional method in which 10 mL of the elution recovery liquid was placed in a flask and the flask was heated to 120°C using a block heater, it took 30 minutes to obtain an evaporated concentrate, even though the amount of liquid was small. From this, it was found that in the test of this example using the evaporator unit 41, the time required for concentration to dryness per unit amount of liquid could be reduced to 1 / 6 compared to the comparative test.

[0058] Furthermore, apart from the three tests described above, when 60 mL of radioactive solution was subjected to a concentration process using evaporator unit 41 (a process corresponding to the first evaporation concentration step of the present invention), the pH of the concentrated solution in flask 411 was "1," which was strongly acidic. Therefore, 10 mL of ethanol was added to this concentrated solution and heated, and then ethanol was added again and heated (a process corresponding to the second evaporation concentration step of the present invention). As a result, the pH of the evaporated concentrate in flask 411 became "6.5," which was almost neutral. This process took 4 minutes. When 10 mL of ethanol was added to the concentrated solution and the treatment was performed only once, the treatment was completed in 2 minutes, but the pH of the resulting evaporated concentrate was 3, and it was still acidic.

[0059] In addition, the results obtained in the three tests in this example 64 The amount of ethanol remaining in Cu-ATSM was measured by gas chromatography (Shimadzu Corporation), and was found to be below the standard value (5000 ppm).

[0060] From the above results, 64 The method of the present invention, in which ethanol (a low-boiling organic solvent) is added to the concentrated solution in the step of evaporating and concentrating Cu, can shorten the time required to obtain the evaporated concentrate to about one-third to one-half compared to the conventional method, and further, 64 Since the Cu evaporation and concentration process produces a neutral evaporative concentrate, this evaporative concentrate can be used without the intervention of workers. 64 It was found that it was possible to proceed to the Cu labeling process. Therefore, by using the evaporation and concentration method of the present invention, when producing a radiolabeled substance, 64 From the Cu melting process 64 All steps up to the Cu labeling step can be automated. Furthermore, by automating all steps, the amount of radiation exposure to workers can be significantly reduced (according to experiments by the inventors, this was reduced to about 1 / 5), and it becomes possible to stably mass-produce radioactively labeled substances such as radiopharmaceuticals.

[0061] In the above embodiment, 64 To ensure that the evaporated concentrate obtained in the Cu second evaporation and concentration step is in the neutral region, a low-boiling organic solvent was added to flask 411 and azeotropically distilled with the first eluate twice, but in some cases, the azeotropic distillation may be performed only once. For example, by appropriately setting the conditions, such as increasing the amount of low-boiling organic solvent added to the concentrated solution in flask 411 or extending the heating time with heater 412, it is possible to evaporate almost all of the first eluate contained in the concentrated solution in a single azeotropic distillation, thereby obtaining an evaporated concentrate in the neutral region.

[0062] As radioactive metal nuclides 64 Although Cu was used, the evaporation and concentration method according to the present invention can be applied to any radioactive metal nuclide that is dissolved in an acidic aqueous solution during the process for producing a radioactively labeled substance and that can be adsorbed to an ion exchange resin. 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 28 Mg, 43 Sc, and 68 Ga is one example.

[0063] The acidic aqueous solution in which the radioactive metal nuclide is dissolved is selected depending on the type of radioactive metal nuclide, and examples thereof include hydrochloric acid, nitric acid, and phosphoric acid. In the above embodiment, ethanol is used as the low-boiling organic solvent, but the present invention is not limited to this, and any solvent having a boiling point lower than that of water, such as acetonitrile, acetone, etc. In addition, the low-boiling organic solvent may be one type of organic solvent or a mixed solvent consisting of multiple types of organic solvents. [Explanation of symbols]

[0064] 100...Manufacturing System 1…Dissolving device 10...Gas supply device 101...Nitrogen gas supply unit 102...Air supply section 11…Dissolution tank 12...Dilution tank 13...Cleaning tank 14…Dissolution liquid tank 2...Radioactive label manufacturing equipment 3...Separation and purification section 31...Buffer tank 32...Column 32...the column 321...Flow sensor 322...RI sensor 323...Tube pump 33...Column washing tank 34...Column washing solution tank 35…1st eluate tank 36…Second eluate tank 37…Third eluate tank 38...Waste tank 4...Evaporation and concentration section 41...Evaporator unit 411...Flask 412...Heater 413...Rotary holder 414...lid body 415...Decompression tube 416...Pressure tube 417...Introducing tube 418...Outlet tube 42...Organic solvent tank 43...Syringe pump 44...Vacuum pump 45...Dewar flask 5…Sign part 51...Reaction liquid vessel 52…Dissolution liquid tank 53...Additive liquid tank 6...Hot Cell

