JP2022097320A - Manufacturing apparatus for 18f-labeled compound and manufacturing method for 18f-labeled compound - Google Patents

Abstract

To provide a manufacturing apparatus for an 18F-labeled compound capable of drastically improving a yield of the 18F-labeled compound.SOLUTION: An introduction control unit 10 introduces neon into a nuclear reaction vessel 10a. An irradiation control unit 11 irradiates the nuclear reaction vessel 10a into which the neon is introduced with gamma ray R for a predetermined time to induce a nuclear reaction on the neon. An adjustment control unit 12 guides neon containing 18F and 18Ne of generated seed species after the nuclear reaction discharged from the nuclear reaction vessel 10a into a flow passage 12a connecting between the nuclear reaction vessel 10a and a synthesis vessel 13a, and adjusts a flow rate of the neon in the flow passage 12a or a length of the flow passage 12a so as to make the neon retain in the flow passage 12a for a predetermined time until the 18Ne is converted to 18F. A synthesis control unit 13 synthesizes an 18F-labeled compound by allowing the 18F contained in the neon after retention to react with a liquid compound C having a hydroxyl group which can be replaced with the 18F in the synthesis vessel 13a.SELECTED DRAWING: Figure 1

Description

The present invention relates to an 18F-labeled compound production apparatus and an 18F-labeled compound production method.

In recent years, positron emission tomography (hereinafter referred to as PET) examination has become a trend of cancer diagnostic methods using radiation.

Radioisotope-labeled compounds (RI-labeled compounds) are basically used in PET examinations. This RI-labeled compound takes advantage of the fact that it has the same chemical properties as a normal compound by replacing the atom at a specific position of the compound that tends to accumulate in the lesion of cancer with a radioisotope (RI). .. The RI-labeled compound is different from a normal compound, and by detecting the radiation emitted from the RI, it is possible to identify in which part of the living body the RI-labeled compound is accumulated. In the PET examination, as a typical example of the RI-labeled compound, 18F-2-fluoro-2-deoxy-D-glucose (referred to as 18F-FDG) in which 18-fluorine isotope (18F) is incorporated into glucose (dextrose) is used. When administered to cancer patients, the positrons emitted from 18F of 18F-FDG are paired with electrons and emit two gamma rays with an energy of 511 keV, which are detected by a radiation measuring instrument installed outside the body. By doing so, the distribution of 18F-FDG in the body is photographed, and the cancer-affected part where glucose metabolism is remarkable is identified.

Since a special RI-labeled compound is used in the PET examination, there is a problem that the inspection cost is high. For example, a PET examination is said to cost about 100,000 yen at a time. In Japan, PET examinations cost hundreds of billions of yen each year to perform diagnostic imaging for cancer treatment.

Here, the 18F of 18F-FDG used in the PET examination is usually obtained by irradiating the 18-oxygen isotope (18O) with a proton beam by a small cyclotron and utilizing the 18O (p, n) 18F reaction. Manufacture 18O to 18F.

By the way, in natural oxygen, the abundance ratio of 16-oxygen isotope (16O) is 99.762%, and the abundance ratio of 17-oxygen isotope (17O) is 0.038%, which is used in the nuclear reaction18. -The abundance ratio of oxygen isotope (18O) is as low as 0.200%. Therefore, in the production of 18F for PET inspection, expensive 18O concentrated water in which 18O is concentrated is used. For example, Japanese Patent Application Laid-Open No. 2004-59356 (Patent Document 1) discloses a technique relating to 18O concentrated water for an 18F fluoride ion-producing raw material.

Further, when the small cyclotron used for manufacturing the 18F is used, it is inevitable that the workers involved in the manufacturing of the 18F will be exposed to a considerable amount of radiation. That is, since 18F is produced by irradiating 18O concentrated water with a high-intensity proton beam from a small cyclotron, a large amount of radioactive material derived from the proton beam take-out window or the like is inevitably mixed. Since the beam take-out window may be damaged, it is necessary to replace it regularly and maintain the proton beam irradiation device regularly. This work inevitably causes a large amount of radiation exposure.

Therefore, in recent years, various methods for producing 18F without using 18O concentrated water have been developed. For example, Japanese Patent Application Laid-Open No. 2018-84570 (Patent Document 2) irradiates neon gas with gamma rays to generate 18F by a nuclear reaction of neon, and reacts 18F with a liquid compound to obtain an 18F-labeled compound. An apparatus for producing an RI-labeled compound to be synthesized is disclosed. As a result, the target gas can be reused, the production efficiency of radioisotopes is high, the possibility of radiation exposure is close to zero, and it is possible to supply it at a low price.

Japanese Unexamined Patent Publication No. 2004-59356 Japanese Unexamined Patent Publication No. 2018-8457

In the technique described in Patent Document 1, it is necessary to use 18O concentrated water, and there are problems of contamination with impurity RI and exposure to a large amount of radiation. Further, although the technique described in Patent Document 2 can synthesize an 18F-labeled compound at a low price, there is a problem that the yield of 18F is poor because neon in a gaseous state is nuclear-reacted with gamma rays.

