JP3133252B2 - FDG synthesizer incorporating a three-way switch cock - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] 1. Field of the Invention [0002] The present invention relates to an apparatus for synthesizing FDG as a labeling compound in a positron emission tomography (PET) system.

[0002]

2. Description of the Related Art In the medical field, as one of methods for observing and diagnosing the state of the inside of a human body by using an image, an image diagnosis method using a PET system using a substance that emits a positron has recently attracted attention. According to the diagnostic imaging method using the PET system, not only morphological images of diseases such as cancer, but also functional images such as movements of blood and oxygen in the body can be obtained, which has great power in diagnosing brain disorders and heart diseases. Be demonstrated.

The PET system is a diagnostic imaging system using a short half-life radioisotope, and the outline of the system is as follows. (1) Accelerate ions to high energy in a cyclotron. (2) A radioactive nuclide is generated by irradiating accelerated ions to a material called a target in a target box as a reaction vessel. (3) Using the radionuclide as a raw material, a compound labeled with a radioisotope that can be administered to the human body is prepared in a labeled compound synthesizer. (4) The labeled compound thus prepared is administered into a human body, the distribution of the labeled compound taken into the human body is detected by a scanner, and the detection result is imaged by a computer.

FD as a labeling compound for PET systems
G (Fluoro deoxy glucose) is known. FDG converts a portion of glucose to the positron emitting nuclide F-18 (half-life 11
9.7 minutes), and is used for brain function and diagnosis of malignant tumors.

[0005] As a method for synthesizing FDG, Hamacher et al. Is known. This method comprises the steps of a labeling reaction for binding a radioisotope F-18 to a compound, and
It consists of a hydrolysis reaction step of separating a protecting group (usually an acetyl group) from the labeled intermediate product. FIG. 1 shows a conventional FDG synthesis method.

[0006] O-18 water is irradiated with proton particles accelerated by a cyclotron (not shown) to produce F-18 negative ions in a target box. The thus produced O-18 water containing F-18 negative ions (hereinafter referred to as target water) is taken out of the target box 1 and, as shown in FIG.
Send to Next, the target water from the target water intermediate container 2 is passed through the anion exchange resin 3, the F-18 negative ions are trapped by the anion exchange resin, and the O-18 water is collected in the collection container 4.

[0007] Next, the aqueous potassium carbonate solution is sucked from the container 5 with the syringe 6 and then flown into the anion exchange resin 3 to extract F-18. The F- extracted in this way
18 is sent to the reaction vessel 7. Next, an acetonitrile solution of Kryptofix 222 is sent from the container 8 to the reaction container 7. Next, the reaction vessel 7 is heated to evaporate the water in the vessel.
Further, after the water in the container evaporates, acetonitrile is sucked from the container 9 with the syringe 10, and
The reaction vessel 7 is heated again to sufficiently evaporate the water in the vessel.

Then, after the reaction vessel 7 is sufficiently evaporated, the reaction substrate 1,3,4,6-Tetra-0-acetyl-2-0-tri
An acetonitrile solution of fluoromethanesulfonyl-β-D-mannopyranose (hereinafter referred to as triflate) is sent from the vessel 11 to the reaction vessel 7, and then at a temperature of 80 ° C. for about 5 minutes.
Perform labeling reaction.

Then, after completion of the labeling reaction, water is added to the container 12.
Is sucked with a syringe 13 and sent to the reaction vessel 7. Next, the solution in the reaction vessel 7 is separated from the reaction vessel 7 by SepPakC-18.
Through the cartridge 14, 4-acetyl-FDG in the solution, which is a reaction intermediate, is trapped in the cartridge 14, and the waste liquid containing unreacted F-18 and Kryptofix 222 is sent to the waste liquid container 15. Thus, 4-acetyl-FDG is separated from unreacted F-18 and Kryptofix222.

Next, acetonitrile is sucked from the container 9 with the syringe 10, and the purified reaction intermediate is extracted from the cartridge 14 and sent to the reaction container 7 again.
Next, after heating the reaction vessel 7 to evaporate the organic solvent, the aqueous hydrochloric acid solution is sucked from the vessel 16 with the syringe 17 and added to the reaction vessel 7. Next, the reaction vessel 7 is
The hydrolysis reaction is performed by heating at a temperature of 10C for 10 to 20 minutes.

