Patent Description:
Beta radiation, which is a kind of radioactive ray, has the property of having a low level of substance penetrability and accordingly giving off a high amount of energy per unit length of penetration. Using this property of beta radiation, a radioactive therapeutic agent has been developed in which a radioactive metal nuclide that emits beta radiation is combined with a compound that has the property of gathering on the cells in the lesion area of a disease. Once internally administered, this radioactive therapeutic agent gathers on the lesion area and emits beta radiation at that area, whereby the cells in the lesion area are selectively destroyed, and the disease is thereby cured.

One of the radioactive metal nuclides that emit beta radiation is <NUM>Cu. <NUM>Cu is expected to be used for cancer therapeutic drugs since it emits not only beta radiation but also a special type of electron (Auger electron) which can effectively damage the DNA of cancerous cells.

<NUM>Cu is produced by inducing the <NUM>Ni(p,n)<NUM>Cu nuclear reaction by irradiating a target, such as metallic nickel (Ni) plated on a gold substrate, with a proton beam. The <NUM>Cu formed on the target is dissolved and collected by using an acid solution, such as hydrochloric acid or nitric acid. Since the collected solution contains not only <NUM>Cu but also Ni and other products, it is necessary to separate and purify <NUM>Cu from the other products.

The task of separating and purifying <NUM>Cu from a solution containing <NUM>Cu, Ni and other substances is normally performed by the following method:
Initially, the dissolving liquid containing <NUM>Cu, Ni and other substances is passed through a column packed with an anion-exchange resin to cause <NUM>Cu in the dissolving liquid to be adsorbed onto the anion-exchange resin. Subsequently, an acidic separator solution, such as hydrochloric acid, is passed through the column, whereby the <NUM>Cu adsorbed on the anion-exchange resin is desorbed from the same resin and collected along with the separator solution (<NUM>Cu separation process).

The separator solution containing <NUM>Cu is subsequently put into a flask. The flask is rotated and heated with a heater to evaporate the separator solution. The separator solution is thereby concentrated, and <NUM>Cu is precipitated (<NUM>Cu concentration process).

The <NUM>Cu obtained in the concentration process is dissolved in an appropriate dissolving liquid, and this liquid is subsequently mixed with a reaction liquid containing a label-target compound (therapeutic agent). Consequently, the <NUM>Cu combines with the label-target compound, and a radioactive therapeutic agent labeled with <NUM>Cu is obtained (<NUM>Cu.

Conventionally, the previously described series of tasks from the <NUM>Cu separation process to the <NUM>Cu labeling process are normally performed by manual operations. However, the manual operations inevitably cause radiation exposure of the operator. Accordingly, for some of those processes or some steps in any one of those processes, a device for automatically performing those process steps has been developed (Patent Literature <NUM>).

Another prior art method for evaporatively concentrating a radioactive metal nuclide is known from <NPL>.

However, the <NUM>Cu concentration process has been difficult to automatize for the following reason: For a radioactive metal nuclide, like <NUM>Cu, the process steps in the <NUM>Cu-separation and <NUM>Cu concentration processes are performed on the radioactive metal nuclide dissolved in an acidic solution, such as hydrochloride acid or nitric acid. When the separator solution obtained in the <NUM>Cu separation process is heated in the <NUM>Cu concentration process, the acidic solution contained in the separator solution cannot be sufficiently evaporated, so that a portion of the acidic solution remains within the flask. Consequently, the product collected in the <NUM>Cu concentration process is acidic.

Since the reaction between the <NUM>Cu contained in the collected product and the label-target compound must be performed under a neutral condition, the task of adding an appropriate dissolving liquid to the collected product to adjust its pH value is performed before the collected product is mixed with the reaction liquid containing the label-target compound. The pH value of the collected product depends on the amount of residue of the acidic solution contained in the collected product, while the amount of residue of the acidic solution varies due to various factors. Furthermore, since the amount of collected product is small, it is difficult to measure the pH value of the collected product. Thus, the operator must gradually add the dissolving liquid to the collected product while measuring the pH value from time to time.

The problem to be solved by the present invention is to make it possible to perform, without manual intervention, the processing from the separation of a radioactive metal nuclide from a radioactive solution formed by dissolving the radioactive metal nuclide in an acidic aqueous solution, to the production of a radioactive labeled substance by causing the radioactive metal nuclide to react with a label-target compound.

The first aspect of the present invention developed for solving the previously described problem is a method for evaporatively concentrating a radioactive metal nuclide, including:.

