JP4524389B2 - Radiolabeled drug automatic synthesizer - Google Patents

Description

  The present invention relates to an automatic synthesizer for radiolabeled drugs used in radiology, and more particularly to an automatic synthesizer for radiolabeled drugs suitable for the synthesis of positron emission tomography (PET) labeled drugs.

Conventionally, a radiolabeled drug (hereinafter sometimes simply referred to as a labeled drug) using a radioisotope nuclide (hereinafter referred to as a nuclide) has been used for cancer diagnosis or the like.
As such radiolabeled drugs, labeled drugs containing ¹²³ I, ²⁰¹ Tl, ⁶⁷ Ga, etc. are used for single-photon emission computed tomography (SPECT) for cancer diagnosis, blood flow measurement, and myocardial viability. Widely used for measurement and the like. In addition, a labeling drug labeled with a positron nuclide for PET capable of performing these measurements with higher sensitivity and accuracy has attracted attention. Particularly recently, the application of health insurance has been recognized for the diagnosis of malignant tumors by PET using 2-deoxy-2- ¹⁸ F fluoro-D-glucose (hereinafter referred to as ¹⁸ FDG) as a labeling agent. Diagnosis by is rapidly spreading.

Most of the radiolabeled drugs are labeled drugs in which a radionuclide is incorporated into an organic compound or the like by a chemical synthesis reaction. For example, N-isopropyl-p-iodoamphetamine having ¹²³ I used when diagnosing cancer by SPECT, or The ¹⁸ FDG and the like used for PET are exemplified.
As a labeling agent for PET, in addition to the most widely used ¹⁸ FDG, various ¹¹ C-labeling agents using ¹¹ CH ₃ I, ¹³ NH ₃ aqueous solution, H ₂ ¹⁵ O solution, ¹⁸ F- Various ¹⁸ F-labeled drugs using a fluoroalkylation reaction or ¹⁸ F-substitution reaction are used.
Furthermore, research and development of new labeling drugs are being actively conducted in order to expand the application range of PET.

However, the synthesis of radiolabeled drugs has many difficult problems as described below.
First, nuclides, which are the raw materials for radiolabeled drugs, emit extremely strong γ-rays and β ⁺ -rays and other radiation, so facilities that block radioactivity are required. For example, when manufacturing a labeling drug for PET, all operations must be performed in a narrow facility called a hot cell shielded with a lead of about 5 cm thick. In addition, since radiolabeled drugs are drugs that are administered to the human body by intravenous injection or the like, special attention should be paid to contamination and sterility.
Furthermore, in the case of labeling drugs for PET, the half-life of most nuclides is as short as 2 minutes to 2 hours, so it is necessary to perform multi-step chemical reactions, separation and purification, preparation treatment, etc. in a short time. There is a restriction that there is.
In other words, when producing a radiolabeled drug, it is necessary to prevent radiation exposure of a labeled drug synthesizer and the like, to prevent foreign substances from being mixed, and to complete these operations in a short time. For this reason, it is necessary to eliminate human intervention as much as possible when producing radiolabeled drugs, and an automatic synthesizer is indispensable.

As automated synthesizer such radiolabeling agent, for example, an automated synthesizer apparatus is disclosed for synthesizing 3- ¹¹ C-pyruvate in Patent Document 1.
Patent Document 1, ¹¹ CH ₃ and ¹¹ C-alanine synthesized from I, and the desired product 3- ¹¹ C-pyruvic acid by immobilized enzyme, and ultrafiltration foreign substances (enzymes to be suitable as injection drug, fever An automatic synthesizer for removing substances, bacteria, pyrogens, etc.) is disclosed.
Japanese Patent Laid-Open No. 10-295361 (paragraph 0006, FIG. 1)

However, conventional automatic synthesizers are limited in the types of labeling drugs that can be produced as seen in Patent Document 1, and most are manufactured using one specific type of labeling drug or one type of reaction. It was for producing only the labeling drug.

  For this reason, conventionally, when producing different types of labeling drugs, a new automatic radiolabeling drug synthesis apparatus corresponding to the synthesis method for each type of target labeling drug or reaction is required. In addition, each labeling drug is liquid or gas as a starting material, and no reaction occurs even if a small amount of moisture is mixed. Despite the growing demand for radiation medicine, such as PET, due to the unique characteristics of manufacturing, such as failure to meet the standards, different synthesis routes for each reaction type, and different types and arrangements of parts to be used An apparatus for synthesizing a labeling drug using a plurality of types of radionuclides or reactions in one unit has not been realized.

  The problem described above can be solved by installing a large number of radiolabeled drug synthesizing apparatuses for each type. However, since it is a pharmaceutical that uses radioactive substances, it would be necessary to install a large number of labeling drug synthesizers, which would require new facilities and a large site for handling radioactive substances and producing pharmaceuticals, and a large amount of money. It is difficult to realize.

  The present invention has been made in view of such a problem. By exchanging a part of one radiolabeling drug automatic device, a wide variety of labeling drugs using various kinds of reactions can be manufactured. It is an object of the present invention to provide a radiolabeled drug automatic synthesizer that can synthesize a plurality of types of labeled drugs on the same day.