Then, after the completion of the hydrolysis reaction, water is sucked from the container 12 with a syringe and added to the reaction container 7.
Next, the solution in the reaction vessel 7 thus treated is sequentially passed through the ion delay resin column 18 and the purification column 19,
The synthesized FDG is stored in the FDG container 20 (hereinafter, referred to as FDG container 20).
Prior art 1).

In the prior art 1, the FDG synthesized was processed by the same process as in the prior art 1 except that an aqueous solution of sodium hydroxide was used instead of the ion-delay resin to remove hydrochloric acid by a neutralization reaction. (Hereinafter referred to as Prior Art 2).

In the prior arts 1 and 2, a phase transfer catalyst of Kryptofix222 or tetrabutylammonium bicarbonate (TBAHCO ₃ ) is added at the time of the labeling reaction, so a process for removing the added phase transfer catalyst is required. . Furthermore, since the above-mentioned phase transfer catalyst is used, it is necessary to completely remove water by evaporation to dryness, and there is a problem that it takes time to remove water. Furthermore, a special process using an anion exchange resin is required for the recovery of O-18 water, and there is a problem that the process of synthesizing the FDG becomes complicated. The half-life of F-18 is about 2 hours, and if synthesis takes too long, FDG
There is a problem that the yield of coconut is reduced.

Further, a container for accommodating an aqueous hydrochloric acid solution or an aqueous sodium hydroxide solution during the hydrolysis is required, and an ion retarding resin or a neutralizing reagent for removing the aqueous hydrochloric acid solution or the aqueous sodium hydroxide solution is required. is there. Furthermore, when using an ion-delay resin, it is necessary to sufficiently wash the ion-delay resin before use, since bacteria easily propagate in the ion-delay resin and bacterial toxins (pyrogen) are easily mixed in the resin. . Furthermore, when using a neutralization reaction, hydrochloric acid or sodium hydroxide is lost during the hydrolysis reaction, so that it is difficult to carry out an exact equivalent amount of the reaction. However, there is a problem that phosphoric acid and the like as impurities are mixed in the FDG. Further, it is necessary to replace the reagent and the reaction container each time, and to wash the liquid contact parts of the pipes and valves. As a result, it is necessary to set up the apparatus every time synthesis is performed, which causes a variation in the quality of the synthesized FDG. Further, the synthesizing operation is complicated, and the synthesizing operation may fail due to an error in the synthesizing operation. Since PET diagnosis has a very short half-life of the radioisotope used, it is necessary to simultaneously prepare a patient while performing drug synthesis in a hospital, and synthesis failure or variation in FDG production is greatly affected by a patient's clinical schedule. There is a problem of affecting.

Further, in the prior arts 1 and 2, a pinch valve is used as a valve. In the pinch valve, when the valve is closed, a line may not be completely closed due to a material of a tube. When the valve is opened, a situation occurs in which the closed line is not completely opened. As a result, there is a problem that line switching failure occurs and FDG synthesis fails. Furthermore,
There is a problem that the number of pinch valves is large and the device becomes large.

[0016]

SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to solve the above-mentioned problems of the prior art, and the preparation operation for FDG synthesis is simplified, and the FDG synthesis apparatus is simplified. , The synthesis yield is improved, and the synthesis time is shortened, and the uniformity of quality and quality control can be facilitated.
An object of the present invention is to provide a compact FDG synthesizer.

[0017]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems. As a result, FDG
The synthesizer comprises a disposable cartridge unit, and a valve drive unit for driving a valve, a syringe drive unit for driving a syringe, a heater unit for heating a column, and a gas supply unit for liquid transport and drying. It has been found that the above-described problem can be solved by configuring the apparatus to be composed of a synthesizer main body and using a three-way switching cock instead of the pinch valve.