In the previously described method, when a radioactive solution is heated in the first evaporative concentration process, the water which is a solvent in the radioactive solution is mainly evaporated, and a concentrated liquid in which both the concentration of the dissolved radioactive metal nuclide and the acidic concentration are higher than in the radioactive solution is obtained. Subsequently, in the second evaporative concentration process, a low-boiling organic solvent is added to the concentrated liquid, and the mixture is heated, which induces azeotropic boiling of the concentrated liquid (or the concentrated acidic aqueous solution contained in this liquid) and the low-boiling organic solvent, whereby the low-boiling organic solvent and the acidic aqueous solution are evaporated, and an evaporative concentrate of the radioactive metal nuclide is obtained. Since the acidic aqueous solution contained in the concentrated liquid is evaporated, the evaporative concentrate is closer to neutrality than the concentrated liquid.

In the previously described method for evaporatively concentrating a radioactive metal nuclide, after the concentrated liquid is heated with the low-boiling organic solvent added in the second evaporative concentration process, a low-boiling organic solvent which is the same kind of solvent as, or a different kind of solvent from, the aforementioned low-boiling organic solvent may be once more added to the concentrated liquid, and the concentrated liquid may be heated to obtain the evaporative concentrate.

By this method, a larger amount of acidic aqueous solution can be removed from the evaporative concentrate.

Here, an acidic aqueous solution containing a kind of acid selected from a group of acids that can be evaporatively concentrated, such as hydrochloric acid, nitric acid or phosphoric acid, can be used as the acidic aqueous solution.

Solvents available as the low-boiling organic solvent include ethanol (boiling point: approximately <NUM> degrees Celsius), acetonitrile (boiling point: approximately <NUM> degrees Celsius), and acetone (boiling point: approximately <NUM> degrees Celsius).

The radioactive metal nuclide is a kind of metal nuclide selected from the group consisting of <NUM>Cu, <NUM>Cu, <NUM>Cu, <NUM>Cu, <NUM>Cu, <NUM>Mg, <NUM>Sc and <NUM>Ga all of which adsorb onto an ion-exchange resin and can also be eluted with an acidic eluent.

The second aspect of the present invention developed for solving the previously described problem is a method for producing a radioactive labeled substance formed by labeling a compound with a radioactive metal nuclide, including:.

The third aspect of the present invention developed for solving the previously described problem is a device for evaporatively concentrating a radioactive metal nuclide, including:.

Furthermore, the fourth aspect of the present invention developed for solving the previously described problem is a device for producing a radioactive labeled substance, including:.

In the present invention, when a radioactive solution formed by dissolving a radioactive metal nuclide in an acidic aqueous solution is heated in the process of concentrating a radioactive metal nuclide, a low-boiling organic solvent is added to the radioactive solution, so that the acidic aqueous solution contained in the radioactive solution is removed by the azeotropic boiling with the low-boiling organic solvent. Therefore, the evaporative concentrate of the radioactive metal nuclide becomes neutral. Accordingly, unlike the conventional method, the process of neutralizing the evaporative concentrate before causing the radioactive metal nuclide to react with the label-target compound is unnecessary. Therefore, the operations from the collection of the radioactive metal nuclide from the radioactive solution formed by dissolving the radioactive metal nuclide in an acidic aqueous solution, such as hydrochloric acid, to the production of the radioactive labeled substance through the reaction of the radioactive metal nuclide with the label-target compound, can be performed without manual intervention.

A mode for carrying out the present invention is hereinafter described with reference to the drawings.

<FIG> shows a schematic general configuration of a production system <NUM> for a radioactive labeled substance. In the present description, a radioactive labeled substance formed by labeling a compound with <NUM>Cu, which is a kind of radioactive metal nuclide, is taken as an example of the radioactive labeled substance.

The production system <NUM> includes a dissolving device <NUM>, radioactive labeled substance production device <NUM>, and gas supply device <NUM>. The radioactive labeled substance production device <NUM> has a separation-purification section <NUM>, evaporative concentration section <NUM>, and labelling section <NUM>. The dissolving device <NUM>, radioactive labeled substance production device <NUM>, and gas supply device <NUM> are integrally arranged within a hot cell <NUM>.

<FIG> shows a schematic general configuration of the dissolving device <NUM> and the gas supply device <NUM>. As shown in <FIG>, the dissolving device <NUM> and the gas supply device <NUM> are vertically arranged within the hot cell <NUM>.