The present invention has been made to solve the above problems, and an object of the present invention is to provide an 18F-labeled compound production apparatus and an 18F-labeled compound production method capable of dramatically improving the yield of the 18F-labeled compound. And.

The 18F labeled compound manufacturing apparatus according to the present invention includes an introduction control unit, an irradiation control unit, an adjustment control unit, and a synthesis control unit. The introduction control unit introduces neon into the nuclear reaction vessel. The irradiation control unit irradiates the nuclear reaction vessel into which the neon is introduced with gamma rays for a predetermined time to cause the neon to undergo a nuclear reaction. The adjustment control unit guides neon containing 18F and 18Ne of the nuclides produced after the nuclear reaction discharged from the nuclear reaction vessel into the flow path connecting the nuclear reaction vessel and the synthesis vessel, and guides the neon to the flow path connecting the nuclear reaction vessel and the synthesis vessel. By adjusting the flow velocity of neon in the flow path or the length of the flow path, the neon is retained in the flow path for a predetermined time until the 18Ne is converted to 18F. The synthesis control unit synthesizes an 18F-labeled compound by reacting 18F contained in the neon after retention with a liquid compound having a hydroxyl group substitutable for 18F in the synthesis container.

Further, the method for producing an 18F-labeled compound according to the present invention includes an introduction control step, an irradiation control step, an adjustment control step, and a synthesis control step. Each step of the 18F-labeled compound production method according to the present invention corresponds to each part of the 18F-labeled compound production apparatus according to the present invention.

In the present invention, the yield of the 18F-labeled compound can be dramatically improved.

It is a conceptual diagram of the 18F labeled compound manufacturing apparatus which concerns on embodiment of this invention. It is a flowchart which shows the execution procedure of the 18F labeled compound production method which concerns on embodiment of this invention. It is a perspective view of the prototype of the 18F labeled compound manufacturing apparatus which concerns on embodiment of this invention. It is a spectrum of radiation at the time of collection of 18F. It is a decay curve of the radiation dose for each elapsed time.

Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings for the purpose of understanding the present invention. It should be noted that the following embodiment is an example embodying the present invention and does not limit the technical scope of the present invention.

There are two processes for producing 18F by irradiating gamma rays with neon (Ne) as a target, which is the basis of the present invention, and one is 20Ne (γ, 2n) 18Ne, 18Ne → which undergoes two steps. It is 18F + β-, and the other is a direct 20Ne (γ, pn) 18F reaction. Since the half-life of 18Ne generated in the intermediate stage of the first process is as short as 1.67 seconds, 18Ne is converted to 18F in about 20 seconds.

However, to put it the other way around, in the first process, 18Ne is not converted to 18F until about 20 seconds have passed after the nuclear reaction in the first stage. The previous patent (Patent No. 6274689) filed and granted by the present inventor had a low yield of 18FDG because this point was not taken into consideration.

In the present invention, this point is improved and the yield of 18F is greatly improved. That is, the system (device) was set so that the time required for introducing neon from the nuclear reaction moiety to the synthetic moiety of the 18F-labeled compound was sufficiently long for 18Ne to convert to 18F.

As shown in FIG. 1, the 18F labeled compound manufacturing apparatus 1 (18F labeled compound manufacturing system) according to the embodiment of the present invention includes an introduction control unit 10, an irradiation control unit 11, an adjustment control unit 12, and a synthesis control unit. 13 and.

The introduction control unit 10 introduces neon into the nuclear reaction vessel 10a. The irradiation control unit 11 irradiates the nuclear reaction vessel 10a into which neon is introduced with gamma rays R for a predetermined time to cause the neon to undergo a nuclear reaction.

The adjustment control unit 12 guides 18F, 18Ne, and neon of the nuclides produced after the nuclear reaction discharged from the nuclear reaction vessel 10a into the flow path 12a connecting between the nuclear reaction vessel 10a and the synthesis vessel 13a. By supplying) and adjusting the flow velocity (flow rate) of neon in the flow path 12a or the length of the flow path 12a, neon is retained in the flow path 12a for a predetermined time until 18Ne is converted to 18F. ..

The synthesis control unit 13 synthesizes an 18F-labeled compound by reacting 18F contained in the neon after retention with a liquid compound C having a hydroxyl group substitutable for 18F in the synthesis container 13a.

This makes it possible to dramatically improve the yield of the 18F-labeled compound. That is, in the present invention, by irradiating neon with gamma rays R, as described above, 20Ne (γ, 2n) 18Ne in the first process is converted to 18F through β decay to 18F, and the second A nuclear reaction (photonuclear reaction) that converts the 20Ne (γ, pn) 18F reaction in the process to 18F is adopted. This nuclear reaction is extremely useful for the production of 18F because the generation of radioactive impurities is dramatically reduced.

Here, the present inventor has studied each of the above-mentioned reactions for many years, and in the first process, the nuclear reaction proceeds from the time when neon is irradiated with gamma-ray R, and the nuclear reaction proceeds. It is known that it takes a predetermined time (for example, about 20 seconds) from 18Ne to the time when 18F is produced later as a nuclide.

