Patent Application
20100101943
The present invention relates to a radioactive fluoride anion concentrating device by which 18F− ions obtained by irradiating [18O]H2O with protons accelerated by a cyclotron are separated from the [18O]H2O to produce an organic solvent solution containing the 18F− ions.
PET (Positron Emission Tomography) is one of the medical diagnostic techniques using radioactive tracer compounds, but most of the radioactive nuclides used in PET have relatively short half-lives. For example, the half-life of 18F− is about 110 minutes. Therefore, it is necessary to efficiently introduce such a radioactive nuclide into a tracer compound in a short period of time to radioactivate the tracer compound.
Further, [18O]H2O as a raw material of 18F− ions is expensive, and therefore, there is a demand for reuse of [18O]H2O to reduce the cost of diagnosis by PET.
A radioactive tracer compound used in, for example, PET has a time limit due to a short lifetime of a radioactive nuclide used, and therefore, the synthesis of a compound labeled with 18F is required to achieve both a reduction in time on the minute time scale and a high synthetic rate.
Conventional methods for separating 18F− ions from [18O]H2O containing 18F− ions to produce an organic solvent solution containing the separated 18F− ions can be divided into two types (hereinafter, referred to as “conventional method 1” and “conventional method 2”).
According to a conventional method 1, [18O]H2O containing 18F− ions is passed through a column packed with an anion-exchange resin to allow the resin to capture 18F− ions to separate 18F− ions from the [18O]H2O. Then, the 18F− ions captured by the resin are again eluted using an aqueous potassium carbonate solution, and the aqueous potassium carbonate solution containing 18F− ions is recovered. Then, the recovered aqueous potassium carbonate solution is concentrated under reduced pressure to completely remove water, and then an organic solvent for performing an organic reaction is added thereto to obtain an organic solvent solution containing the separated 18F− ions. The concentration of 18F− ions in the organic solvent solution can be controlled by adjusting the amount of the organic solvent added.
According to a conventional method 2, 18F− ions contained in [18O]H2O are captured by a glassy carbon rod electrode, and then the solvent is exchanged from [18O]H2O to an organic solvent. It can be expected that [18O]H2O obtained by separating 18F− ions from [18O]H2O containing 18F− ions by this method can be reused because it is free from eluted organic substances. A device for separating 18F− ions from a [18O]H2O solution containing 18F− ions has been reported in Patent Document 1 and Non-Patent Document 1.
The basic structure of the device is described in detail in Non-Patent Document 1. The device uses a cell having a glassy carbon rod electrode and a platinum electrode. A voltage is applied to the glassy carbon rod electrode as a positive electrode to deposit 18F− ions on the glassy carbon rod electrode to separate 18F− ions from [18O]H2O containing 18F− ions. Then, the 18F− ions deposited on the positive electrode are recovered using an organic solvent (dimethylsulfoxide (DMSO)) to react the 18F− ions with an organic compound.
It is to be noted that a combination use of a graphite-like carbon electrode and a platinum electrode for depositing 18F− ions on the graphite-like carbon electrode was first reported in Non-Patent Document 2.
Patent Document 1: Japanese Unexamined Patent Publication No. 2005-519270
Non-Patent Document 1: Appl. Radiat. Isot 2006 (64) 989-994.
Non-Patent Document 2: Appl. Radiat. Isot. 1989 (40) 1-6.
In the case of the conventional method 1, 18F− ions can be speedily separated from [18O]H2O containing 18F− ions by an ion-exchange resin. However, as described above, many operational steps have to be performed to obtain an organic solvent solution containing 18F− ions recovered from the ion-exchange resin, which takes much time. In addition, so many operational steps require the use of many tools and many kinds and large amounts of reagents. The separated [18O]H2O cannot be reused because trace amounts of organic substances are eluted from the ion-exchange resin.