The dissolving device <NUM> has a dissolving tank <NUM>, dissolving liquid tank <NUM>, dilution water tank <NUM>, and washing water tank <NUM>. The dissolving tank <NUM> is a tank for producing a radioactive dissolving liquid by dissolving a nickel plating (gold plate) on which <NUM>Cu has been produced by irradiation with a proton beam. The dissolving liquid tank <NUM> holds an acidic dissolving liquid, such as a nitric acid solution or hydrochloric acid solution. In the following description, a solution containing a radioactive metal nuclide obtained in the dissolving device <NUM>, i.e., a solution obtained by dissolving, into an acidic dissolving liquid, a piece of raw metal on which a radioactive metal nuclide has been formed, is called a "radioactive dissolving liquid". The radioactive dissolving liquid is a solution before the radioactive metal nuclide is separated therefrom in the separation-purification section, which will be described later.

The dilution water tank <NUM> holds dilution water which is to be added to the radioactive dissolving liquid prepared in the dissolving tank <NUM> so as to adjust the concentration of the radioactive dissolving liquid (nitric acid concentration or hydrochloric acid concentration). The washing water tank <NUM> holds washing water for flushing a passage R1 extending from the dissolving device <NUM> to the radioactive labeled substance production device <NUM> (evaporative concentration section <NUM>).

The gas supply device <NUM> has a nitrogen gas supply <NUM> and an air supply <NUM>. The nitrogen gas supply <NUM> supplies nitrogen gas, which is an inert gas, through a gas supply passage G1 to the related sections of the dissolving device <NUM> and the radioactive labeled substance production device <NUM>. The air supply <NUM> supplies air through a gas supply passage G2 to the related sections of the dissolving device <NUM> and the radioactive labeled substance production device <NUM>. Valves are provided in the gas supply passages G1 and G2, allowing the destination of the nitrogen gas or air to be switched by an open/close operation of the valves.

<FIG> shows a schematic general configuration of the separation-purification section <NUM>. The separation-purification section <NUM> corresponds to the separation-collection section in the present invention. As shown in this drawing, the separation-purification section <NUM> has a buffer tank <NUM>, column <NUM>, column-washing water tank <NUM>, column-cleaning liquid tank <NUM>, first eluent tank <NUM>, second eluent tank <NUM>, third eluent tank <NUM>, and waste tank <NUM>.

The column <NUM> is packed with an ion-exchange resin for separating <NUM>Cu from Ni and other components. The passage R1 is connected to the inlet of the buffer tank <NUM>. Through this passage, a radioactive dissolving liquid delivered from the dissolving device <NUM> is introduced into the buffer tank <NUM>. The radioactive dissolving liquid introduced into the buffer tank <NUM> flows through a passage formed by a tube pump (peristaltic pump) <NUM>, column <NUM> and other elements, to be received by the waste tank <NUM>. Through this process, <NUM>Cu as well as Ni and other components are adsorbed in the column <NUM>. The ejection port of the tube pump <NUM> is connected to the evaporative concentration section <NUM> via the passage R2. A flow sensor <NUM> is provided in the passage R1 at a position near the inlet of the column <NUM>. A radioactivity (RI) sensor <NUM> is provided between the column <NUM> and the tube pump <NUM>.

The buffer tank <NUM> collects, via the passage R1, the washing water flown from the washing water tank <NUM> to wash the dissolving tank <NUM> and the passage R1.

The first eluent tank <NUM> holds an eluent for <NUM>Cu elution. The eluent for <NUM>Cu elution is an acidic aqueous solution. The second and third eluent tanks <NUM> and <NUM> hold eluents for Ni collection. The eluents held in the second and third eluent tanks <NUM> and <NUM> may be of the same kind or different kinds of eluents. In the following description, an eluate which contains <NUM>Cu and is pushed out of the column <NUM> by a flow of the eluent for <NUM>Cu elution through the column <NUM> is called a "radioactive solution". In other words, the solution containing a radioactive metal nuclide separated in the separation-purification section <NUM> is called a "radioactive solution" and distinguished from the radioactive dissolving liquid mentioned earlier. Additionally, in the following description, the acidic aqueous solution used for eluting the radioactive metal nuclide in the separation-purification section <NUM> is called the "acidic aqueous solution" and distinguished from the acidic dissolving liquid mentioned earlier.