That is, in the first process, from the time of gamma ray irradiation of neon to the time of formation of 18F, 18Ne is, so to speak, an intermediate state, and even if this intermediate comes into contact with a liquid compound, it is an intermediate. Since 18F is not present in, no 18F-labeled compound can be produced.

On the other hand, neon, which has passed a certain period of time after the nuclear reaction, contains 18F, but 18F is extremely easy to react with impurities containing minute water, so that 18F is immediately converted into a liquid compound after 18F is generated. Without contact, the generated 18F will react with the impurities. This reduces the yield of the 18F labeled compound.

Therefore, in the present invention, the neon is retained in the flow path 12a for a predetermined time from the time of gamma ray irradiation of neon to the time of generation of 18F, and 18Ne contained in the neon is left until the generation of 18F. do. This predetermined time corresponds to the decay time of 18Ne. This makes it possible to reliably convert to 18F via the intermediate of 18Ne in the first process generated from stable 20Ne. The 18F generated in the second process is naturally contained in neon.

Further, in the present invention, neon after retention is immediately introduced into the synthesis container 13a and reacted with the liquid compound to synthesize an 18F-labeled compound. As a result, the 18F produced in the first process and the second process can be efficiently used for the 18F-labeled compound, so that a large amount of the 18F-labeled compound can be efficiently produced, and as a whole, it becomes possible to produce a large amount of the 18F-labeled compound. It is possible to increase the yield of the 18F-labeled compound.

Further, in the present invention, since the 18F-labeled compound is continuously synthesized by flowing neon, these controls can be performed by a control device such as a computer. That is, since each component of the present invention can be performed fully automatically, the 18F labeled compound can be obtained by remote control. Therefore, the operator rarely approaches the device, and the possibility of radiation exposure can be reduced.

Here, the configuration of the introduction control unit 10 is not particularly limited, but for example, a neon cylinder for storing neon is connected to the inlet on-off valve 10c of the nuclear reaction vessel 10a via the compressor 10b, and the introduction control unit 10 is connected to the compressor. By driving 10b and opening the inlet on-off valve 10c, neon is introduced into the nuclear reaction vessel 10a.

The introduction method of the introduction control unit 10 is not particularly limited, but for example, the outlet on-off valve 10d of the nuclear reaction vessel 10a is provided, and the introduction control unit 10 drives the compressor 10b to open the inlet on-off valve 10c. At the same time, neon is filled in the nuclear reaction vessel 10a by closing the outlet on-off valve 10d, and then the introduction control unit 10 seals the neon in the nuclear reaction vessel 10a by closing the inlet on-off valve 10c. May be. Further, an adjustment valve 10e is provided between the compressor 10b and the inlet on-off valve 10c, and the introduction control unit 10 drives the compressor 10b to open the inlet on-off valve 10c and the outlet on-off valve 10d, and the adjustment valve 10e is used. By adjusting the flow rate of neon, neon may flow in the nuclear reaction vessel 10a. In this case, the irradiation control unit 11 irradiates gamma rays to continuously carry out a neon nuclear reaction.

Further, when the neon is introduced into the nuclear reaction vessel 10a, the introduction control unit 10 may set the pressure of the introduced neon to a high pressure of normal pressure (0.1 MPa) or more. By increasing the pressure of neon, it is possible to increase the density of neon in the nuclear reaction vessel 10a, promote the nuclear reaction of neon to a single gamma-ray irradiation, and increase the amount of 18F produced. The neon may be a gas or a high-density liquid.

Further, the configuration of the nuclear reaction vessel 10a is not particularly limited, but for example, a material having excellent heat conduction can be adopted. Specifically, by adopting a SiC ceramic container whose heat conduction is similar to that of copper, even if heat is generated in the container due to absorption of gamma rays R, heat is dissipated by heat conduction and the pressure inside the container increases. Can be prevented. Moreover, since SiC does not chemically react with 18F, the purity of the manufactured 18F can be guaranteed. In addition, a container whose inner surface is coated with a Teflon (registered trademark) material having excellent corrosion resistance may be adopted in consideration of the erosion property of the generated fluorine.

Further, the introduction control unit 10 opens the nuclear reaction vessel 10a and drives the heating device installed in the nuclear reaction vessel 10a to heat the inside of the nuclear reaction vessel 10a before introducing neon into the nuclear reaction vessel 10a. Then, the water existing in the nuclear reaction vessel 10a may be vaporized and released to the outside. Specifically, a heating device is provided on the outer surface of the nuclear reaction vessel 10a, and the introduction control unit 10 sets the inlet on-off valve 10c and the outlet on-off valve 10d at the stage before introducing neon into the nuclear reaction vessel 10a. It may be opened and the heating device may be driven to heat the inside of the nuclear reaction vessel 10a to vaporize the water present in the nuclear reaction vessel 10a and release the water to the outside. After that, the introduction control unit 10 introduces neon into the nuclear reaction vessel 10a. This makes it possible to prevent the generated 18F from reacting with moisture. The configuration of the heating device is not particularly limited, but any configuration such as circulation of a heater or a heating medium may be used.