The radiolabeled drug automatic synthesizer of the present invention that has solved the above-mentioned problems is capable of fitting together a synthesizing unit including a labeling drug synthesizing unit, a main body including a labeling drug synthesis assisting unit, and communicating electrical signals. A first connection member in which one of the multi-pin connectors is fixed to the composite unit, and the other end of the multi-pin connector is fixed to the main body, a first joint member in which a first pipe is inserted in advance, and a second pipe Are combined and fixed so as to be connected or communicated with a second joint member inserted in advance, so that various pure gases including inert gas, compressed air, vacuum, exhaust, etc. are supplied from the main body to the synthesis unit . , liquid nitrogen, a second connecting part Ru is communicated connected or communicated collectively utility supply pipe for supplying any of the gas used in the synthesis reaction, the synthesis unit, the positioning relative to the body, before And a guide part to which the first and second connection parts are connected simultaneously with the setting of the synthesis unit to the main body, and the synthesis unit is attached to the main body in a replaceable manner.

A synthesis unit in which expensive labeling drug synthesis assisting means such as sensors that are not directly involved in the reaction is provided in the main body, while labeling drug synthesis means such as a reactor having a different configuration for each labeling drug is attached to the main body in a replaceable manner. Since it is provided, it is possible to synthesize a plurality of types of labeling drugs by exchanging a part of one automatic radiolabeling drug device. Furthermore, the first connecting part can be fitted to easily position the composite unit with respect to the main body, and the utility connection piping to the composite unit can be collectively connected by the second connecting part. Since the units can be replaced quickly and easily, a plurality of types of labeling drugs can be synthesized on the same day.
Normally, even after the synthesis is completed, radioactive substances remain in the synthesis unit, so that the synthesis unit can be replaced quickly and easily, which means that the radiation exposure dose of the worker can be minimized within the annual allowable dose. This greatly contributes to the increase in the number of productions possible per day.
Furthermore, the composition unit can be configured to include a guide portion for positioning with respect to the main body. The radiolabeled drug automatic synthesizer having such a configuration can more easily position the synthesis unit with respect to the main body.

Further, the radiolabeled drug automatic synthesizing apparatus of the present invention that has solved the above-mentioned problem is that the labeling drug synthesis assisting means of the main body comprises a heating / cooling device for the reactor provided in the synthesizing unit, a radioactivity sensor, and a temperature sensor. The labeling drug synthesis means of the synthesis unit includes a primary labeling raw material separation and purification unit, the reactor connected to the primary labeling raw material separation and purification unit, and a reagent storage tank connected to the reactor. It is the structure characterized by this.
Here, the primary labeling raw material is generated directly in a target connected to a cyclotron, or converted and purified online by a catalyst column or purification column connected to the target, etc. ¹⁸ F, ¹¹ C, ¹⁵ This refers to a nuclide ion exemplified by O or ¹³ N, or a reaction intermediate containing a nuclide.

  Since the primary labeling raw material separation and purification unit is provided in the synthesis unit, it can be labeled with different nuclides by one radiolabeling drug automatic device by replacing the synthesis unit and attaching a different primary labeling raw material separation and purification unit. In addition, it is possible to synthesize a wide variety of labeling drugs using the primary labeling raw material, and it is possible to synthesize a plurality of types of labeling drugs many times on the same day.

  Further, another radiolabeled drug automatic synthesizer of the present invention includes a labeling drug synthesis auxiliary means of the main body as a primary labeling raw material separation and purification unit, a heating / cooling device for a reactor provided in the synthesis unit, a radioactivity sensor, a temperature The labeling agent synthesis means of the synthesis unit includes a reactor connected to the primary labeling raw material separation and purification unit, and a reagent storage tank connected to the reactor.

Since the main body of the primary labeling raw material separation / purification unit is provided, the structure of the synthesis unit is extremely simple and small, and multiple types of labels are used on the same day for the same nuclide using an inexpensive and small synthesis unit. It becomes possible to synthesize drugs.
Such a radiolabeled drug automatic synthesizer is suitable when a specific type of nuclide is frequently used, or when the structure of a specific type of primary labeling material separation and purification unit is complicated and difficult to incorporate into a synthesis unit. and, for example, especially the type number, ¹⁸ F which is widely used ^- is suitable for the case where the labeling agent for PET using synthesized two or more on the same day.

A hollow needle inserted into the reactor; a needle holding part that holds the hollow needle; and a needle drive mechanism that moves the needle holding part and the hollow needle including a vertical component. Can be configured.
According to such a configuration, the reaction liquid can be transferred through the hollow portion of the hollow needle inserted into the reactor, and by bubbling while supplying the inert gas to the reaction liquid through the same hollow needle. Can be stirred.
By using the hollow needle as both the reaction solution transferring means and the stirring means, the automatic synthesizer can be miniaturized. Moreover, since the stirring means of such a reaction liquid generates little dust, it is suitable for the production of a radiolabeled drug that is finally used as an injection.

Contact name, the term "synthetic" in this invention is not only to be added to other compounds by a chemical reaction species, after the separation and purification of primary label material, as it is intended to include the case of using as a label agent.

According to the radiolabeled drug automatic synthesizer of the present invention, a single apparatus can synthesize a plurality of types of labeled drugs on the same day.
In addition, by providing the synthesis unit with the primary labeling raw material separation and purification unit, it is possible to synthesize a plurality of types of labeled drugs labeled with different nuclides on the same day a plurality of times with one apparatus.