The column-washing water tank <NUM> and the column-cleaning liquid tank <NUM> respectively hold the washing water and the cleaning liquid for washing and cleaning the ion-exchange resin in the column <NUM>. The waste tank <NUM> is a tank for collecting the washing water and the cleaning liquid passed through the column <NUM>, or an eluate containing Ni and other components.

<FIG> shows a schematic general configuration of the evaporative concentration section <NUM>. As shown in this figure, the evaporative concentration section <NUM> has an evaporator unit <NUM>, organic solvent tank <NUM>, syringe pump <NUM>, vacuum pump <NUM>, and Dewar vessel <NUM>. The organic solvent tank <NUM> holds an organic solvent having a lower boiling point than water (low-boiling organic solvent). The syringe pump <NUM> has a syringe (not shown) fitted therein and supplies the evaporator unit <NUM> with the low-boiling organic solvent contained in the syringe by operating the same syringe. The evaporator unit <NUM> includes a flask <NUM> serving as a concentration container, a heater <NUM> configured to heat the flask <NUM>, and a rotary holder <NUM> configured to hold the flask <NUM>. The flask <NUM> is either an eggplant flask or a round flask having a hemispherical bottom surface. The flask <NUM> held in the rotary holder <NUM> is rotated by the same rotary holder <NUM>.

The mouth of the flask <NUM> is hermetically closed with a cover element <NUM>. The cover element <NUM> has a pressure-reducing tube <NUM> for reducing the pressure within the flask <NUM> and a pressure-increasing tube <NUM> for increasing the pressure within the flask <NUM>. The pressure-reducing tube <NUM> is connected to the vacuum pump <NUM> via the Dewar vessel <NUM>, while the pressure-increasing tube <NUM> is connected to the nitrogen gas supply <NUM> (see <FIG>) through a gas passage.

The cover element <NUM> additionally has an introduction tube <NUM> and a drawing tube <NUM>. The introduction tube <NUM> is a tube for introducing, into the flask <NUM>, the radioactive solution delivered from the separation-purification section <NUM> and the low-boiling organic solvent supplied from the syringe pump <NUM>. The drawing tube <NUM> is a tube for drawing the content in the flask <NUM> into the labeling section <NUM>. The introduction tube <NUM>, the passage extending from the syringe pump <NUM> to the introduction tube <NUM>, and the passage extending from the organic solvent tank <NUM> to the flask <NUM> correspond to the introduction passage in the present invention. The introduction passage, syringe pump <NUM>, vacuum pump <NUM> and control section <NUM> constitute the introducing section.

<FIG> shows a schematic general configuration of the labeling section <NUM>. The labeling section <NUM>, which has a reaction liquid tank <NUM>, dissolving liquid tank <NUM>, and additive liquid tank <NUM>, is located above the separation-purification section <NUM> within the hot cell <NUM>. The reaction liquid tank <NUM> holds a reaction liquid containing a label-target compound. The dissolving liquid tank <NUM> holds an appropriate kind of dissolving liquid to be used for dissolving a radioactive metal nuclide. The additive liquid tank <NUM> holds an additive liquid necessary for the reaction between the radioactive metal nuclide and the compound.

In the present embodiment, a container whose bottom surface has a V-shaped section is used as each of the reaction liquid tank <NUM>, dissolving liquid tank <NUM> and additive liquid tank <NUM>. This is aimed at helping the entire amount of liquid be taken out from each tank, regardless of whether the amount of liquid contained in the tank is large or small.

Although no detailed description will be given, the dissolving device <NUM> as well as the separation-purification section <NUM>, evaporative concentration section <NUM> and labeling section <NUM> in the radioactive labeled substance production device <NUM> have liquid passages for passing various kinds of liquids, such as the washing water or cleaning liquid, and gas passages for passing the nitrogen gas or air delivered through the gas passages G1 and G2, in addition to the passages R1-R3. Those liquid and gas passages are provided with valves so that the flow of liquids and gases can be changed by an open/close operation of the valves.

<FIG> is a schematic block configuration diagram of the production system <NUM>. As shown in this figure, the production system <NUM> includes a control section <NUM>. Connected to this control section <NUM> are the flow sensor <NUM>, temperature sensor <NUM>, RI sensor <NUM>, pressure sensor <NUM>, flow meter <NUM>, heater <NUM>, tube pump <NUM>, rotary holder <NUM>, syringe pump <NUM>, vacuum pump <NUM>, gas supply device <NUM> (nitrogen gas supply <NUM> and air supply <NUM>), solenoid valves <NUM> for liquid passages, solenoid valves <NUM> for gas passages, and operation unit <NUM>. The temperature sensor <NUM> detects the temperature of the flask <NUM>. The pressure sensor <NUM> detects the pressure of the gas supplied from the gas supply device <NUM>.