Further, before introducing neon into the nuclear reaction vessel 10a, the introduction control unit 10 drives a vacuum drawing device connected to the nuclear reaction vessel 10a to evacuate the inside of the nuclear reaction vessel 10a to make the inside of the nuclear reaction vessel 10a vacuum, and the nuclear reaction vessel 10a. It may be configured to remove the water present in the container. Specifically, a vacuum drawing device is connected to either or both of the inlet on-off valve 10c and the outlet on-off valve 10d, and the introduction control unit 10 vacuums before introducing neon into the nuclear reaction vessel 10a. The on-off valve to which the pulling device is connected is opened, the other on-off valves are closed, and the vacuum pulling device is driven to evacuate the inside of the nuclear reaction vessel 10a. After that, the introduction control unit 10 introduces neon into the nuclear reaction vessel 10a. This makes it possible to prevent the generated 18F from reacting with moisture. Of course, the above-mentioned heating device and the evacuation device may be combined.

The configuration of the irradiation control unit 11 is not particularly limited, but for example, the irradiation control unit 11 is provided in the vicinity of the electron beam irradiation unit 11a for irradiating an electron beam having a predetermined energy and the nuclear reaction vessel 10a. It is provided with a gamma ray emitting unit 11b that emits gamma ray R when irradiated with an electron beam. Thereby, the gamma ray R can be easily irradiated. Here, for the gamma ray emitting unit 11b, a target that generates gamma ray R by an electron beam such as tungsten (W), platinum (Pt), or tantalum (Ta) is selected. Specifically, it utilizes the fact that gamma rays R of bremsstrahlung are generated by irradiating tungsten with an electron beam having an energy of 30 MeV.

Here, when the gamma ray R of the target's bremsstrahlung is used by irradiating the target with an electron beam, the target window is made of Si or C, and the half-life of the residual radioactive material generated by the photonuclear reaction is half-life. Is about millisecond, so there is virtually no radioactive material. Also, no long-lived residual radioactive material is produced and there is no need to replace the target device.

For example, if an electron beam accelerator (electron linac) is used, the electron beam irradiation unit 11a can be operated with a single switch, and fully automated and remote control can be easily controlled. With the electron beam accelerator, even an amateur can handle it. Since there is almost no radioactive material in the electron beam accelerator and most of it can be treated as industrial waste, the electron beam accelerator has an advantage in terms of disposal.

Furthermore, by using gamma rays, the nuclear reaction vessel 10a (target target) can be made thicker. In the present invention, the possibility of radiation exposure can be dramatically reduced by using the gamma ray R and configuring the gamma ray R to be generated by the electron beam accelerator.

The predetermined time (irradiation time) for the irradiation control unit 11 to irradiate the gamma ray R is not particularly limited, but is preferably set within the range of 1 to 5 times the half-life of the generated 18F, for example. .. Since the half-life of 18F is 110 minutes, for example, the irradiation time is set within the range of 110 minutes to 550 minutes.

The configuration of the adjustment control unit 12 is not particularly limited, but is appropriately designed depending on the method of retaining neon after the nuclear reaction. For example, when adjusting the flow velocity of neon after the nuclear reaction, the upstream adjustment valve 12b is located on the upstream side of the flow path 12a between the outlet on-off valve 10d of the nuclear reaction vessel 10a and the inlet on-off valve 13b of the synthetic vessel 13a. The downstream adjustment valve 12c is provided on the downstream side of the flow path 12a, and the adjustment control unit 12 adjusts the opening / closing condition of the upstream adjustment valve 12b and the opening / closing condition of the downstream adjustment valve 12c. The flow velocity of neon flowing through the flow path 12a can be adjusted so that the neon after the nuclear reaction can be retained in the flow path 12a for a predetermined time. The neon flow velocity may be adjusted by either the upstream adjustment valve 12b or the downstream adjustment valve 12c, or both. Further, a pressure gauge 12d is provided between the upstream adjustment valve 12b and the downstream adjustment valve 12c, and the adjustment control unit 12 checks the value of the pressure gauge 12d while checking the opening / closing condition of the upstream adjustment valve 12b. The opening / closing condition of the downstream adjustment valve 12c may be adjusted.

Further, for example, when adjusting the length of the flow path 12a through which neon flows after the nuclear reaction, the flow path 12a between the outlet on-off valve 10d of the nuclear reaction vessel 10a and the inlet on-off valve 13b of the synthetic container 13a is extended. The flow path 12a can be extended, the flow velocity of neon flowing through the flow path 12a can be adjusted, and the neon after the nuclear reaction can be retained in the flow path 12a for a predetermined time. The length of the flow path 12a is preferably in the range of 1 m to 40 m, more preferably in the range of 1 m to 20 m, although it depends on, for example, the flow velocity of neon introduced into the flow path 12a. Similarly, an upstream adjustment valve 12b is provided on the upstream side of the flow path 12a, a downstream adjustment valve 12c is provided on the downstream side of the flow path 12a, and the adjustment control unit 12 is the upstream adjustment valve 12b. The opening / closing condition and the opening / closing condition of the downstream adjustment valve 12c may be adjusted to adjust the flow velocity of neon as well as the length of the flow path 12a. Further, a buffer may be appropriately provided in the flow path 12a in order to adjust the flow velocity of neon.