A labeling drug synthesis system including an automatic radiolabeling drug synthesizer will be described by taking as an example the case of producing a radiolabeled drug using positron nuclides.
As shown in FIG. 1, the labeling drug synthesis system includes a target unit 21, a radiolabeled drug automatic synthesizer 1, a separation / purification dispensing unit 22, a utility unit 23, and a control unit 24. The target unit 21 supplies a compound containing a nuclide or a nuclide ion to the radiolabeled drug automatic synthesizer 1 of the present invention. The separation / purification dispensing unit 22 purifies the labeling drug synthesized by the synthesis unit 2 to obtain an injection.
Furthermore, the control part 24 which controls a labeling drug synthesis system and the utility part 23 which supplies compressed air, an inert gas, a vacuum, etc. to a labeling drug synthesis system are provided.

More specifically, from the target unit 21, gas ¹⁸ F ₂ , ¹¹ CO ₂ , ¹⁵ O ₂ , which is directly generated in a target connected to a cyclotron, or is a primary reaction source material captured by a catalyst column or the like, Liquid ¹⁸ F ⁻ , ¹³ NH ₃ or the like is supplied.
In the separation and purification dispensing unit 22, the labeling reaction mixture synthesized in the synthesis unit 2 is separated and purified by HPLC or the like, and the target compound is evaporated to dryness, dissolved in physiological saline, sterilized, and converted into a safe injection. The

  In the utility unit 23, various pure gases, compressed air, and vacuum whose flow rate and pressure are controlled are automatically supplied to the pneumatic valve, hot air heater of the radioactive label automatic synthesizer 1, the evaporator of the separation and purification dispensing unit 22, and the like. It is the driving force for operating the synthesizer. As the pure gas, an inert gas such as nitrogen or helium can be mainly used. Further, in order to prevent the entry of particulate foreign matter into the labeling drug, it is preferable to use the inert gas or compressed air after passing through a 0.22 μm sterile filter.

The control unit 24 performs a series of controls according to the control of each device included in the labeling drug synthesis system and the program according to the type of the labeling drug to be synthesized, and the entire apparatus cooperates to efficiently drive. I'm in charge.
Normally, the device part excluding the target part and the control part is installed in a hot cell surrounded by lead having a thickness of about 5 cm.

  Next, details of embodiments of the present invention will be described with reference to the drawings as appropriate. FIG. 2 is a schematic configuration diagram showing a configuration of the radiolabeled drug automatic synthesizer 1 (hereinafter referred to as an automatic synthesizer) according to the first embodiment of the present invention. In FIG. 2, the entire automatic synthesizing apparatus 1 is controlled by the control unit 24. Unless otherwise specified, the operation of the valve 33 using an electromagnetic valve or a pneumatic valve or the monitoring of sensors is performed by this control. This is performed by the unit 24.

The automatic synthesizer 1 of this embodiment includes a synthesis unit 2 provided with a labeling drug synthesizing unit and a main body 3 provided with a synthesis assisting unit for assisting the labeling drug synthesizing unit. The synthesizing unit 2 is connected to the main body 3 with a first connection part 4 for exchanging electrical signals and a second connection capable of collectively connecting utility supply piping such as inert gas from the main body 3 to the synthesizing unit 2. Connected via the unit 5.
The synthesis unit 2 includes a primary labeling raw material separation / purification unit 10, a reactor 11, and a reagent storage tank 12 having different configurations for each labeling drug, and a hollow needle inserted into the reactor 11. 26.
On the other hand, the main body 3 synthesizes the heating / cooling device 6 of the reactor 11, the radioactivity sensor 7, the temperature sensor 8, the valve 33, the needle drive mechanism 14, and the like that are commonly required to synthesize the labeling drug. It is provided as an auxiliary means.

<Details of synthesis unit 2>
The labeling drug synthesizing means of the synthesis unit 2 of this embodiment includes a primary labeling raw material separation and purification unit 10, a reactor 11 connected to the primary labeling raw material separation and purification unit 10, and a reagent storage tank 12 connected to the reactor 11. And.
Utility supply piping from the second connecting portion 5 between the primary labeling raw material separation and purification unit 10 and the reactor 11, between the reactor 11 and the reagent reservoir 12, and an inlet through which the utility supply pipe is introduced into the reactor 11 and the reagent reservoir 12. Or the like can be provided with a valve 33 for changing the flow path of the labeled drug fluid, or for turning the fluid supply on and off.

The valve 33 is preferably made of a radioactive material or a material having corrosion resistance at a portion in contact with the liquid, and having a structure with a low possibility of liquid retention.
In order to simultaneously switch the multi-channel, the automatic six-way valve disclosed in Japanese Patent Application No. 2004-7296 can be used more suitably. By using such a multi-way valve, it becomes possible to flow different fluids through a plurality of flow paths with a simple configuration or to simplify the synthesis path. In addition, as a piping material between each apparatus and apparatus, such as connection between the primary labeling raw material separation and purification unit 10 and the reactor 11, a glass tube, a stainless steel tube, a PEEK (registered trademark) or a tube made of polytetrafluoroethylene, etc. It can be used suitably.

