JPH04318499A - Synthesis method for labeled compound - Google Patents

Abstract

PURPOSE:To prevent a trouble in a solution injection device and shorten an operating time by adding a sensor valve to detect the displacement of a cylinder, and confirming the filling up state within the cylinder. CONSTITUTION:When a device is operated, a piston rod 51 is raised from the position of a sensor 54 by a driver 52, and liquids within vessels 20, 23 are sucked up into cylinders 21, 24 through three way valves 22, 25. The rod 51 stops when its lower end is detected by the upper detecting sensor 53. Next, three way valves 15, 16 are switched, a valve 56 is closed, the piston rod 51 is pushed down by the driver 52, it is judged that a sucked quantity is insufficient when that lower end is detected by a sensor 55, and the device is stopped and inspected. On the other hand, when the lower end is not detected by the sensor 55, the valve 56 is opened, the liquid is put into a cation exchange resin column 17. When the lower end of the piston rod 51 is detected by the sensor 54, the driver 52 is stopped, the putting in of the liquid is ended.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for synthesizing compounds used, for example, in PET systems, using an automatic synthesizer.

0002

[Prior art] PET (Positron Emiss
The ion tomography (ion tomography) system injects a positron radioisotope into the patient's body, measures the gamma rays generated by the positrons emitted from this isotope, determines the distribution of radioisotopes in each cross section, and uses this to diagnose the affected area. It is used as a diagnostic method. As a method for synthesizing this radioisotope, for example, pyruvic acid-1-11C
A method for synthesizing is disclosed in JP-A-1-294639. This method uses a cyclotron to collect 11CO
In this method, 2 is produced, and this is exchange-reacted with non-radioactive pyruvic acid and 11CO2. During synthesis, syringes are used for injecting NaOH and moving substrate solutions, etc.
There is no indication of checking whether enough of these medicinal solutions have been aspirated into the syringe.

Next, 13, which is used in PET systems etc.
As a production technology for N-ammonia, one using the apparatus shown in FIG. 2 is conventionally known (RADIO ISOTO
PES, vol. 30, pp1-6, 1981
). As a method for producing 13N-ammonia using this device, a certain amount of target water is poured into a three-way cock 27,
It is fed into the irradiation cell 8 through the two-way cock 28. Next, the cock 27 is switched, and the target water remaining in the liquid feeding pipe 30 is fully charged into the irradiation cell 8 using helium gas or nitrogen gas as a pressure feeding gas. At this time, cook 3
1 is left open and the pressurized gas is discharged from the pipe 32. Then, the cocks 27, 28, and 31 are closed, and when the proton beam 10 is irradiated, the oxygen atoms in the target water undergo a nuclear reaction to generate 13N. This nitrogen atom reacts with surrounding oxygen atoms and 13N-nitrate ion (1
3N-NO3-) is produced. Next, open the cock 34,
Further, the cocks 27 and 28 are opened and the irradiated target water is poured into the reaction container 35. So cook 3
6. Open the cock 37 and pour the reagent TiCl3 contained in the vial 38 into the reaction container 35. More cock 39
, open the cock 40 and remove the reagent N in the vial 41.
Charge aOH to reaction vessel 35. Next, the heater 42
The reaction vessel is heated to cause a reaction, and 13N-nitric acid ions are converted to 13N-ammonia. This is distilled and recovered into a vial 45 via a pipe 43. Conventionally, 13N-ammonia was produced as described above. Since water is also distilled and condensed in the vial 45, it can be used as an injection by measuring the amount of water in the vial and adding salt according to the amount. An isotonic solution was obtained. It is not disclosed that this device is used to inject liquid using a syringe.

[0004] By the way, there are a syringe method and a vial method as means for automatically transferring a fixed amount of a medicinal solution or the like to another container. The syringe method is a method in which a syringe is filled with the required amount of liquid in advance and the piston of the syringe is pushed down when necessary to deliver the liquid.For example, RADIO ISO
TOPES, vol. 33, pp706-709
, 1984, Video Information, 3, 1981, etc. The vial method involves filling a vial with the required amount of liquid in advance, and when necessary, pouring the entire amount into He, N2
This is a method of pressure feeding using a gas such as Int. Appl
．． Radiat. Isot. , vol. 36,
No. 6, pp469-474, 1985, ib
id. , vol. 35, No. 6, pp445
~454, 1984, etc.

[0005]

[Problem to be solved by the invention] When drawing liquid into a syringe, if the piping is clogged, the piping is poorly connected, or the piping is damaged, the amount of liquid sucked into the syringe may be reduced. Run short. Conventional automatic synthesis equipment does not have a function to check this, so even in such cases, the process automatically proceeds to the next step, causing trouble. Furthermore, I had to wait a certain amount of time before drawing into the syringe. Furthermore, even if the same liquid is used regardless of the vial method or syringe method, it is necessary to set the vial or syringe for the number of times it is used.