The flow velocity of neon adjusted by the adjustment control unit 12 is not particularly limited as long as the neon can be retained in the flow path 12a for a predetermined time, but for example, in the case of a small manufacturing apparatus. It is preferably in the range of 50 mL / min to 200 mL / min.

Further, the adjustment control unit 12 opens the flow path 12a and drives the heating device installed in the flow path 12a to heat the inside of the flow path 12a before guiding the neon after the nuclear reaction to the flow path 12a. Then, the water existing in the flow path 12a may be vaporized and discharged to the outside. After that, the adjustment control unit 12 guides the neon after the nuclear reaction to the flow path 12a. This also prevents the 18F from reacting with moisture. The heating device is the same as described above.

Further, the adjustment control unit 12 drives a vacuum drawing device connected to the flow path 12a to evacuate the inside of the flow path 12a before guiding the neon after the nuclear reaction to the flow path 12a, so that the flow path 12a is evacuated. It may be configured to remove the water existing inside. Specifically, a step before the adjustment control unit 12 guides the neon after the nuclear reaction to the flow path 12a by connecting a vacuuming device to either or both ends of the flow path 12a of the adjustment control unit 12. Then, the end to which the vacuuming device is connected is opened, the other end is closed, and the vacuuming device is driven to evacuate the inside of the flow path 12a. After that, the adjustment control unit 12 guides the neon after the nuclear reaction to the flow path 12a. This also prevents the 18F from reacting with moisture. The evacuation device is the same as described above. Of course, the above-mentioned heating device and the evacuation device may be combined.

Further, a pressure gauge 12e is provided between the vicinity of the outlet on-off valve of the flow path 12a and the inlet on-off valve 13b of the synthetic container 13a, and the adjustment control unit 12 adjusts the upstream side while checking the value of the pressure gauge 12e. The opening / closing degree of the valve 12b and the opening / closing degree of the downstream adjustment valve 12c may be adjusted.

The configuration of the synthesis control unit 13 is not particularly limited, but for example, when the 18F-labeled compound is 18F-FDG, the synthesis control unit 13 uses glucose (for example, D-glucose, L-glucose) as the liquid compound C. Bubbling the synthetic container 13a for storing saccharide solutions such as glucose and mannose, the inlet on-off valve 13b connected to the outlet on-off valve of the flow path 12a, and the neon discharged from the flow path 12a into the liquid compound C of the synthetic container 14a. It is provided with a bubbling portion 13c and the like. Thereby, by bubbling the neon after retention in the glucose solution of the liquid compound C, 18F in the neon reacts with glucose C, and 18F-FDG can be easily synthesized. Here, specifically, the hydroxyl group of glucose is replaced with 18F to generate 18F-FDG. Since the gas neon that has not undergone a nuclear reaction is inactive, even if it is bubbled to glucose C, it passes through without reacting. As a result, the gaseous neon can be recovered and used again as a raw material.

Here, the synthesis control unit 14 puts the outlet on-off valve 13d that releases neon after bubbling, the supply port 13e that supplies the liquid compound C into the synthesis container 13a, and the 18F-labeled compound after the reaction in the synthesis container 13a. It is preferable to provide a take-out port 13f. This facilitates the replenishment of the liquid compound C and the removal of the 18F labeled compound. A supply valve 13g for controlling the supply of the liquid compound C is provided upstream of the supply port 13e, and a take-out valve 13h for controlling the removal of the 18F-labeled compound after the reaction is provided downstream of the take-out port 13f. The synthesis control unit 13 may further include a temperature control unit that keeps the temperature of the reaction vessel 13a constant, if necessary.

Here, the 18F-labeled compound does not need to be particularly limited to 18F-FDG. For example, when the 18F-labeled compound is Na-18F, the synthesis container 13a of the synthesis control unit 13 stores a sodium hydroxide (NaOH) aqueous solution as the liquid compound C, and the bubbling unit 14b undergoes a nuclear reaction with the sodium hydroxide aqueous solution. Bubbling the later gas neon. Then, the hydroxyl group of NaOH in the sodium hydroxide aqueous solution is replaced with 18F to generate Na-18F. In addition, Na-18F is an ion of Na + and 18F- in an aqueous solution. That is, any liquid having a hydroxyl group substitutable for 18F can be used as an 18F-labeled compound. Examples of the liquid having a hydroxyl group substitutable for 18F include alcohols, carboxylic acids, amino acids and the like.

By the way, in the present invention, by discharging neon to the outside from the outlet on-off valve 13d of the synthesis container 13a, one neon is passed through the nuclear reaction container 10a, the flow path 12a, and the synthesis container 13a to synthesize the 18F-labeled compound. The batch-type generation method may be used, or the neon discharged from the outlet on-off valve 13d of the synthetic vessel 13a is returned to the neon cylinder or the compressor 10b again, and the neon is transferred to the nuclear reaction vessel 10a, the flow path 12a, and the synthetic vessel 13a. A cyclical production method for synthesizing the 18F-labeled compound may be used.