The primary labeling raw material separation and purification unit 10 is a part that separates a nuclide simple substance or a compound containing a nuclide generated in a target connected to a cyclotron by physical adsorption or chemical adsorption, and removes and purifies unnecessary coexisting substances. . For chemisorption, a ¹⁵ O compound produced by a nuclear reaction of ¹⁴ N (d, n) ¹⁵ O, such as H ₂ ¹⁵ O, is collected after reacting with hydrogen in a column packed with catalyst. Or the case where the ¹⁵ O compound is generated through a heated activated carbon column a) and then collected, such as C ¹⁵ O. As described above, the primary labeling raw material separation and purification unit 10 is configured using a tube, a container, or a column filled with an adsorbent, an ion exchange resin, and a catalyst according to the properties of the primary labeling raw material. Can do.

When synthesizing an ¹¹ C-labeled drug in the primary labeling raw material separation and purification unit 10, a polytetrafluoroethylene having an inner diameter of 0.1 to 4 mm and a tube length of 100 to 500 mm disclosed in Japanese Patent Application No. 2003-206541 is disclosed. An apparatus in which a thin tube made of fluoroethylene or stainless steel has a loop shape as shown in FIG. 2 can be used. In this case, the primary labeling raw material is captured by cooling the loop with a heating / cooling device 6 provided in the main body 3.
The primary labeling material is released by heating the loop with the heating / cooling device 6 while flowing an inert gas such as nitrogen or helium from the second connection portion to the reactor 11. The release of the primary labeling material from the loop can be detected by monitoring the radiation dose of the loop with the radioactivity sensor 7.

As another primary labeling raw material separation and purification unit 10, as shown in FIG. 3, a column 25 filled with an adsorbent such as an ion exchange resin that selectively adsorbs the primary labeling raw material, and the adsorbed primary labeling raw material are used. The primary labeling raw material eluate storage container 30 storing the liquid to be eluted can be used. Such an arrangement can be particularly suitably used in ¹⁸ FDG, ^{13 13} Synthesis of NH ₄ OH or the like of the labeled drug with N having a ¹⁸ F.
In this case, the primary labeling raw material is captured by adsorbing the primary labeling raw material to an ion exchange resin or the like in the column 25, and the primary labeling raw material is released using a solution for eluting the primary labeling raw material as a primary labeling raw material eluate storage container. 30 to the reactor 11 through the column 25. Confirmation of the completion of the release of the primary labeling raw material is preferably performed by the radioactivity sensor 7.

The supply of the eluate from the primary labeling raw material eluate storage container 30 to the column 25 can be performed by supplying an inert gas from the second connection portion 5 to the primary labeling raw material eluate storage container 30 and pressurizing it. . The eluent supplied from the primary labeling raw material eluate storage container 30 is usually used for elution of the intended primary labeling raw material such as potassium carbonate solution in the case of ¹⁸ F ⁻ and physiological saline for injection in the case of ¹³ NH ₄ ^+. Can be used.

  As shown in FIG. 2, the reactor 11 is connected to the primary labeling raw material separation and purification unit 10, and synthesizes the labeling drug from the primary labeling raw material transferred from the primary labeling raw material separation and purification unit 10. . A reagent storage tank 12 for supplying a reagent necessary for the synthesis reaction of the labeling drug is connected to the reactor 11 via a valve 33. Further, the reactor 11 is disposed at a position where the reactor 11 is accurately fitted to the heating / cooling device 6 when attached to the main body 3.

The reactor 11 and the reagent storage tank 12 are preferably made of glass because radioactive substances and highly corrosive reagents are used, and it is preferable to use a container having a shape whose diameter decreases toward the bottom in order to handle a small amount of reagents. However, it is not limited to these.
The reagent is transferred from the reagent reservoir 12 to the reactor 11 by supplying an inert gas from the second connection portion 5 to the reagent reservoir 12 via the valve 33 and pressurizing the inside of the reagent reservoir 12. It can be carried out.

Moreover, as shown in FIG. 4, it is movable at the front end of a pipe for supplying the primary labeling raw material from the primary labeling raw material separation / purification unit 10 to the reactor 11 with the component in the vertical direction with respect to the liquid level inside the reactor 11. It is preferable to insert a hollow needle 26 so that the hollow needle 26 can contact the bottom of the reactor 11.
4A to 4C, the needle drive mechanism 14 and the heating / cooling device 6 are fixed to the main body 3, and the reactor 11 is held by the synthesis unit 2 and fitted to the heating / cooling device 6. . The hollow needle 26 is held by the needle holder 15 and supported by the needle drive mechanism 14 together with the needle holder 15. And the front-end | tip of the hollow needle | hook 26 is adjusted so that it may become a predetermined position of the reactor 11, and is inserted.
In order to keep the insertion portion of the hollow needle 26 into the reactor 11 airtight, known sealing means such as an O-ring or a bellows-shaped cover can be used.

A flexible material such as a tube made of polytetrafluoroethylene can be suitably used for the pipe for supplying the primary labeling raw material. As the hollow needle 26, a glass tube, a stainless tube, or a tube made of PEEK (registered trademark) can be used.
Further, the hollow needle 26 only needs to have a shape in which the tip can come into contact with the bottom of the reactor 11. For example, the hollow needle 26 has a shape whose outer diameter decreases toward the tip, or the tip is cut obliquely. The thing of a shape can be used conveniently. In addition, a thin tube having an outer shape of, for example, 1 mm or less can be used.