That is, first, instead of the conventional reaction vessel for performing the labeling reaction, a disposable cartridge type in which a polystyrene resin is filled with an immobilized phase transfer catalyst resin obtained by immobilizing a phosphonium salt or a pyridinium salt. Use a disposable cartridge type column filled with cation exchange resin, and use a disposable cartridge type purification column and various containers instead of the hydrolysis reaction vessel. Then, these are attached to a disposable cartridge portion, and each column, various containers, a line connecting between syringes, and a switching valve comprising a three-way switching stopcock are incorporated in the cartridge portion, and the entire disposable is disposable. Constructed as a cartridge, and set into the synthesizer body with one touch It by, FDG synthesis process is simplified, synthesis yield is improved, synthesis time is shortened, and was found that it is possible to obtain a compact FDG synthesizer.

An FDG synthesizing apparatus using a disposable cartridge according to the present invention is based on the above findings, and comprises a disposable cartridge section, a valve driving section for driving a valve, and a syringe. A syringe drive section, a heater section for heating the cartridge type cation exchange resin column, and a liquid transfer and cartridge section.
And a synthesizing apparatus main body comprising a gas supply unit for drying the resin column for the di-labeling reaction. The cartridge unit contains F-18 contained in O-18 water containing F-18 negative ions . Trap −18 negative ions, and then add the F-18 negative ions to 1,3,4,6-
La-0-acetyl-2-0-trifluoromethanesulfo
For performing a labeling reaction with nyl-β-D-mannopyranose , a cartridge-type labeling reaction resin column comprising a column packed with an immobilized phase transfer catalyst resin, and
A cartridge type cation exchange resin column for bringing the intermediate product obtained by the labeling reaction into contact with a cation exchange resin prepared in H + form and heating to carry out a hydrolysis reaction is attached. the labeling reaction resin column, lines and switching valve communicates the cation exchange resin column are incorporated, before
The two columns are installed outside the cartridge section.
Vignetting, and the valve is characterized in that it incorporates a three-way switching stopcock.

[0020]

Next, the present invention will be described with reference to the drawings. FIG. 2 is a schematic explanatory view showing one embodiment of the FDG synthesizing apparatus of the present invention. The device of the present invention
A not-shown valve driving unit for driving a valve, a syringe driving unit for driving a syringe, a heater unit for heating a column, and a synthesizing apparatus main body including a gas supply unit for liquid transport and drying, and FIG. As shown in the figure, the apparatus comprises a cartridge type resin column for labeling reaction, a cartridge type cation exchange resin column, and a disposable cartridge section 30 to which various containers are attached, which can be set in the synthesis apparatus main body with one touch.

In the cartridge type cation exchange resin column according to the present invention, the flow rate of the intermediate product containing the organic solvent passing through the column and the temperature in the column are adjusted so that the rate at which the solvent evaporates in the column can be adjusted to a new value. By reducing the speed of the solvent flowing into the column, the solvent is evaporated off in the cation exchange resin column, and the intermediate product of FDG, from which the organic solvent has been removed, is brought into contact with the resin of the column.

The cartridge type cation exchange resin column has heating means for adjusting the temperature in the column, and flow rate control means for controlling the flow rate of the intermediate product containing the organic solvent. By heating means, the inside of the column is 9
The temperature is adjusted to a temperature in the range of 0 to 150 ° C., and the flow rate of the intermediate product containing the organic solvent is controlled by flow rate control means.
Control is performed within the range of 0.5 to 1.5 cc / min.

As the cation exchange resin column of the present invention, a cation exchange resin containing water or a cation exchange resin in a dry state can be used. When using a cation exchange resin containing water, it is preferable to use a sufficient amount of the cation exchange resin. When a cation exchange resin in a dry state is used, separation of an organic solvent and an intermediate product becomes easy, and an effective hydrolysis rate can be achieved with a small amount of the cation exchange resin.
When a dried cation exchange resin is used, it is necessary to add water at the time of hydrolysis.

In FIG. 2, 4 is a cartridge type resin column for labeling reaction, and 17 is a cartridge type cation exchange resin column. The cartridge type labeling resin column 4 is a column in which a phosphonium salt or a pyridinium salt is immobilized on a polystyrene resin, that is, a column filled with an immobilized phase transfer catalyst resin composed of an immobilized phosphonium salt or an immobilized pyridinium salt. . In the resin column 4, the target water is passed through to trap F-18 negative ions contained in the target water, then the acetonitrile solution is passed through, the inside of the column is dried, and then the triflate solution To perform a labeling reaction between the trapped F-18 anion and triflate.