Here, in the case of the circulation type generation method, a removal control unit 14 for removing neon impurities discharged from the outlet on-off valve 13d of the synthesis container 13a may be provided. The configuration of the removal control unit 14 is not particularly limited, and for example, the removal control unit 14 includes a cooling container that cools the neon after the reaction released from the outlet on-off valve 13d of the synthesis container 13a to 0 ° C. or lower. As a result, the neon after the reaction in the synthetic vessel 13a is likely to contain impurities such as water mixed when bubbling with the liquid compound C (for example, a liquid having a hydroxyl group), and thus such impurities. To remove the neon, cool the neon to 0 degrees or less once. Then, the impurities are liquefied or solidified, and impurities such as water can be separated from neon. By surely removing impurities, even if the removed neon is returned to the nuclear reaction vessel 10a again, the impurities do not react with 18F, so that the production efficiency of 18F is maintained and the target 18F-labeled compound can be used. It is possible to prevent a decrease in yield.

In the cooling container, a cooling medium can be used from the viewpoint of simplicity, and as the cooling medium, for example, liquid nitrogen cooled to minus 196 degrees (77K) can be used. Further, the cooling medium is not limited to liquid nitrogen, and may be, for example, methanol containing dry ice. Methanol containing dry ice can be cooled to -30 degrees Celsius.

Further, in the above description, the removal control unit 14 has adopted a method of liquefying impurities in neon by cooling the neon after the reaction and removing the impurities from the neon, but even if another removal method is adopted. I do not care. For example, the removal control unit 14 may include an impurity adsorption unit that adsorbs water and small molecule impurities and allows only neon to pass through. In the impurity adsorbing section, molecules are adsorbed in the porous pores, and the target gas after the reaction is passed through a molecular sieve (desiccant) that strongly adsorbs water molecules in particular. In addition, the removal control unit 14 may include an impurity catalyst unit that removes impurities by reacting the catalyst with impurities. The catalyst may be used in, for example, an exhaust gas purification device, and thus may be another removal method, and the removal method may be used alone or in combination.

Further, in the circulation type generation method, neon decreases with the production of 18F and the synthesis of the 18F-labeled compound by circulation, so that it is preferable to further include, for example, a gas replenishing unit for replenishing neon.

Next, an execution procedure of the method for producing an 18F-labeled compound according to the present invention will be described. First, when the operator activates the 18F-labeled compound manufacturing apparatus 1, the introduction control unit 10 of the 18F-labeled compound manufacturing apparatus 1 introduces neon into the nuclear reaction vessel 10a (FIG. 2: S101).

Here, the introduction control unit 10 removes the water content in the nuclear reaction vessel 10a by heating and evacuating the inside of the nuclear reaction vessel 10a, for example, before introducing neon. Then, the introduction control unit 10 drives the compressor 10b and opens the inlet on-off valve 10c to introduce neon into the nuclear reaction vessel 10a. At this time, the introduction control unit 10 closes the outlet on-off valve 10d, and when the nuclear reaction vessel 10a is filled with neon, closes the inlet on-off valve 10c and seals the nuclear reaction vessel 10a.

When neon is introduced into the nuclear reaction vessel 10a, the irradiation control unit 11 of the 18F-labeled compound manufacturing apparatus 1 then irradiates the nuclear reaction vessel 10a into which neon is introduced with gamma rays R for a predetermined time. It causes a nuclear reaction in neon (Fig. 2: S102).

Here, for example, the irradiation control unit 11 irradiates the gamma ray emitting unit 11b with an electron beam for a predetermined time to emit the gamma ray R from the gamma ray emitting unit 11b and irradiate the nuclear reaction vessel 10a. Let me.

After the gamma ray irradiation is completed, the adjustment control unit 12 of the 18F-labeled compound manufacturing apparatus 1 then synthesizes 18Ne and neon of the produced nuclides after the nuclear reaction discharged from the nuclear reaction vessel 10a with the nuclear reaction vessel 10a. By guiding into the flow path 12a connecting to the container 13a and adjusting the flow velocity of neon in the flow path 12a or the length of the flow path 12a, a predetermined time until 18Ne of the generated nuclide is converted to 18F. For this time, neon is retained in the flow path 12a (FIG. 2: S103).

Here, the adjustment control unit 12 removes the water content in the flow path 12a by heating and / or evacuating the inside of the flow path 12a, for example, before guiding the neon. The adjustment control unit 12 opens the outlet on-off valve 10d of the nuclear reaction vessel 10a and guides 18Ne and neon after the nuclear reaction into the flow path 12a. When the adjustment control unit 12 adjusts the flow velocity of neon including 18Ne, it adjusts the opening / closing condition of the upstream adjustment valve 12b and the opening / closing condition of the downstream adjustment valve 12c, and adjusts the flow velocity of neon including 18Ne. , 18Ne and neon after the nuclear reaction are retained in the flow path 12a for a predetermined time. Further, when the adjustment control unit 12 adjusts the length of the flow path 12a, the neon is guided to the extended flow path 12a or the meandering flow path 12a, and the neon has a predetermined length. By moving inside, neon after the nuclear reaction is retained in the flow path 12a for a predetermined time. This makes it possible to effectively generate 18F from 18Ne of the nuclide produced after the nuclear reaction.