The hollow needle 26 is supported by the needle driving mechanism 14 together with the needle holding unit 15 and is inserted into the reactor 11.
After adjusting the insertion position so that the tip of the hollow needle 26 is in contact with the bottom of the reactor 11, the position of the hollow needle 26 is fixed with a nut or the like provided in the needle holder 15. As a result, the tip of the hollow needle 26 can be moved with respect to the liquid level in the reactor 11 using the needle driving mechanism 14 that supports the needle holding portion 15. The needle drive mechanism 14 can be a known drive means such as an air cylinder or an electric actuator.

The needle holder 15 may be integrally attached to the needle drive mechanism 14 or may be rotatably attached with a screw, a pin, or the like. Alternatively, the needle holding unit 15 may be provided separately from the needle driving mechanism 14 to hold the hollow needle 26, and then fitted to the needle driving mechanism 14 and fixed with screws or pins.
In order to replace the synthesis unit 2 quickly, a hollow needle 26 to which the needle holder 15 is attached in advance is inserted into a predetermined position of the reactor 11, and the needle holder 15 is attached to the needle drive mechanism 14 at the time of attachment. It is preferable to fit in the provided fitting part.

  The tip of the hollow needle 26 is placed below the liquid level by the needle drive mechanism 14 after the primary labeling raw material is transferred from the primary labeling raw material separation and purification unit 10 to the reactor 11 as shown in FIG. . Then, an inert gas can be circulated from the second connection portion 5 to the hollow needle 26, and the liquid inside the reactor 11 can be stirred by bubbling. When stirring is unnecessary, the tip of the hollow needle 26 is placed on the liquid surface by the needle drive mechanism 14 as shown in FIG.

  The agitation by the hollow needle 26 is suitable for downsizing of the automatic synthesizer because it generates less dust and does not require special equipment compared to the case of using a stirring blade or a magnetic stirrer. In particular, it is suitable for the production of radiolabeled drugs used as injections.

  Further, when the liquid after the reaction in the reactor 11 is transferred to the next step, the hollow needle 26 is lowered by the needle drive mechanism 14 until it contacts the bottom of the reactor 11 as shown in FIG. . Then, an inert gas is introduced from an opening of the reactor 11 different from the opening provided with the hollow needle 26 to pressurize the reactor 11, whereby almost all of the liquid inside the reactor 11 is hollowed out. It can be transferred through the needle 26 to the next step, that is, to the reactor 11 or the separation / purification dispensing unit 22 on another downstream side.

  The labeling agent can be synthesized by heating or cooling to a predetermined temperature with the heating / cooling device 6 while monitoring the temperature of the reactor 11 with the temperature sensor 8 provided in the main body 3. In the transfer of the labeling drug from the reactor 11 to the separation / purification dispensing unit 22, the inert gas is supplied to the reactor 11 from the second connection portion with the hollow needle 26 lowered until it contacts the bottom of the reactor 11. This can be done through the hollow needle 26 by pressurization.

  If the synthesis unit 2 of the first embodiment is used, a synthesizer is constituted by the primary labeling raw material separation / purification unit 10, the reactor 11, the reagent storage tank 12, the valve 33 and the like suitable for the labeling drug to be synthesized. Furthermore, the labeling drug can be automatically synthesized using a control program corresponding to the configuration. Also, by replacing the synthesis unit 2 having a different configuration for each labeling drug and attaching it to the main body 3, a plurality of types of labeling drugs having different primary labeling raw materials can be produced on the same day.

<Description of body 3>
The synthesis auxiliary means of the main body 3 includes a heating / cooling device 6 for the reactor 11 provided in the synthesis unit 2, a radioactivity sensor 7, and a temperature sensor 8 as shown in FIG. 2.
The heating / cooling device 6 heats and cools the reactor 11 of the synthesis unit 2 to assist the synthesis. It can also be used to heat and cool the primary labeling raw material separation and purification unit 10. The radioactivity sensor 7 mainly monitors the movement of nuclides, and the temperature sensor 8 monitors the temperatures of the primary labeling raw material separation and purification unit 10 and the reactor 11, and both are used as synthesis assisting means. Further, a valve 33 for controlling the flow path of fluid such as compressed air or inert gas can be provided as a synthesis assisting means.

  The heating / cooling device 6, the radioactivity sensor 7, and the temperature sensor 8 are monitored by the control unit 24. The heating / cooling device 6 is disposed at a position where the heating / cooling device 6 is fitted to the reactor 11 provided in the synthesis unit 2. It is preferable that the radioactivity sensor 7 and the temperature sensor 8 do not interfere with the reactor 11 when the synthesis unit 2 is attached to the main body 3, and the detection unit of each sensor is disposed below the liquid level of the liquid containing the nuclide. .

Heating of the heating / cooling device 6 can be performed with an electric heater or hot air, and cooling can be performed with liquid nitrogen or compressed air cooled using adiabatic expansion. As such a heating / cooling device 6, for example, it is preferable to use the heating / cooling device 6 disclosed in Japanese Patent Application No. 2003-377124 with very little dust generation in order to maintain a clean drug production environment. In addition, nitrogen gas or compressed air for heating with hot air and liquid nitrogen for cooling are supplied from the utility unit 23.
The radioactivity sensor 7 and the temperature sensor 8 are not particularly specified and commercially available ones can be used.