Claims

1. a first evaporation concentration step of heating a radioactive solution in which at least a radioactive metal nuclide is dissolved in an acidic aqueous solution to evaporate the solvent in the radioactive solution, thereby obtaining a concentrated solution of the radioactive metal nuclide; a second evaporation and concentration step of adding a low-boiling organic solvent having a boiling point lower than that of water to the concentrated solution, and heating the mixture to form an azeotropic mixture between the low-boiling organic solvent and the concentrated solution, thereby obtaining an evaporated concentrate of the radioactive metal nuclide; A method for evaporatively concentrating a radioactive metal nuclide, comprising: The method for evaporatively concentrating a radioactive metal nuclide, wherein in the second evaporative concentration step, the concentrated solution is azeotropically distilled with the low-boiling organic solvent so that the pH of the evaporated concentrate of the radioactive metal nuclide becomes substantially neutral.

2. The method for evaporatively concentrating radioactive metal nuclides according to claim 1, In the second evaporation and concentration step, the low-boiling point organic solvent is added to the concentrated solution, the mixture is heated, and then a low-boiling point organic solvent of the same type as the low-boiling point organic solvent or a different type from the low-boiling point organic solvent is added again, and the mixture is heated, so that the pH of the evaporated concentrate becomes substantially neutral.

3. The method for evaporatively concentrating a radioactive metal nuclide according to claim 1 or 2, A method for evaporatively concentrating radioactive metal nuclides, wherein the acidic aqueous solution contains one acid selected from the group consisting of hydrochloric acid, nitric acid, and phosphoric acid.

4. The method for evaporatively concentrating a radioactive metal nuclide according to any one of claims 1 to 3, A method for evaporative concentration of radioactive metal nuclides, wherein the low-boiling organic solvent is one solvent or a mixed solvent of two or more solvents selected from the group consisting of ethanol, acetonitrile, and acetone.

5. The method for evaporatively concentrating a radioactive metal nuclide according to any one of claims 1 to 4, The radioactive metal nuclides are adsorbed on an ion exchange resin and can be eluted with an acidic eluent. ６１ Cu, ６２ Cu, ６４ Cu, ６６ Cu, ６７ Cu, ２８ Mg, ４３ Sc, and ６８ A method for evaporating and concentrating a radioactive metal nuclide, which is one selected from Ga.

6. A method for producing a radiolabeled compound by labeling a compound with a radioactive metal nuclide, comprising the steps of: an adsorption step of passing a radioactive solution obtained by dissolving radioactive metal nuclides in an acidic solution through an ion exchange resin to adsorb the radioactive metal nuclides onto the ion exchange resin; an elution step of passing an acidic eluate through the ion exchange resin to ion-exchange the radioactive metal nuclides adsorbed on the ion exchange resin with the eluate, thereby recovering the radioactive metal nuclides as a radioactive solution; a first evaporation concentration step of heating the radioactive solution recovered in the elution step to evaporate the solvent in the radioactive solution to obtain a concentrated solution of the radioactive metal nuclide; a second evaporation and concentration step of adding a low-boiling organic solvent having a boiling point lower than that of water to the concentrated solution, and heating the mixture to form an azeotropic mixture between the low-boiling organic solvent and the concentrated solution, thereby obtaining an evaporated concentrate of the radioactive metal nuclide; a labeling step in which the radioactive metal nuclide contained in the evaporated concentrate is reacted with a compound to be labeled to obtain a radioactively labeled product; A method for producing a radiolabeled substance, comprising: In the second evaporation and concentration step, the concentrated solution is azeotropically distilled with the low-boiling organic solvent so that the pH of the evaporated concentrate of the radioactive metal nuclide becomes substantially neutral.