In the case of the conventional method 2, the cell described in the above documents is of a batch type, and therefore, capturing of 18F− ions by the glassy carbon rod electrode cannot be performed in a state where [18O]H2O containing 18F− ions is flowing through the cell, and the amount of [18O]H2O containing 18F− ions that can be treated at one time is as small as about the internal volume of the cell. When a voltage of about 20 V is applied to the glassy carbon rod electrode, it takes about 8 minutes to trap 18F− ions in the cell. Further, it takes about 5 minutes to recover 18F− ions deposited on the glassy carbon rod electrode using an organic solvent.
The volume of the obtained organic solvent solution containing 18F− ions is as large as about a fraction of the volume of the treated [18O]H2O containing 18F− ions, and therefore, the level of concentration of 18F− ions is not so high.
Therefore, it is an object of the present invention to provide a radioactive fluoride anion concentrating device capable of concentrating 18F− ions speedily and efficiently, and a radioactive fluoride anion concentrating method using such a device.
More specifically, it is an object of the present invention to achieve the following (1) to reduce the time required to separate 18F− ions from [18O]H2O containing 18F− ions and recover the 18F− ions using an organic solvent as compared to the conventional methods 1 and 2; (2) to separate 18F− ions from [18O]H2O containing 18F− ions in a state where the [18O]H2O is flowing through a cell so that a larger amount of [18O]H2O containing 18F− ions can be treated as compared to the conventional method 2; (3) to reduce an applied voltage required to separate 18F− ions from [18O]H2O containing 18F− ions as compared to the conventional method 2; and (4) to reduce the volume of an obtained organic solvent solution containing 18F− ions to achieve a higher level of concentration of 18F− ions as compared to the conventional method 2.
The present invention is directed to a radioactive fluoride anion concentrating device including a flow cell having a pair of plate electrodes which are opposed to each other in parallel, and at least one of which is a carbon plate electrode, and a flow channel provided between the plate electrodes spaced 500 μm or less apart to allow a [18O]H2O solution containing 18F− ions to flow therethrough; a power source connected between the plate electrodes to apply a direct current voltage between the plate electrodes and capable of reversing the polarity of the direct current voltage; and a liquid sending device for sending the solution to the flow channel.
The carbon plate electrode may be a glassy carbon electrode or a graphite electrode. A first embodiment using a glassy carbon electrode as the carbon plate electrode of the flow cell and a second embodiment using a graphite electrode as the carbon plate electrode of the flow cell will be described later. The present invention can be carried out as long as at least one of the pair of plate electrodes contains carbon.
The other plate electrode may be, for example, a metal plate electrode obtained by forming a film made of a metal material on an insulating plate substrate. Examples of the metal material include platinum, gold, aluminum, tungsten, copper, silver, conductive silicon, titanium, and chromium.
The radioactive fluoride anion concentrating device according to the present invention may further include an insulating sheet having a through groove serving as the flow channel. In this case, the insulating sheet is sandwiched between the plate substrates. This is advantageous in that the flow channel can be provided between the plate electrodes without forming a groove or the like in one or both of the plate electrodes.
The present invention is also directed to a radioactive fluoride anion concentrating method using the radioactive fluoride anion concentrating device according to the present invention, the method including the steps of: capturing 18F− ions by a carbon plate electrode, which is one of the pair of plate electrodes, by applying a voltage to the carbon plate electrode as a positive electrode and flowing a [18O]H2O solution containing 18F− ions as radioactive nuclides through the flow channel; and recovering a solution containing 18F− ions or a reaction product labeled with 18F− by applying a voltage to the carbon plate electrode as a negative electrode and flowing a solution for recovering 18F− ions through the flow channel.
Examples of the solution for recovering 18F− ions include a solution containing an agent for recovering 18F− ions and a solution containing an organic reactive substrate.