The present invention has been made to solve the above-mentioned problems, and provides a means for preventing troubles by checking whether the necessary amount of liquid has been sucked into the cylinder. The purpose is to

Another object of the present invention is to provide a means for performing operations in a short time by omitting the waiting time when drawing a syringe. This is particularly effective when using short half-life radioisotopes such as 13N.

[0008]

[Means for Solving the Problem] The above problem is to provide a labeled compound synthesis method that includes a step of injecting a liquid into a container, in which a predetermined amount of the liquid is sucked from the liquid reservoir into a syringe, and the liquid is injected from the syringe into the container. When the piping connecting between the syringe and the container is closed, the piston of the syringe is pushed down to detect the displacement of the piston, and when the displacement exceeds a predetermined value, the liquid is discharged into the syringe. This problem is solved by a method for synthesizing a labeled compound, which is characterized in that it is determined that the amount of suction is insufficient, and if the displacement is less than a predetermined value, the piping is opened and the liquid is injected into the container.

[0009] The type of liquid is not critical, and may include acids and alkalis, substrate liquid, ion exchange resin cleaning liquid, eluent liquid, etc., depending on the type of synthesis reaction.

[0010] The container into which the liquid is poured is not particularly limited, and may be appropriately selected depending on the shape, size, sealability, etc. of the application.

A syringe is used to inject liquid into a container. This is to ensure that a constant amount of liquid is delivered each time by using a syringe. The syringe is piped to a reservoir of liquid, and first sucks a predetermined amount of liquid from the reservoir. The piston of the syringe is driven by a power source such as a motor or compressed air. Therefore, there is a need for a mechanism that determines the starting and stopping points of the piston and instructs the piston to start and stop at those points. The starting point and stopping point can be changed as necessary. Any known means for detecting the starting point and stopping point may be used; for example, passage through a specific portion such as the piston itself or a piston rod connecting it to a drive source may be detected using a sensor, a switch, or the like. The syringe drive mechanism is also configured to be able to stop when a certain pressure is exceeded so as not to destroy the syringe and the synthesis device.

Next, when injecting the liquid from the syringe into the container, the piping connecting between the syringe and the container is temporarily closed. As a means of closing the piping,
This can be done by closing a valve provided in the piping, and additional valves may be added if necessary for this purpose. If the piping is made of a flexible material, the valve may be of a pinch type. With the piping closed, the piston's drive source is activated to push the piston down, and its displacement is detected. A sensor, a switch, or the like may be used as the detection means, and may be arranged so as to be able to detect a predetermined value. Displacement is the distance the piston moves. When this displacement exceeds a predetermined value, it is determined that the amount of liquid sucked into the syringe is insufficient, while if it is less than a predetermined value, the piping is opened and the liquid is injected into the container. be. The predetermined value serving as the criterion for the above judgment varies depending on the purpose of use of the liquid, the amount of gas allowed in the syringe during normal operation, the pushing pressure of the piston, etc., and is set in consideration of these factors. When it is determined that the amount of suction in the syringe is insufficient, an alarm is issued and actions such as stopping the device are taken.

[0013]

[Operation] By sucking up the liquid from the liquid reservoir into the syringe, a certain amount of liquid is reliably injected into the container each time. If you push down the piston of the syringe with the piping that connects the syringe and the container closed, if there is a blockage in the piping or insufficient suction of liquid, the pressure inside the syringe will be reduced during suction. Therefore, the displacement when pressing down becomes large, and if there is a faulty connection or damage to the piping, outside air will be sucked in and accumulate in the syringe, resulting in displacement due to the amount of gas compressed when pressing down. . If there is a poor connection or damage between the three-way valve at the branch and the syringe, the liquid will flow out of the pipe when it is pressed down, resulting in even greater displacement. Therefore,
By measuring this displacement, an abnormality in the amount of liquid sucked can be detected and countermeasures can be taken.

[0014]

EXAMPLE FIG. 2 is a flow sheet showing an outline of the apparatus used in the example of the present invention. The method for producing ammonia water containing 13 nitrogen for injections using this device is to first send a certain amount of water (target water), which is a target material, to an intermediate container 3 through a three-way cock 1 and a two-way cock 2. Enter. As a result, the circulation line side becomes filled with water, and the gas in the system collects in the intermediate container. Next, the cock 1 is switched to force-feed the target water remaining in the liquid feeding pipe with hydrogen gas and put the entire amount into the intermediate container, and the gas remaining in the intermediate container 3 is purged with hydrogen gas. The purged gas is discharged to the outside of the system through the cock 4. Next, the cock 4 is closed, and while measuring the pressure with the pressure gauge 5, the inside of the target box is pressurized to the required pressure with hydrogen gas, and the cocks 1 and 2 are closed. Next, the liquid feed pump 6 is operated to circulate the target water in the intermediate container 3 through the circulation line that returns to the intermediate container 3 through the cock 7, the irradiation cell 8, and the cock 9. When the proton beam 10 is irradiated in this state, the oxygen atoms in the target water undergo a nuclear reaction to generate 13N. This nitrogen atom reacts with hydrogen to produce 13N-ammonia in the target water.