The O-18 water that has passed through the labeling reaction resin column 4 and has been separated from the trapped F-18 negative ions is separated into a collection vessel 5 by operating the three-way switching valve 11.
The acetonitrile solution and the like are collected in the waste liquid container 12 by operating a three-way switching valve. As described above, in the resin column for labeling reaction, F-18 negative ions are trapped and then the labeling reaction is performed, so that a separate process for recovering the O-18 water is not required, and the labeling reaction is performed. By removing the water that hinders the reaction, by forming the reaction vessel into a column, the water in the column can be removed only by passing the organic solvent through the column. Furthermore,
Since the catalyst is immobilized on the resin, a separate process for separating and removing the catalyst is not required, and the labeling reaction rate is improved. Further, since the labeling reaction resin column 4 is of a cartridge type, it can be easily replaced, the setup is easy, and the variation of the FDG synthesis yield and quality can be prevented.

Cartridge type cation exchange resin column 1
In 7, a hydrolysis reaction process for separating a protecting group (usually an acetyl group) from an intermediate product labeled by the labeling reaction in the labeling resin column 4 is performed. That is, the triflate solution is passed through the resin column 4 in which F-18 negative ions are trapped, and the solution subjected to the labeling reaction is brought into contact with a cation exchange resin adjusted to H ⁺ type,
At the same time, acetonitrile is evaporated and then heated at a temperature of 130 ° C. for 10 to 15 minutes to carry out a hydrolysis reaction. Therefore, during the hydrolysis reaction, an aqueous hydrochloric acid solution or an aqueous sodium hydroxide solution becomes unnecessary, and a reaction vessel becomes unnecessary.
Further, since the cation exchange resin column 17 is of a cartridge type, it can be easily replaced, the setup is easy, and the variation in the yield and quality of FDG synthesis can be prevented.

After the hydrolysis reaction, sterile water is added, and the mixture is passed through the purification column 25 to synthesize FDG.
That is, after the hydrolysis, FDG can be obtained in an aqueous solution by a simple operation of flowing out with water.

The target water container 1, acetonitrile container 7, triflate container 14, sterile water container 20, and syringe pumps 2, 6, 21 are attached to the cartridge unit 30. Cartridge connectors are easy to install and remove. For example, a luer-type connector is preferable. Valves 3, 9, 10, 8, 13, 11, 15,
16, 18, 22, and 19 are three-way switching valves. The line (liquid contact part) connecting between the valve and the valve or connector is made of a Teflon tube or a polypropylene tube. Further, the line may directly form a through hole or the like in the cartridge unit 30 itself.

[0029]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The apparatus of the present invention will be described in detail with reference to embodiments. The cartridge-type labeling reaction resin column used in the apparatus of the present invention is a mixed solvent of ethanol and water,
The slurry is formed by mixing a resin of 100 to 200 mesh to form a slurry into a cylindrical, e.g., stainless steel column having an inner diameter of 2 mm and a length of 5 cm. Further, the cartridge type cation exchange resin column used in the apparatus of the present invention is formed by packing a cation exchange resin prepared in H ⁺ type into a cylindrical column having an inner diameter of 12 mm and a length of 4 cm. Target water from a target box (not shown), that is,
Irradiated O-18 water containing F-18 negative ions was sent to the target water container 1. As shown in FIG. 2, the target water is sucked from the target water container 1 into the syringe pump 2, the three-way switching valve 3 is switched, the target water is sent to the resin column 4, and F-18 is trapped in the resin. The O-18 water was separated and sent to an O-18 water recovery container connected to the connector 5. Next, acetonitrile contained in the acetonitrile container 7 is sucked by the syringe pump 6, the three-way switching valve 8, the three-way switching valve 9
And acetonitrile is passed through the resin column 4,
The inside of the resin column 4 was washed, and the three-way switching valve 10 was switched to flow He gas to sufficiently dry the inside of the resin column 4. Acetonitrile was supplied to the waste liquid container connected to the connector 12 by switching the three-way switching valve 11.