According to the present invention, the distance between the electrodes constituting the flow cell is 500 μm or less, and therefore, a potential gradient between the electrodes is large even when a voltage applied between the electrodes is low so that a large force acts on 18F− ions. Further, by providing a space having a volume of several hundred microliters or less as the flow channel of the flow cell, it is possible to increase the specific surface area of the glassy carbon electrode per unit volume of the flow channel. Therefore, the radioactive fluoride anion concentrating device according to the present invention can achieve the following: (1) to treat [18O]H2O containing 18F− ions in a shorter period of time as compared to the conventional methods 1 and 2; (2) to treat a larger amount of [18O]H2O containing 18F− ions as compared to the conventional method 2; (3) to treat [18O]H2O containing 18F− ions at a lower applied voltage as compared to the conventional method 2; and (4) to reduce the volume of an obtained organic solvent solution containing 18F− ions to achieve a higher efficiency of concentration of 18F− ions as compared to the conventional method 2.
Hereinafter, embodiments of the present invention will be described in detail.
As shown in
<Structure of Flow Cell>
The flow cell 11 is constituted from a metal plate electrode 21, an insulating sheet 23, and a glassy carbon electrode 25. The electrodes 21 and 25 are arranged so that the electrode sides thereof are opposed to each other, and the insulating sheet 23 is sandwiched between the electrodes 21 and 25. In the flow cell 11 shown in
The metal plate electrode 21 can be obtained by, for example, forming a film made of a metal material (e.g., platinum, gold, aluminum, tungsten, copper, silver, conductive silicon, titanium, or chromium) on an insulating plate. The insulating sheet 23 can be obtained by, for example, forming a through groove serving as a flow channel 26 in a rubber sheet made of, for example, PDMS (polydimethylsiloxane). The thickness of the insulating sheet 23 varies depending on conditions for the use of the flow cell, but is preferably about 100 to 500 μm. The flow cell 11 is fixed by a fixing jig 27 provided on the upper surface of the flow cell 11 and a fixing jig 29 provided on the lower surface of the flow cell 11.
The metal plate electrode 21 has a sample inlet 31 and a sample outlet 33, and the inlet 31 is connected to one end of the flow channel 26 and the outlet 33 is connected to the other end of the flow channel 26. The fixing jig 27 has a through hole 35 connected to the sample inlet 31 and a through hole 37 connected to the sample outlet 33.
The power source 13 is connected between the metal plate electrode 21 and the glassy carbon electrode 25 to apply a direct current voltage between the electrodes 21 and 25. The power source 13 can reverse the polarity of the direct current voltage.
<Production of Flow Cell>
As shown in
In the case of the flow channel pattern shown in
In this case, as described above, the rubber sheet 23 for forming the flow channel 26 is made of PDMS, and the chip is formed by sandwiching the PDMS sheet 23 between the metal electrode 21 obtained by forming a metal electrode on a quartz member and the glassy carbon electrode 25.
Hereinafter, methods for forming members for use in the flow cell 11 will be described.
The metal plate electrode 21 is formed by sputtering a platinum film on a quartz member having a size of 25 mm×48 mm and a thickness of 1 mm obtained by dicing. As the glassy carbon electrode 25, a molded article having a size of 25 mm×48 mm and a thickness of 1 mm is used. The PDMS sheet 23 is formed by spin coating to have a thickness of 100 μm, and is then cut into pieces, each having a length of 25 mm and a width of 48 mm by a cutting plotter, and part of each of the pieces is cut out by the cutting plotter to form the flow channel 26 having a desired shape. The shape of the flow channel 26 will be discussed later.
Hereinafter, the procedure of assembling these members into the flow cell will be described.
(1) The metal plate electrode 21 and the PDMS sheet 23 having the flow channel 26 formed therein are subjected to oxygen plasma treatment to activate the surfaces thereof, and are then bonded together and left for 12 hours or longer to fix the metal plate electrode 21 and the PDMS sheet 23 to each other.