When the retention of neon elapses for a predetermined time, the synthesis control unit 13 reacts the 18F contained in the retained neon with the liquid compound C (glucose) having a hydroxyl group substitutable for 18F in the synthesis container 13a. , 18F labeled compound is synthesized (FIG. 2: S104).

Here, the synthesis control unit 13 synthesizes an 18F-labeled compound by reacting 18F in the neon with the glucose solution C by bubbling neon into the glucose solution C of the synthesis container 13a, for example, in the bubbling unit 13c. .. That is, by immediately introducing the neon after retention into the synthesis container 13a, the produced 18F can be brought into contact with the liquid compound C without waste, so that a large amount of 18F-labeled compound can be synthesized.

Then, the operator can obtain the 18F-labeled compound by taking out the synthesized 18F-labeled compound from the take-out port 13f. Further, if the glucose C is low, the operator may supply the glucose C through the supply port 13e.

Furthermore, after introducing neon into the nuclear reaction vessel 10a once, gamma-ray irradiation is started. At this time, the outlet on-off valve 10d is opened during irradiation, and neon is guided to the synthesis container 13a via the flow path 12a. Further, the neon that did not react with the liquid compound C in the synthetic vessel 13a is guided from the synthetic vessel 13a to the nuclear reaction vessel 10a by using a predetermined introduction tube to circulate in the apparatus and the inlet on-off valve 10c. Return to the nuclear reaction vessel 10a. This circulation cycle is continuously repeated during gamma-ray irradiation to accumulate the 18F-labeled compound in the synthesis vessel 13a. This makes it possible to produce a large amount of 18F-labeled compound.

Hereinafter, the present invention will be specifically described with reference to Examples and the like, but the present invention is not limited thereto.

First, a prototype (Example) of the 18F labeled compound manufacturing apparatus 1 was prepared based on the drawings shown in FIGS. 1 to 2. As shown in FIG. 3, the 18F labeled compound manufacturing apparatus 1 includes an introduction control unit 10 and an adjustment control unit 12. The introduction control unit 10 includes a nuclear reaction vessel 10a that receives neon introduction from the front via a tubular introduction pipe, and an inlet on-off valve 10c that is provided in the introduction pipe and controls the introduction of neon. An outlet on-off valve 10d (not shown) is provided behind the nuclear reaction vessel 10a. The adjustment control unit 12 includes a tubular flow path 12a connected to the rear of the nuclear reaction vessel 10a, and an adjustment valve 12b for adjusting the flow velocity or the flow rate in the flow path 12a at a predetermined position of the flow path 12a. ..

Here, an opening of a predetermined metal can 15 (for example, an aluminum can) is connected to the tip of the flow path 12a so that neon emitted from the flow path 12a can be filled. In the actual synthesis of the 18F-labeled compound, the metal can 15 is replaced with the synthesis container 13a.

By the way, the prototype of the 18F labeled compound manufacturing apparatus 1 was carried into the facility of the electron beam accelerator (electron linac), and the manufacturing test of 18F was performed. The electron beam accelerator corresponds to the irradiation control unit 11.

The nuclear reaction vessel 10a has a diameter of 2 cm and a length of 50 cm, the outlet on-off valve 10d is closed, and neon is sealed in the nuclear reaction vessel 10a from the inlet on-off valve 10c of the nuclear reaction vessel 10a. After that, the inlet on-off valve 10c is closed, tungsten is provided at the tip of the electron beam accelerator, the electron beam is irradiated to the tungsten by the electron beam accelerator, the gamma ray R of bremsstrahlung is irradiated to the nuclear reaction vessel 10a, and the gamma ray is neon. R was irradiated for a predetermined time. The electron beam energy of the electron beam accelerator was 40 MeV, the current value was 3 μA, and the photon flux was 10 ¹² photon / sec. After that, the outlet on-off valve 10d is opened, neon including 18F and 18Ne is guided to the flow path 12a, the flow velocity of the neon is minimized by the adjustment valve 12b, and the neon is allowed to flow in the flow path 12a for a predetermined time. It was allowed to stay (about 20 seconds). Then, the neon after staying was filled in a metal can 15 and collected. The detection surface of the CdTe detector for radiation detection was applied to the outer surface of the metal can 15, and the spectrum of radiation generated from 18F filled in the metal can 15 was measured over time, and the change over time of the spectrum was determined. Further, the analysis of the radiation spectrum was performed by a predetermined terminal device.