  The main body 3 can be provided with a needle driving mechanism 14 that moves the hollow needle 26 up and down. The needle drive mechanism 14 moves the tip of the hollow needle 26 including the vertical component with respect to the liquid level. The needle drive mechanism 14 is preferably an air cylinder that operates with compressed air from which foreign matter has been removed with a sterilizing filter or the like in order to prevent dust generation. In addition, pneumatic equipment, compressed gas, liquid nitrogen, and the like used during synthesis maintain a clean environment during drug manufacture by suppressing dust generation by the method disclosed in Japanese Patent Application No. 2003-340894, for example. Preferred above.

  As described above, the main body 3 of the present embodiment includes a commonly required device as a synthesis assisting unit regardless of the type of labeling drug. These common devices include parts such as expensive, delicate and bulky sensors. As a result, most of the parts of the single automatic synthesis apparatus 1 are integrated into the main body 3, and a plurality of units can be replaced by replacing the synthesis unit 2 that incorporates only some parts that are relatively inexpensive and simple to operate. It becomes possible to synthesize various kinds of labeling drugs.

<First and second connection portions>
Connection of the synthesis unit 2 and the main body 3 is performed by the first connection portion 4 and the second connection portion 5. The first connecting portion 4 is a connecting portion for allowing the main body 3 to communicate electric signals with the combining unit 2. It is also possible to supply drive power for the synthesis unit 2. The second connection portion 5 is configured to be able to collectively connect pipes, tubes, and the like that supply an inert gas such as nitrogen, utilities such as vacuum, exhaust, and compressed air to the synthesis unit 2. In addition to the second connection part 5, other connection parts may be provided, such as supplying a utility necessary only for the manufacture of a specific labeling drug from other than the second connection part 5.

For the first connection portion 4, a multi-pin connector that is normally used can be used.
As shown in FIG. 2, one of the multi-pin connectors is fixed to the synthesis unit 2 as the first connection portion 4, and the other is fixed to a corresponding position on the main body 3. And when attaching the synthetic | combination unit 2 to the main body 3, it becomes possible to perform positioning fixation with respect to the main body 3 of the synthetic | combination unit 2 easily by fitting both correctly, and on the synthetic | combination unit 2 with respect to the heating-cooling apparatus 6 The reactor 11 and the like can be positioned quickly and easily. Thereby, it becomes possible to shorten the time required for replacement | exchange of the synthesis | combination unit 2, and can manufacture a different kind of labeling agent on the same day easily.
Thus, since the synthesis unit 2 can be exchanged in a short time, human intervention in the synthesis of the labeling drug can be minimized. As a result, it is possible to prevent the labeled drug synthesizer from being exposed and to prevent foreign substances from being mixed.

  The 2nd connection part 5 can connect the utility supply piping from the main body 3 to the synthetic | combination unit 2 collectively, for example, the one-touch coupling shown to FIG. 5A can be used. In this one-touch joint, the first joint member 31 and the second joint member 32 are inserted with the first pipe 50A and the second pipe 50B in advance, respectively. A large number of pipes can be connected in a lump by combining with the joint member 32 and fixing with the fixing screw 51. In the example shown in FIG. 5B, the first pipe 50 </ b> A and the second pipe 50 </ b> B are collectively communicated in the insertion hole of the connector 56 in the second joint member 32.

  By using this one-touch joint, multiple utility supply pipes can be connected together in a narrow hot cell, and these pipes can be easily attached and detached in a short time. 1 can be miniaturized. Furthermore, this one-touch joint is easy to maintain and can be thoroughly cleaned after use, and is therefore suitable for the synthesis of a radiolabeled drug that is an injection.

  Thereby, it becomes possible to shorten the time required for replacement | exchange of the synthetic | combination unit 2 combined with a 1st connection part, and can manufacture a different kind of labeled | labeling medicine in multiple times on the same day easily.

  In order to facilitate positioning of the synthesis unit 2 with respect to the main body 3, it is preferable to provide a guide portion 13. Such a guide part 13 makes it possible to further shorten the replacement time. Naturally, the positions of the first connection part 4, the second connection part 5, the reactor 11, etc. installed in each synthesis unit 2 must exactly coincide with the corresponding positions of the main body 3. By mounting the guide portion, the first and second connection portions are connected simultaneously with the setting of the synthesis unit, and the replacement work can be performed in a very short time and easily. At this time, of course, the reactor 11 and the heating / cooling device 6 can be accurately fitted simultaneously, and the needle driving mechanism 14 and the hollow needle 26 can be easily fixed.

By means of the first connection part 4 and the second connection part 5, the synthesis unit 2 having various configurations can be attached to the main body 3 to automatically synthesize the labeled drug.
That is, if there is one main body 3, the labeling drug can be synthesized for most nuclides used for PET by exchanging the synthesis unit 2. Furthermore, the part contaminated with the used reagent can be replaced with the synthesis unit 2 by a simple operation, and since the replacement operation is easy, the next synthesis can be started in a short time. Can be increased.

Next, a second embodiment of the present invention will be described with reference to FIG.
This embodiment is different from the first embodiment in that a primary labeling raw material separation / purification unit 10 is provided in the main body 3. In addition, it is a matter which overlaps with 1st embodiment, Comprising: About the content already demonstrated, the overlapping description is abbreviate | omitted.