(2) The surface of the glassy, carbon electrode 25 and the surface of the PDMS sheet 23, which has been fixed to the metal plate electrode 21 in the above step (1), are subjected to oxygen plasma treatment, and are then bonded together immediately after the oxygen plasma treatment to fix the insulating sheet 23 and the glassy carbon electrode 25 to each other.
Hereinafter, the procedure of concentrating 18F− ions will be described with reference to
(1) A solution containing 18F− ions is introduced into the flow cell 11 through the sample inlet 31.
(2) The power source 13 applies a voltage between the metal plate electrode 21 and the glassy carbon electrode 25 to allow the glassy carbon electrode 25 to capture 18F− ions.
(3) The solution contained in the flow channel 26 is discharged from the flow cell 11 through the sample output 33.
(4) The flow cell 11 is filled with acetonitrile containing an agent for recovering 18F− ions, and then the polarity of the voltage applied to the glassy carbon electrode 25 is reversed to recover the 18F− ions captured by the glassy carbon electrode 25 using the acetonitrile.
(5) The acetonitrile containing 18F− ions is discharged from the flow cell 11 through the sample outlet 33.
(6) The flow cell 11 is filled with acetonitrile introduced through the sample inlet 31 to clean the inside of the flow cell 11.
(7) The cleaning fluid (acetonitrile) is discharged from the flow cell 11 through the sample outlet 33.
(8) The cleaning of the flow cell 11 with an acetonitrile solution is performed twice.
In a case where the flow cell 11 shown in
Hereinafter, one example of a fluorine concentration experiment performed according to the concentrating method described with reference to the first embodiment will be described with reference to
<Concentration Experiment>
(1) A [18O]H2O solution was introduced into the liquid sending device 15 (e.g., a syringe pump), and was then sent into the flow cell 11 using the syringe pump at a flow rate of 500 μL/min. The volume of the [18O]H2O solution used was 2000 μL and the [18O]H2O solution contained 1355 μCi of 18F− ions.
(2) The direct-current power source 13 applied a voltage of 10.0 V to the glassy carbon electrode 25.
(3) After the completion of sending the [18O]H2O solution to the flow cell 11, the [18O]H2O solution was pushed out of the flow cell 11 by a compressed gas. The amount of 18F− ions captured by the glassy carbon electrode 25 was 1238 μCi (which was measured after a lapse of 2 minutes from the initial dosimetry measurement).
(4) The flow cell was filled with 17.6 μL of an acetonitrile solution containing 0.34 mg of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]-hexacosane (Kryptofix 222 (registered trademark), [K⊂2.2.2]2CO3). The polarity of the voltage applied by the direct-current power source 13 was reversed and a voltage of −3.3 V was applied to the glassy carbon electrode 25. The flow cell 11 was heated by the heating device 19 at 80° C. for 1 minute.
(5) After a lapse of 1 minute from the start of heating, the acetonitrile solution was pushed out of the flow cell 11 by a compressed gas and recovered. The flow channel 26 provided in the flow cell 11 was cleaned with 17.6 μL of an acetonitrile solution twice.
<Results of Concentration Experiment>
The capture rate (%) of 18F− ions by the glassy carbon electrode 25 at room temperature was determined by changing the applied voltage and the flow velocity of the [18O]H2O solution in the chip (mm/sec). The voltage applied to the glassy carbon electrode 25 was changed at three levels (i.e., 3.3 V, 6.7 V, and 10.0 V), and as a result, the capture rate of 18F− ions exceeded its target of 90% when the applied voltage was 10.0 V. Therefore, in the first embodiment, a voltage applied to the glassy carbon electrode 25 to allow the glassy carbon electrode 25 to capture 18F− ions was set to 10.0 V.
On the other hand, a voltage of −3.3 V was applied to the glassy carbon electrode 25 while the flow cell 11 was heated at 80° C. for 1 minute when the 18F− ions captured by the glassy carbon electrode 25 were recovered using a liquid for recovering 18F− ions.