As shown in FIG. 4, the radiation spectrum at the time of sampling on the 18th floor is represented by a count (count / keV) on the vertical axis and an energy (keV) on the horizontal axis, but only the peak with an energy of 511 keV is seen extremely strongly. It is understood that it will be done. This 511 keV peak corresponds to the peak caused by β + decay at 18F. Furthermore, surprisingly, the count of peaks at 511 keV was over 1200. In the previous patent (Patent No. 6274689), the amount was about 600, so in this example, an extremely large production amount of 18F could be confirmed.

Next, the area of the radiation spectrum measured for each elapsed time was calculated to create a radiation dose attenuation curve. As shown in FIG. 5, the created radiation dose attenuation curve is represented by the total count (count / 200 sec) on the vertical axis and the elapsed time (sec) on the horizontal axis. Here, using the 109.77 minutes half-life of 18F, the equation for the decay curve was inserted, and the attenuation of the radiation dose over time fit the decay curve of the half-life of 18F from 1 second to 8000 seconds. From this, it was possible to confirm that the product collected in the metal can was approximately 18F. From the attenuation curve, it was found that the radioactivity of 18F at an elapsed time of 0 seconds was about 30 kHz.

As a result of taking into account the ratio of the peak count of 511 keV and other conditions according to FIG. 4-FIG. 5, in this embodiment, the yield of the previous patent (Patent No. 6274689) is compared with respect to the production of 18F. The yield was about 4 times higher. By reacting this 18F with a liquid compound (for example, glucose), the yield of the 18F-labeled compound could be further increased as compared with the previous patent.

Therefore, it was confirmed that the prototype of the 18F-labeled compound manufacturing apparatus 1 can produce the 18F-labeled compound in an extremely high yield.

Next, in the flow path 12a of the prototype of the 18F labeled compound manufacturing apparatus 1, with the adjustment valve 12b open, the length of the flow path 12a is extended to a predetermined length (about 20 m), and the nuclear reaction vessel is used. The neon emitted by opening the outlet on-off valve 10d of 10a was adjusted to pass through the flow path 12a over a predetermined time (about 20 seconds) and reach the metal can 15. Similarly, when neon was irradiated with gamma rays to produce 18F, a large amount of 18F could be produced in the same manner as described above.

As described above, the 18F-labeled compound manufacturing apparatus and the 18F-labeled compound manufacturing method according to the present invention are useful for all tests using 18F-labeled compounds such as PET scans, and are not limited to medical use but also for research and industrial use. It can be used for the production of 18F-labeled compounds used in various industries such as food products. Further, it is effective as an 18F-labeled compound production apparatus and an 18F-labeled compound production method capable of dramatically improving the yield of the 18F-labeled compound.

1 18F Labeled compound manufacturing equipment 10 Introduction control unit 11 Irradiation control unit 12 Adjustment control unit 13 Synthesis control unit

Claims (4)

An introduction control unit that introduces neon into the nuclear reaction vessel,
An irradiation control unit that causes a nuclear reaction in the neon by irradiating the nuclear reaction vessel into which the neon is introduced with gamma rays for a predetermined time.
The neon containing 18F and 18Ne of the nuclides produced after the nuclear reaction discharged from the nuclear reaction vessel is guided into the flow path connecting between the nuclear reaction vessel and the synthesis vessel, and the neon in the flow path is guided. By adjusting the flow velocity or the length of the flow path, the adjustment control unit that causes the neon to stay in the flow path for a predetermined time until the 18Ne is converted to 18F, and the adjustment control unit.
A synthesis control unit that synthesizes an 18F-labeled compound by reacting 18F contained in the neon after retention with a liquid compound having a hydroxyl group substitutable for 18F in the synthesis container.
18F labeled compound manufacturing apparatus. Before guiding the neon after the nuclear reaction to the flow path, the adjustment control unit drives a vacuum drawing device connected to the flow path to evacuate the inside of the flow path and enter the flow path. Removes existing water,
The 18F labeled compound manufacturing apparatus according to claim 1. Before introducing neon into the nuclear reaction vessel, the introduction control unit drives a vacuum drawing device connected to the nuclear reaction vessel to evacuate the inside of the nuclear reaction vessel and puts the inside of the nuclear reaction vessel into the nuclear reaction vessel. Removes existing water,
The 18F labeled compound manufacturing apparatus according to claim 1 or 2. Introductory control steps to introduce neon into the nuclear reaction vessel,
An irradiation control step in which the neon-introduced nuclear reaction vessel is irradiated with gamma rays for a predetermined time to cause a nuclear reaction in the neon.
The neon containing 18F and 18Ne of the nuclides produced after the nuclear reaction discharged from the nuclear reaction vessel is guided into the flow path connecting between the nuclear reaction vessel and the synthesis vessel, and the neon in the flow path is guided. The adjustment control step of retaining the neon in the flow path for a predetermined time until the 18Ne is converted to 18F by adjusting the flow velocity or the length of the flow path.
A synthesis control step for synthesizing an 18F-labeled compound by reacting 18F contained in the neon after retention with a liquid compound having a hydroxyl group substitutable for 18F in the synthesis container.
A method for producing an 18F-labeled compound.

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