After the irradiation is completed, cocks 7 and 9 are switched, cocks 1 and 2 are opened, and target water containing 13N-ammonia is supplied from the target box to pipe 1.
1 and taken out through the two-way cock 12 into the intermediate container 13. Next, the cock 14 is opened to supply the pressure-feeding gas, and the cocks 15, 16, and 18 are opened to flow the target water containing 13N-ammonia from the intermediate container 13 into the cation exchange resin column 17. The waste liquid that has passed is put into the waste liquid container 19. At that time, only 13N-ammonia is collected on the cation exchange resin. A fixed amount of sterile water is sucked from the sterile water container 20 with the syringe 21, and the three-way cocks 22 and 15 are switched to the cation exchange resin column 1.
7, run sterile water to wash away all remaining target water in the resin layer. The cleaning waste liquid enters the waste liquid container 19. Next, the saline is poured into the syringe 24 from the saline container 23.
A fixed amount is suctioned with the button, and the three-way cocks 25, 16, and 18 are switched to flow the physiological saline into the cation exchange resin column. As a result, the 13N that had been collected on the cation exchange resin
-Ammonia is eluted and together with saline 13N-
It enters the ammonia liquid container 26.

In the above device, the syringes 21 and 2
4, an L-shaped piston rod 51 was attached to the piston 50, as shown in FIG. An upper detection sensor 53 detects the piston rod 51 within the drive device 52.
A piston rod detection sensor 55 is provided slightly below the upper detection sensor 53.
has been established. A two-way valve 56 is provided below the three-way valves 15 and 16. When this device is operated, the piston rod 51 with its lower end is moved to the drive device 52 according to the instruction from the sensor 54.
The liquid in the containers 20 and 23 is sucked up into the syringes 21 and 24 through the three-way valves 15 and 16. When the lower end of the piston rod is detected by the upper detection sensor 53, the piston rod stops. Next, the three-way valve 15,
16, closes the valve 56, and then operates the drive device 52 in a direction to push down the piston rod. and,
The lower end of the piston rod is the piston rod detection sensor 5
If 5 is detected, it is determined that the suction amount is insufficient, the device is stopped, and inspection is started. On the other hand, when the lower end of the piston rod is not detected by the piston rod detection sensor 55, the valve 56 is opened and the liquid is passed through the cation exchange resin column 17. When the lower end of the piston rod is detected by the lower detection sensor 54, the drive device 52 stops, and the fluid passage ends.

[0017] By the above method, by changing the hydrogen pressure,
N-ammonia water was produced. The manufacturing conditions are shown below.

Target box internal volume: 7ml Target water amount: 3-5ml Hydrogen pressure: 0.7kg/cm2 Circulation speed: 100ml/min Irradiation time: 10 minutes Irradiation particles: Proton 12MeV Irradiation current: Approximately 15μA Ion exchange resin: Strong acidity Cation exchange resin Na type (product name Sep Cartridge IC-H) 0
．． 5ml Washing water volume: 3ml Physiological saline volume: 10ml

The yield and purity are as follows.

[0020]

[Table 1]

The amount of ammonia produced was determined by measuring 13N radioactivity using a radioactivity meter. Furthermore, radiochemical purity was determined by analyzing the target water after irradiation using a high performance liquid chromatograph.

While the synthesis of 13N-ammonia was repeated in this manner, when the valve 56 was closed and the piston rod 51 was pushed down, the lower end of the piston rod was detected by the piston rod detection sensor 55. Therefore,
When the synthesis equipment was inspected, it was found that the pipes were clogged and the suction amount was 10 to 20% less than the specified amount.

[0023]

Effects of the Invention According to the present invention, a sensor valve that can detect the displacement of the syringe is added to make it possible to check whether the syringe is sufficiently filled with the solution. You can prevent problems from occurring.

[Brief explanation of drawings]

1 is a detailed view of the portion of the apparatus of FIG. 2 that supplies liquid to a cation exchange resin column; FIG.

FIG. 2 is a flow sheet showing an overview of the apparatus used in the examples of the present invention.

FIG. 3 is a flow sheet showing an overview of equipment used in conventional synthesis methods.

Claims (1)

[Claims] 1. A labeled compound synthesis method comprising the step of injecting a liquid into a container, in which a predetermined amount of the liquid is sucked from the liquid reservoir into a syringe, and when the liquid is injected from the syringe into the container, the syringe and the container Once the piping connecting between the two is closed, the piston of the syringe is pushed down and the displacement of the piston is detected. If the displacement exceeds a predetermined value, it is determined that the amount of liquid sucked into the syringe is insufficient. A method for synthesizing a labeled compound, the method comprising: determining the displacement and, if the displacement is less than a predetermined value, opening the pipe and injecting the liquid into the container.