The amount of 18F− ions recovered using the acetonitrile solution according to the concentrating method described above was 1032 μCi (which was measured after a lapse of 4 minutes from the initial dosimetry measurement). It is to be noted that in this experiment, the distance between the electrodes 21 and 25 of the flow cell 11 was 100 μm.
By setting the distance between the electrodes 21 and 25 of the flow cell 11 to 500 μm or less and providing a microspace having a volume of several hundred microliters or less as the flow channel 26, it is possible to maintain a large potential gradient between the electrodes 21 and 25 even at a low applied voltage, thereby increasing electrostatic force acting on 18F− ions. This is attributed to an area where electrostatic force acts on 18F− ions is increased by increasing the specific surface area of the electrode per unit volume of the flow channel.
According to the method described with reference to the first embodiment, the time required to treat 2.0 mL of the [18O]H2O solution was reduced to about 4 minutes, which was shorter as compared to the conventional methods. Further, at this time, the amount of 18F− ions captured by the glassy carbon electrode 25 was about 93% of the total amount of 18F− ions contained in the [18O]H2O solution, which was a sufficiently high capture rate.
Then, about 84% of the 18F− ions deposited on the glassy carbon electrode 25 could be recovered using the acetonitrile solution. At this time, the time required to recover 18F− ions using the acetonitrile solution was about 3 minutes.
The recovered acetonitrile solution containing 18F− ions had a volume of about 53 μL and contained about 78% of the total 18F− ions present in the [18O]H2O solution.
The rate of change of the concentration of 18F− ions was calculated as follows: 2000/53×0.78≅29. As a result, it was confirmed that the concentration of 18F− ions was increased about 29 times.
Hereinafter, a radioactive fluoride anion concentrating device according to another embodiment of the present invention will be described.
The radioactive fluoride anion concentrating device according to a second embodiment of the present invention has the same structure as the first embodiment shown in
The flow cell 11 has the metal plate electrode 21, the insulating sheet 23, and the graphite electrode 25. In the flow cell 11, the metal plate electrode 21 and the graphite electrode 25 are arranged so that the electrode sides thereof are opposed to each other, and the insulating sheet 23 is sandwiched between the metal plate electrode 21 and the graphite electrode 25.
It is to be noted that in the flow cell 11 shown in
Hereinafter, the procedure of concentrating 18F− ions will be described with reference to
(1) A solution containing 18F− ions is introduced into the flow channel 26 of the flow cell 11 through the sample inlet 31.
(2) The power source 13 applies a voltage between the metal plate electrode 21 and the graphite electrode 25 to allow the graphite electrode 25 to capture 18F− ions.
(3) The solution contained in the flow channel 26 is discharged from the flow cell 11 through the sample outlet 33.
(4) An acetonitrile solution containing an agent for recovering 18F− ions is introduced into the flow cell 11 through the sample inlet 31, and then the polarity of the voltage applied to the graphite electrode 25 is reversed to recover the 18F− ions captured by the graphite electrode 25 using the acetonitrile solution.
(5) The acetonitrile solution containing 18F− ions is discharged from the flow cell 11 through the sample outlet 33.
(6) Acetonitrile is introduced into the flow cell 11 through the sample inlet 31 to clean the inside of the flow cell 11 with the acetonitrile.
(7) The cleaning fluid (acetonitrile) is discharged from the flow cell 11 through the sample outlet 33.
(8) The cleaning of the flow cell 11 with an acetonitrile solution is performed twice.
In a case where the flow cell 11 shown in
Hereinafter, one example of a fluorine concentration experiment performed according to the concentrating method described with reference to the second embodiment will be described with reference to
<Concentration Experiment>
(1) A [18O]H2O solution was introduced into the liquid sending device 15 (syringe pump), and was then sent into the flow cell 11 by the syringe pump at a flow rate of 500 μL/min. The [18O]H2O solution used had a volume of 2000 μL and contained 717 μCi of 18F− ions.
(2) A voltage of 10.0 V was applied to the graphite electrode 25 by the direct-current power source 13.