  As shown in FIG. 3, in the automatic synthesizer 1 of the present embodiment, the labeling drug synthesizing means of the synthesis unit 2 includes a reactor 11 connected to a primary labeling raw material separation and purification unit 10 provided in the main body 3, and a reaction. And a reagent reservoir 12 connected to the vessel 11. The synthesizing unit 2 is connected to the main body 3 via the first connecting portion 4 and the second connecting portion 5.

The synthesis assisting means of the main body 3 is configured to include a heating / cooling device 6, a radioactivity sensor 7, and a temperature sensor 8 for the reactor 11 provided in the synthesis unit 2 as in the first embodiment. The main body 3 can be provided with a needle driving mechanism 14 that moves the hollow needle 26 up and down. The difference is that the primary labeling raw material separation / purification unit 10 is connected to the synthesis unit 2 above the main body 3.
The structure of the 1st connection part 4 and the 2nd connection part 5 is also the same structure as 1st embodiment.

And the synthetic | combination unit 2 from which a kind differs can be attached interchangeably with respect to the main body 3, and an automatic synthesis | combination of a labeled | labeling medicine can be performed.
That is, according to the main body 3 of the present embodiment, by exchanging the synthesis unit 2, different types of labeled drugs can be easily synthesized for the same primary labeling raw material. Furthermore, since the part contaminated with the reagent used in a simple operation can be replaced together with the synthesis unit 2, the next synthesis can be started in a short time, and the number of synthesis per day can be increased.

In addition, when synthesizing a labeling drug that does not require purification of the primary labeling raw material, or when a primary labeling raw material purification unit is built in the synthesis unit, the primary labeling raw material purification unit built in the main unit of the synthesizer is bypassed. Thus, also in this embodiment, a wide variety of labeled drugs labeled with different nuclides can be produced.
That is, the labeling drug can be produced by attaching the synthesis unit 2 according to the first embodiment including the primary labeling raw material separation and purification unit 10 to the main body 3 according to the second embodiment. Even such a mode of use falls under the practice of the present invention.

As described above, the embodiment of the present invention has been described by taking as an example the case of producing a radiolabeled drug using positron nuclides, but the present invention is not limited to the above embodiment.
It is also possible to produce a labeled drug using ¹²³ I used for other radionuclides, for example SPECT, by exchanging the synthesis unit of the automatic synthesizer according to the present invention, and such use is also included in the present invention. It is.
In the present embodiment, the nuclide is described as being supplied from a cyclotron. However, the present invention is not limited to this, and a radiolabeled drug can be synthesized using a commercially available nuclide.

Alternatively, a drying tube, a purification tube, or the like can be provided on one or both of the inlet side and the outlet side of the reactor 11. When the synthesis reaction is hindered by the presence of water, a drying tube can be provided at the inlet of the reactor 11 to perform the reaction smoothly.
Further, although the synthesis unit 2 has been described as having the primary labeling raw material separation and purification unit 10, the reactor 11, the reagent storage tank 12 and the like attached to one panel, these devices are divided into two or more panels. Can be used as the synthesis unit 2.

Alternatively, supplies mainly inert gas from the utility portion 23, and supplies the ¹⁵ O ₂ is reacted with hydrogen in the presence of a catalyst when synthesizing the H ₂ ¹⁵ O _2, hydrogen from the utility portion 23 The gas used for the synthesis reaction can also be supplied.
Further, although the needle driving mechanism for driving the hollow needle 26 has been described as linearly moving in the vertical direction, the present invention is not limited to this, and the needle driving mechanism may move the hollow needle 26 including the vertical component. It may be anything that moves in an oblique direction, or may move while drawing an arc.

Below, the synthesis | combination example of the labeling agent by the automatic synthesizer 1 of this invention is demonstrated according to an Example. In this example, an ¹¹ C nuclide labeling agent was synthesized using the apparatus shown in FIG.
In FIG. 2, the entire automatic synthesizer 1 is controlled by the control unit 24. Unless otherwise specified, the operation of the valve 33 and the transfer of the reaction mixture by an inert gas, or the reaction temperature / time and sensors. Monitoring was performed by the control unit 24.

In FIG. 2, ¹¹ CO ₂ gas as a raw material was supplied from the target unit 21 and collected in the loop-shaped primary labeling raw material separation and purification unit 10 fitted to the heating and cooling device 6 of the synthesis unit 2. The gas that was not collected was discharged to the utility section 23 via the second connection section 5 by operating the valve 33.

At this time, the primary labeling raw material separation and purification unit 10 was cooled to about −180 ° C. by blowing liquid nitrogen. Next, the cooling of the loop-shaped primary labeling raw material separation and purification unit 10 is stopped, and the collected ¹¹ CO is collected by heating with the heater of the heating and cooling device 6 in which the primary labeling raw material separation and purification unit 10 is fitted. ₂ is vaporized, a LiAlH ₄ / THF solution is added in advance, and liquid nitrogen is intermittently blown from the heating / cooling device 6 fitted in the reactor 11, and then cooled to about −15 ° C. and trapped in the reactor 11 a. Gathered. Next, the reactor 11a was heated by the heating / cooling device 6 fitted with the reactor 11a to distill off THF. The exhaust gas at this time was also discharged to the utility unit 23 via the second connection unit 5.