Based on the input signals from the flow sensor <NUM>, temperature sensor <NUM>, RI sensor <NUM>, pressure sensor <NUM> and flow meter <NUM>, the control section <NUM> controls the driving operation of the heater <NUM>, tube pump <NUM>, rotary holder <NUM>, syringe pump <NUM>, vacuum pump <NUM>, solenoid valves <NUM> for liquid passages, and solenoid valves <NUM> for gas passages according to a program previously stored in the control section <NUM>.

Next, an operation of each of the devices in the previously described production system <NUM>, i.e., the dissolving device <NUM> and the radioactive labeled substance production device <NUM>, is schematically described with reference to <FIG>.

In the dissolving device <NUM>, a process for dissolving a nickel plating (gold plate) on which <NUM>Cu has been produced by irradiation with a proton beam is performed. The <NUM>Cu dissolving process is initiated by placing the nickel plating (gold plate) with <NUM>Cu produced thereon, supplying a predetermined amount of nitrogen gas from the gas supply device <NUM> to the dissolving liquid tank <NUM>, and pumping the acidic dissolving liquid in the dissolving liquid tank <NUM>, such as the nitric acid solution or hydrochloric acid solution, to the dissolving tank <NUM>. Consequently, <NUM>Cu, Ni (including <NUM>Ni) and other products are dissolved in the dissolving liquid, whereby a radioactive dissolving liquid is produced. The Ni (including <NUM>Ni) and other products correspond to the impurity in the present invention.

After a predetermined period of time has elapsed since the dissolving liquid was pumped to the dissolving tank <NUM>, the control section <NUM> controls the gas supply device <NUM> to supply a predetermined amount of nitrogen gas from the nitrogen gas supply <NUM> to the dissolving tank <NUM>. The radioactive dissolving liquid in the dissolving tank <NUM> is thereby pumped through the passage R1 to the buffer tank <NUM> in the separation-purification section <NUM>. As needed, the dilution water may also be pumped from the dilution water tank <NUM> to the dissolving tank <NUM> so as to regulate the acid concentration of the radioactive dissolving liquid before the radioactive dissolving liquid is pumped from the dissolving tank <NUM> to the separation-purification section <NUM>.

In the separation-purification section <NUM>, a process for separating and purifying <NUM>Cu from the radioactive dissolving liquid. The <NUM>Cu separation-purification process is initiated by introducing, into the column <NUM>, the radioactive dissolving liquid in the buffer tank <NUM> delivered from the dissolving tank <NUM>. When the separation-purification process is initiated, the control section <NUM> drives the tube pump <NUM>. The radioactive dissolving liquid introduced into the column <NUM> is thereby passed through the ion-exchange resin. During this process, the <NUM>Cu and Ni which exist in the form of negative ions in the radioactive dissolving liquid are adsorbed onto the ion-exchange resin (<NUM>Cu adsorption process).

Next, the control section <NUM> controls the solenoid valves <NUM> and <NUM> to secure a passage from the column-washing water tank <NUM> through the column <NUM> to the waste tank <NUM>, and energizes the tube pump <NUM> to draw the column-washing water from the column-washing water tank <NUM> and flush the column <NUM>. The control section <NUM> subsequently secures a passage from the column-cleaning liquid tank <NUM> through the column <NUM> to the waste tank <NUM>, and energizes the tube pump <NUM> to draw the column-cleaning liquid from the column-cleaning liquid tank <NUM> and remove impurities from the inside of the column <NUM>. Furthermore, the control section <NUM> subsequently secures a passage from the first eluent tank <NUM> through the column <NUM> to the waste tank <NUM>, and energizes the tube pump <NUM> to draw an eluent for <NUM>Cu elution, which is an acidic aqueous solution containing a nitric acid, hydrochloric acid or similar substance (this eluent is hereinafter called the "first eluent"), from the first eluent tank <NUM> into the column <NUM>. It is hereinafter assumed that a hydrochloric acid solution with a pH of approximately <NUM> is used as the first eluent. By this operation, ion exchange occurs and <NUM>Cu is eluted (<NUM>Cu elution process). In this process, the beginning of the elution of the radioactive <NUM>Cu can be determined by monitoring the RI sensor <NUM> provided on the exit side of the column <NUM>. When the measured value of the RI sensor <NUM> has exceeded the background level, the control section <NUM> controls the solenoid valve which switches to the passage R2 leading to the evaporative concentration section <NUM>, whereby the radioactive solution containing <NUM>Cu is delivered to the evaporative concentration section <NUM>. When the measured value of the RI sensor <NUM> has decreased to a level equal to or lower than the background level, the tube pump <NUM> is deenergized to discontinue the delivery of the liquid.