Next, the three-way valve 13 is switched, the triflate solution is sucked from the triflate container 14 by the syringe pump 6, and the three-way valve 13, the three-way valve 15, 3
The triflate solution was passed through the resin column 4 by switching the valve 16 to perform a labeling reaction in the resin column, and the intermediate product was sent to the cation exchange resin column 17. At that time, the flow rate of the intermediate product containing acetonitrile was 0.7
cc / min and the temperature in the column was 120 ° C.
After the completion of the liquid feeding, the three-way valve 16 and the three-way valve 18 were switched, He gas was flown, and acetonitrile was removed by evaporation in the cation exchange resin column 15, and at the same time, the intermediate product was trapped in the column. Next, in the cation exchange resin column 15, a hydrolysis reaction was performed by heating at a temperature of 130 ° C. for 10 to 15 minutes. At this time, the three-way valve 19 was switched to the waste liquid side.

After the completion of the hydrolysis reaction, sterile water is sucked into the syringe pump 21 from the sterile water container 20, and the three-way switching valve 22, the three-way switching valve 18 is switched and sent to the cation exchange resin column 17, and the three-way switching valve is provided. 1
9, the reaction solution is passed through the purification column 25, and the FD
G was obtained. Table 1 shows the results of FDG synthesis by the FDG synthesis apparatus of the present invention.

[0032]

[Table 1]

As is clear from Table 1, the FDG of the present invention
According to the apparatus, the synthesis process can be simplified to about half that of the prior art, and at the same time, the time required for the synthesis is greatly reduced.

[0034]

According to the apparatus of the present invention, the preparation operation for FDG synthesis is simplified, the process in the FDG synthesis apparatus is simplified, the synthesis yield is improved, the synthesis time is shortened, and the quality is further improved. A compact FDG synthesizer capable of easily homogenizing and controlling quality can be provided, and an industrially useful effect can be obtained.

[Brief description of the drawings]

FIG. 1 is a schematic explanatory view showing a conventional FDG synthesizing apparatus.

FIG. 2 is a schematic explanatory view showing one embodiment of an FDG synthesizing apparatus according to the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Target water container 2 Syringe pump 3 Three-way switching valve 4 Resin column for labeling reaction 5 Recovery container 6 Syringe pump 7 Acetonitrile container 8 Three-way switching valve 9 Three-way switching valve 10 Three-way switching valve 11 Three-way switching valve 12 Waste liquid container 13 Three-way switching valve 14 Triflate container 15 Three-way switching valve 16 Three-way switching valve 17 Cation exchange resin column 18 Three-way switching valve 19 Three-way switching valve 20 Sterile water container 21 Syringe pump 22 Three-way switching valve 25 Purification column 30 Cartridge section

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-55-143999 (JP, A) Tokuhyo Hei 5-507813 (JP, A) Nucl. Med. Biol. , Vol. 17, No. 3 (1990) p. 273-279 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07H 5/02 C07B 59/00

Claims (1)

(57) [Claims] 1. A disposable cartridge unit, and a valve driving unit for driving a valve, a syringe driving unit for driving a syringe, a heater unit for heating a cartridge type cation exchange resin column , and liquid conveying and mosquitoes
And a synthesis device main body comprising a gas supply unit for drying the resin column for the cartridge type labeling reaction. The cartridge unit contains O-18 containing F-18 negative ions.
−18 traps the F-18 negative ions contained in the water, and then combines the F-18 negative ions with 1,3,4
6-tetra-0-acetyl-2-0-trifluorometa
A cartridge type labeling reaction resin column comprising a column filled with an immobilized phase transfer catalyst resin for performing a labeling reaction with sulfonyl-β-D-mannopyranose ;
And converting the intermediate product obtained by the labeling reaction into H
A cartridge-type cation exchange resin column for contacting with a cation exchange resin prepared in the form of + and heating to carry out a hydrolysis reaction is attached, and the resin column for labeling reaction, the cation A line connecting the exchange resin column and a switching valve are incorporated, and the two columns are provided outside the cartridge unit.
Mounted on, and said valve is characterized in that it incorporates a three-way switching stopcock, fluorodeoxyglucose synthesizer incorporating a three-way switching stopcock.