Next, hydrogen iodide (HI) was pumped from the reagent storage tank 12a to the reactor 11a, and the reactor 11a was heated using the heating / cooling device 6 to generate ¹¹ CH ₃ I. The produced ¹¹ CH ₃ I was introduced into the reactor 11b containing the reaction substrate. An Ascalite (trade name of AH Thomas, USA) / P ₂ O ₅ column for purifying ¹¹ CH ₃ I was inserted between the reactor 11 a and the reactor 11 b. In the reactor 11b, the reagent was introduced from the reagent storage tank 12b, and the target labeled compound was obtained by keeping it at a predetermined temperature for a certain time using a heater.

  This reaction mixture was pumped with an inert gas and transferred from the reactor 11b to the separation and purification dispensing unit 22. At this time, the movement of the radioactive substance and the control of the temperature, the gas flow rate, the pressure and the like were performed by communicating signals from the respective sensors installed in the main body 3 with the control unit 24.

[ ¹¹ C] Ro15-1788 (flumazenil) for central benzodiazepine receptor measurement was automatically synthesized by combining the synthesis unit 2 and the main body 3. The irradiation conditions of the target part for generating ¹¹ C were proton 18 MeV, irradiation current value 15 microamperes, and irradiation time 20 minutes.
As a result of the synthesis, an [ ¹¹ C] Ro15-1788 injection with a radioactivity at the end of synthesis of 140 mCi and a specific radioactivity of 5 Ci / μmol or more was obtained.
The total time required for synthesis was 25 minutes. The above results are superior in performance compared with existing dedicated automatic synthesizers. Further, in this example, the time required for exchanging the synthesis unit 2 used for the production of the ¹¹ C nuclide labeling drug was about 40 seconds for the attachment operation and about 20 seconds for the removal operation.

In addition, a reaction tube filled with silver trifluoromethanesulfonate was connected downstream of the above-mentioned Ascarite (trade name of AH Thomas, USA) / P ₂ O ₅ column, and ¹¹ CH ₃ I was replaced with ¹¹ CH ₃ OTf. Then, by introducing it into the reactor 11b, the ¹¹ C methylation reaction can be carried out more efficiently.

It is a conceptual diagram of the radiolabeled drug automatic synthesizer of the present invention. 1 is a schematic configuration diagram of a radiolabeled drug automatic synthesizer according to a first embodiment of the present invention. It is a schematic block diagram of the radiolabeled drug automatic synthesizer according to the second embodiment of the present invention. It is operation | movement explanatory drawing of a hollow needle | hook. It is sectional drawing of a one-touch coupling. It is a perspective view of a one-touch coupling.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Radiolabeled medicine automatic synthesizer 2 Synthesis unit 3 Main body 4 1st connection part 5 2nd connection part 6 Heating / cooling device 7 Radioactivity sensor 8 Temperature sensor 10 Primary labeling raw material separation | purification part 11 Reactor 12 Reagent storage tank 13 Guide part 14 Needle drive mechanism 15 Needle holding part 26 Hollow needle

Claims (6)

A radiolabeled drug automatic synthesizer that synthesizes a radiolabeled drug from a nuclide,
A synthesis unit equipped with a labeling agent synthesis means;
A body equipped with a labeling agent synthesis assisting means;
One of the multi-pin connectors that can be engaged with each other to perform electrical signal communication is fixed to the composite unit, and the other of the multi-pin connectors is fixed to the main body, and the first connection portion,
The first joint member in which the first pipe is inserted in advance and the second joint member in which the second pipe is inserted in advance are combined and fixed so as to connect or communicate with each other. various pure gas containing an inert gas, or compressed air, vacuum, evacuated, liquid nitrogen, the synthesis reaction using either the utility supply piping collectively connect or communicated thereby Ru second supply of gas A connection ,
The combining unit is positioned with respect to the main body, and includes a guide portion to which the first and second connection portions are connected simultaneously with the setting of the combining unit to the main body ;
The synthetic unit is attached to the main body in a replaceable manner. An automatic radiolabeling drug synthesizing device. The labeling agent synthesis assisting means of the main body,
A heating / cooling device for the reactor provided in the synthesis unit, a radioactivity sensor, and a temperature sensor,
The radiolabeled drug automatic synthesizer according to claim 1, further comprising: The labeling agent synthesis means of the synthesis unit is
A nuclide separation and purification section;
The reactor connected to the nuclide separation and purification unit;
The radiolabeled drug automatic synthesizer according to claim 2 , further comprising a reagent storage tank connected to the reactor. The labeling agent synthesis assisting means of the main body,
A nuclide separation and purification section;
A heating / cooling device for the reactor provided in the synthesis unit, a radioactivity sensor, and a temperature sensor,
The radiolabeled drug automatic synthesizer according to claim 1, further comprising: The labeling agent synthesis means of the synthesis unit is
The reactor connected to the nuclide separation and purification unit;
The radiolabeled drug automatic synthesizer according to claim 4 , further comprising a reagent storage tank connected to the reactor. A hollow needle inserted into the reactor;
A needle holding part for holding the hollow needle;
The radiolabeled medicine automatic according to any one of claims 2 to 5, further comprising a needle drive mechanism that moves the needle holding part and the hollow needle including a vertical component. Synthesizer.

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