Next, the control section <NUM> controls the solenoid valves <NUM> and <NUM> to secure a passage from the second eluent tank <NUM> through the column <NUM> to the waste tank <NUM>, and energizes the tube pump <NUM>. The Ni within the column <NUM> is thereby eluted and collected in the waste tank <NUM>. By passing the eluent for Ni collection through the column <NUM> in this manner, the Ni remaining on the ion-exchange resin can be almost completely removed. It should be noted that the number of times to introduce the eluent for Ni collection into the column <NUM> does not need to be two; it may be one, three or more times.

In the evaporative concentration section <NUM>, the evaporative concentration process is performed in which the radioactive solution is heated to evaporate a solvent in the radioactive solution and thereby concentrate <NUM>Cu. The evaporative concentration process is initiated by the introduction of the radioactive solution delivered from the separation-purification section <NUM> through the passage R2 into the flask <NUM> via the introduction tube <NUM>. When the evaporative concentration process is initiated, the control section <NUM> drives the vacuum pump <NUM> to reduce the pressure within the flask <NUM>. The same section <NUM> also heats the flask <NUM> from the heater <NUM> as well as rotates the rotary holder <NUM>. The radioactive solution within the flask <NUM> is thereby heated while this flask <NUM> is being rotated, and the solvents (mainly, the first eluent) contained in the radioactive solution are evaporated. A portion of the evaporated solvent is turned into liquid (i.e., condensed) within the top portion of the flask <NUM> and flows back. Consequently, the <NUM>Cu in the radioactive solution is concentrated, and a concentrated liquid is obtained (first evaporative concentration process for <NUM>Cu). In the first evaporative concentration process for <NUM>Cu, both the water and the hydrochloric acid in the first eluent flow back in a similar manner. Therefore, the hydrochloric acid concentration of the concentrated liquid is almost equal to that of the radioactive solution, and the concentrated liquid is acidic.

Next, the control section <NUM> discontinues the rotation of the rotary holder <NUM> as well as discontinues the heating by the heater <NUM>. When a predetermined period of time has elapsed (at the point in time where the temperature of the concentrated liquid becomes equal to or lower than a predetermined value), the vacuum pump <NUM> is driven to draw a predetermined amount of low-boiling organic solvent from the organic solvent tank <NUM> and add it to the concentrated liquid in the flask <NUM>. Subsequently, the heating of the flask <NUM> by the heater <NUM> and the rotation of the rotary holder <NUM> are resumed. This operation induces azeotropic boiling of the concentrated liquid and the low-boiling organic solvent within the flask <NUM>, whereby the first eluent contained in the concentrated liquid and the low-boiling organic solvent are evaporated. Consequently, <NUM>Cu is left within the flask <NUM> along with a trace amount of hydrochloric acid solution and the low-boiling organic solvent which have not been evaporated.

Next, the syringe pump <NUM> is driven to add a predetermined amount of low-boiling organic solvent to the residue in the flask <NUM>. Subsequently, the heating of the flask <NUM> by the heater <NUM> and the rotation of the rotary holder <NUM> are resumed. This operation induces azeotropic boiling of the first eluent contained in the residue and the low-boiling organic solvent, whereby the trace amount of eluent contained in the residue is almost entirely evaporated with the low-boiling organic solvent. When a predetermined period of time has elapsed since the beginning of the heating by the heater <NUM>, the control section <NUM> deenergizes the heater <NUM>. Consequently, an evaporative concentrate of <NUM>Cu is formed within the flask <NUM> (second evaporative concentration process for <NUM>Cu). The evaporative concentrate of <NUM>Cu consists of either a dried solid of <NUM>Cu or a mixture of the trace amount of first eluate and low-boiling organic solvent as well as <NUM>Cu. Whichever of the dried solid and the mixture is obtained depends on the period of time and temperature of the heating by the heater <NUM> as well as other conditions. In any case, the evaporative concentrate falls within a neutral area since it contains no amount or only an insignificant amount of first eluent, i.e., the acidic aqueous solution.