7. 7. The method for producing a radiolabeled substance according to claim 6, In the second evaporation and concentration step, the low-boiling point organic solvent is added to the concentrated solution, the mixture is heated, and then a low-boiling point organic solvent of the same type as the low-boiling point organic solvent or a different type is added again, and the mixture is heated, so that the pH of the evaporated concentrate becomes substantially neutral.

8. a concentration container; a heater for heating the concentration vessel; an organic solvent tank for storing a low-boiling organic solvent having a boiling point lower than that of water; an introduction section that introduces the low-boiling point organic solvent contained in the organic solvent tank into the concentration vessel through an introduction path; a temperature sensor for detecting the temperature of the concentration vessel; a control unit; a first evaporation concentration step in which the control unit drives the heater to heat the concentration container while a radioactive solution obtained by dissolving radioactive metal nuclides in an acidic aqueous solution is contained in the concentration container, and evaporates a solvent contained in the radioactive solution to obtain a concentrated solution of the radioactive metal nuclides; a second evaporation and concentration step in which the low-boiling organic solvent in the organic solvent tank is introduced into the concentration vessel through the introduction part, and then the heater is driven to heat the concentration vessel, and the concentrated liquid and the low-boiling organic solvent are azeotroped to obtain an evaporation and concentration of the radioactive metal nuclide. In the apparatus for evaporative concentration of radioactive metal nuclides, The apparatus for evaporatively concentrating radioactive metal nuclides, wherein in the second evaporative concentration step, the concentrated solution is azeotropically distilled with the low-boiling organic solvent so that the pH of the evaporated concentrate of the radioactive metal nuclides becomes substantially neutral.

9. The apparatus for evaporating and concentrating radioactive metal nuclides according to claim 8, In the second evaporation and concentration step, the low-boiling point organic solvent is added to the concentrated solution, the mixture is heated, and then a low-boiling point organic solvent of the same type as the low-boiling point organic solvent or a different type from the low-boiling point organic solvent is added again, and the mixture is heated, so that the pH of the evaporated concentrate becomes substantially neutral.

10. a separation and recovery unit that separates the radioactive metal nuclides from a radioactive solution obtained by dissolving the radioactive metal nuclides and impurities in an acidic solution, and recovers the radioactive metal nuclides as a radioactive solution; an evaporation and concentration unit that heats the radioactive solution recovered in the separation and recovery unit to evaporate the solvent in the radioactive solution, thereby evaporating and concentrating radioactive metal nuclides; a labeling unit that reacts the evaporated and concentrated radioactive metal nuclide with a compound to be labeled to produce a radioactively labeled substance; The evaporation concentration section a concentration container; a heater for heating the concentration vessel; an organic solvent tank for storing a low-boiling organic solvent having a boiling point lower than that of water; an introduction section that introduces the low-boiling organic solvent in the organic solvent tank into the concentration vessel through an introduction path; a temperature sensor for detecting the temperature of the concentration vessel; a control unit; a first evaporation concentration step in which the control unit drives the heater to heat the concentration container while a radioactive solution obtained by dissolving radioactive metal nuclides in an acidic aqueous solution is contained in the concentration container, and evaporates a solvent contained in the radioactive solution to obtain a concentrated solution of the radioactive metal nuclides; a second evaporation and concentration step in which the low-boiling organic solvent in the organic solvent tank is introduced into the concentration vessel through the introduction part, and then the heater is driven to heat the concentration vessel, and the concentrated liquid and the low-boiling organic solvent are azeotroped to obtain an evaporation and concentration of the radioactive metal nuclide.

1. A radiolabeled product manufacturing apparatus configured to perform: In the second evaporation and concentration step, the low-boiling organic solvent and the concentrated solution are subjected to azeotropy so that the pH of the evaporated concentrate of the radioactive metal nuclide becomes substantially neutral.

11. The radiolabeled substance manufacturing apparatus according to claim 10, In the second evaporation and concentration step, the low-boiling point organic solvent is added to the concentrated solution, the solution is heated, and then a low-boiling point organic solvent of the same type as the low-boiling point organic solvent or a different type is added again, and the solution is heated, so that the pH of the evaporated concentrate becomes substantially neutral.

12. The radiolabeled substance manufacturing apparatus according to claim 10 or 11, The radiolabeled substance manufacturing apparatus, wherein the labeling section comprises a reaction solution vessel having a bottom surface with a V-shaped cross section.

Images