(3) After the completion of sending the [18O]H2O solution to the flow cell 11, the [18O]H2O solution was pushed out of the flow cell 11 by a compressed gas. At this time, the amount of 18F− ions captured by the graphite electrode 25 was 612 μCi (which was measured after a lapse of 2 minutes from the initial dosimetry measurement).
(4) The flow cell 11 was filled with 17.6 μL of an acetonitrile solution containing 0.34 mg of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]-hexacosane (Kryptofix 222 (registered trademark), [K⊂2.2.2]2CO3). The polarity of the voltage applied by the direct-current power source 13 was reversed and a voltage of −3.3 V was applied to the graphite electrode 25. The flow cell 11 was heated by the heating device 19 at 80° C. for 1 minute.
(5) After a lapse of 1 minute from the start of heating, the acetonitrile solution was pushed out of the flow cell 11 by a compressed gas and recovered. The flow channel 26 of the flow cell 11 was cleaned with 17.6 of an acetonitrile solution twice.
<Results of Concentration Experiment>
The amount of 18F− ions recovered using the acetonitrile solution according to the concentrating method described above was 313 μCi (which was measured after a lapse of 4 minutes from the initial dosimetry measurement).
According to the method described with reference to the second embodiment, the time required to treat the [18O]H2O solution was shorter as compared to the conventional methods.
Further, in this experiment, the amount of 18F− ions captured by the graphite electrode 25 was about 85.3% of the total amount of 18F− ions contained in the [18O]H2O solution, which was a sufficiently high capture rate.
Then, about 51.2% of the 18F− ions deposited on the graphite electrode 25 could be recovered using the acetonitrile solution.
Hereinafter, the shape of the flow channel 26 provided in the flow cell 11 will be discussed.
<Study of Flow Channel Shape>
It can be estimated that 18F− ion capture-efficiency is increased as the electrode area of the flow cell 11 is increased. Therefore, 18F− ion capture efficiency was determined by changing the shape of the flow channel. In this study, three different flow channel patterns shown in
In the case of the flow channel patterns shown in
Then, radiographs (not shown) were taken to check the distribution of 18F− ions in the flow channel patterns shown in
On the other hand, in the case of the flow channel patterns shown in
Based on the results, the most efficient flow channel pattern was selected from the three flow channel patterns. As described above, the flow channel pattern shown in
As a result, the flow channel pattern shown in
The flow cell produced according to the present invention is designed so as to be able to separate 18F− ions from [18O]H2O containing 18F− ions in a state where the [18O]H2O is flowing therethrough, and therefore, it is possible to treat a desired amount of [18O]H2O containing 18F− ions at one time to separate 18F− ions from the [18O]H2O.
In addition, it is also possible to speedily perform solvent exchange by allowing a desired organic solvent to flow through the flow channel, thereby simplifying operation as compared to the conventional method using an ion-exchange resin.
Further, by setting the distance between the electrodes 21 and 25 constituting the flow cell 11 to 500 μm or less, a large potential gradient between the electrodes 21 and 25 is maintained even when a voltage applied between the electrodes 21 and 25 is low. Therefore, a large electrostatic force acts on 18F− ions so that the time required to capture 18F− ions is reduced. Further, by providing a microspace having a volume of several hundred microliters or less as the flow channel 26 in the flow cell 11, the specific surface area of the carbon electrode 25 per unit volume of the flow channel is increased so that the 18F− ion capture efficiency is enhanced.
Further, the volume of an organic solvent to be introduced into the flow channel to recover 18F− ions captured by the electrode is reduced so that the efficiency of concentration of 18F− ions is enhanced.
The present invention can be applied to a flow cell for separating 18F− ions obtained by irradiating [18O]H2O with protons accelerated by a cyclotron from the [18O]H2O to produce an organic solvent solution containing the 18F− ions.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2007/056160 | 3/26/2007 | WO | 00 | 9/24/2009 |