Subsequently, the control section <NUM> controls the solenoid valves <NUM> and <NUM> to secure a passage from the dissolving liquid tank <NUM> in the labeling section <NUM> through the passage R3 to the flask <NUM>, and drives the vacuum pump <NUM> to draw the entire amount of dissolving liquid held in the dissolving liquid tank <NUM> into the flask <NUM>. The rotary holder <NUM> is subsequently rotated to stir the content of the flask <NUM>. After the evaporative concentrate has been dissolved by the stirring, the rotary holder <NUM> and the vacuum pump <NUM> are stopped. Subsequently, the control section <NUM> controls the solenoid valves <NUM> and <NUM> to secure a passage from the flask <NUM> to the passage R3, and delivers the entire amount of dissolving liquid in the flask <NUM> through the passage R3 to the reaction liquid tank <NUM> in the labeling section <NUM>.

In the labeling section <NUM>, a <NUM>Cu labeling process for obtaining a radioactive labeled substance by causing the <NUM>Cu in the dissolving liquid to react with a label-target compound. The labeling process is initiated by the introduction of the dissolving liquid delivered from the evaporative concentration section <NUM> into the reaction liquid tank <NUM>. When the labeling process is initiated, the control section <NUM> controls the gas supply device <NUM> to supply nitrogen gas from the nitrogen gas supply <NUM> to the additive liquid tank <NUM>. The entire amount of additive liquid contained in the additive liquid tank <NUM> is thereby introduced into the reaction liquid tank <NUM>. The reaction liquid, dissolving liquid and additive liquid contained in the reaction liquid tank <NUM>, dissolving liquid tank <NUM> and additive liquid tank <NUM> are prepared beforehand in required quantities for the reaction between <NUM>Cu and the label-target compound. Therefore, within the reaction liquid tank <NUM>, the reaction between <NUM>Cu and the label-target compound progresses with the liquids in exact quantities to produce a radioactive labeled substance.

Hereinafter described is a practical example in which <NUM>Cu-ATSM [<NUM>Cu- diacetyl-bis (N<NUM>-methylthiosemicarbazone)] was produced as a radioactive labeled substance by using the production system <NUM> according to the previous embodiment. <NUM>Cu-ATSM is a radioactive therapeutic agent developed for the treatment of malignant brain tumors.

Both the dissolving device <NUM> and the hot cell <NUM> used in the practical example were products of Sumitomo Heavy Industries, Ltd. As for the ion-exchange resin used for filling the column <NUM>, a cation resin (AG 50W-X8 <NUM>-<NUM>+, manufactured by Bio-Rad Laboratories, Inc. ) was used. The dissolving device <NUM> was connected to the radioactive labeled substance production device <NUM> as well as the gas supply device <NUM> via passages. A single control system was provided to control the dissolving device <NUM>, radioactive labeled substance production device <NUM> and gas supply device <NUM> as well as the valves in the passages in a unified fashion so as to automatically perform the entire process from the <NUM>Cu dissolving process, through the <NUM>Cu separation-purification process and the <NUM>Cu evaporative concentration process, to the <NUM>Cu labeling process.

Before the production of <NUM>Cu-ATSM, a target gold plate coated with <NUM>Ni plating was irradiated with a proton beam generated by a cyclotron (HM-<NUM>, manufactured by Sumitomo Heavy Industries, Ltd. ) to produce <NUM>Cu through the [<NUM>Ni(p,n)<NUM>Cu] nuclear reaction.

The types and amounts of the liquids used in each process were as shown in the following Table <NUM>.

In the present example, a <NUM>Cu-ATSM production test was performed three times. The results were as shown in Table <NUM>.

As shown in Table <NUM>, a therapeutic dose of <NUM>Cu-ATSM conforming to the related quality standards was produced in all three tests.

In the present example, the volume of the radioactive solution introduced from the separation-purification section <NUM> into the flask <NUM> in the evaporative concentration process was <NUM>. By heating this radioactive solution with the evaporator unit <NUM>, an intended evaporative concentrate was successfully obtained after <NUM> minutes from the beginning of the evaporative concentration process.

Meanwhile, as a comparison test, <NUM> of the collected eluate was put in a flask, and an evaporative concentration treatment of the radioactive solution was performed by a conventional method in which the flask was heated to <NUM> with a block heater. Despite the small quantity of liquid, the treatment required <NUM> minutes until the evaporative concentrate was obtained. This demonstrated that the test according to the present example using the evaporator unit <NUM> could reduce the concentrating-and-drying time per unit volume of liquid to one sixth the time as compared to the comparison test.

Apart from the three aforementioned tests, a concentration treatment using the evaporator unit <NUM> was performed on <NUM> of a radioactive solution (this treatment corresponds to the first evaporative concentration process in the present invention). The concentrated liquid within the flask <NUM> had a pH of <NUM> and was highly acidic. Accordingly, a treatment was performed which included the steps of adding <NUM> of ethanol to the concentrated liquid and heating the same liquid, followed by the steps of once more adding ethanol and heating the same liquid (this treatment corresponds to the second evaporative concentration process in the present invention). Consequently, the pH of the evaporative concentrate within the flask <NUM> increased to <NUM>, which was almost neutral. This treatment required <NUM> minutes.

When the treatment including the steps of adding <NUM> of ethanol to the concentrated liquid and heating the same liquid was performed only one time, the treatment was completed in two minutes. However, the obtained evaporative concentrate had a pH of <NUM> and was still acidic.

The amount of residual ethanol in each <NUM>Cu-ATSM product obtained in the three tests in the present example was measured with a gas chromatograph (manufactured by Shimadzu Corporation), which did not exceed the reference value (<NUM> ppm).

The previously described results demonstrate that the method according to the present invention in which ethanol (low-boiling organic solvent) is added to the concentrated liquid in the process of evaporatively concentrating <NUM>Cu can reduce the period of time required for obtaining an evaporative concentrate to roughly one third or one half as compared to the conventional method. Furthermore, an evaporative concentrate which falls within a neutral area is obtained in the <NUM>Cu evaporative concentration process. These facts indicate that this evaporative concentrate can be directly transferred to the <NUM>Cu labeling process without manual intervention by the operator.

Accordingly, the entire processing from the <NUM>Cu dissolving process to the <NUM>Cu labeling process for the production of a radioactive labeled substance can be automatized by using the evaporative concentration method according to the present invention. Furthermore, the automatization of the entire processing can dramatically reduce the radiation exposure of the operator (an experiment by the present inventors showed that the exposure could be reduced to roughly one fifth the amount). It also allows for a stable, mass production of radioactive labeled substances, such as radiopharmaceuticals.

In the previously described example, the treatment of adding a low-boiling organic solvent to the content of the flask <NUM> and inducing the azeotropic boiling of the solvent and the first eluent was performed two times so that the evaporative concentrate to be obtained in the second evaporative concentration process for <NUM>Cu would assuredly fall within a neutral area. In some cases, the azeotropic boiling treatment may only need to be performed one time. For example, under appropriately set conditions, such as a larger amount of low-boiling organic solvent to be added to the concentrated liquid in the flask <NUM> or a longer heating time with the heater <NUM>, it may be possible to almost entirely evaporate the first eluate contained in the concentrated liquid and obtain an evaporative concentrate falling within a neutral area by a single execution of the azeotropic boiling treatment.

Although <NUM>Cu was used as the radioactive metal nuclide, the evaporative concentration method according to the present invention can be applied to any radioactive metal nuclide, provided that the processing for producing a radioactive labeled substance can be performed on the radioactive metal nuclide dissolved in an acidic aqueous solution, and that the radioactive metal nuclide can be adsorbed onto an ion-exchange resin. This type of radioactive metal nuclide includes <NUM>Cu, <NUM>Cu, <NUM>Cu, <NUM>Cu, <NUM>Cu, <NUM>Mg, <NUM>Sc and <NUM>Ga.

The acidic aqueous solution in which a radioactive metal nuclide should be dissolved is selected according to the kind of radioactive metal nuclide. Examples include hydrochloric acid, nitric acid and phosphoric acid.

Claim 1:
A method comprising:
a first evaporative concentration process in which a radioactive solution formed by dissolving at least a radioactive metal nuclide in an acidic aqueous solution is heated to evaporate a solvent in the radioactive solution so as to obtain a concentrated liquid containing the radioactive metal nuclide;
characterised by
a second evaporative concentration process in which a low-boiling organic solvent having a lower boiling point than water is added to the concentrated liquid, and the concentrated liquid is heated to induce azeotropic boiling of the concentrated liquid and the low-boiling organic solvent so as to obtain an evaporative concentrate of the radioactive metal nuclide.