JP2776766B2 - Method and apparatus for producing high specific activity 13N-labeled drug - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a high specific activity type
¹³The present invention relates to a method and an apparatus for producing an N-labeled drug.
You. More specifically, the present invention relates to a positron emitting nuclide.
And useful high specific activity ¹³Method for producing N-labeled compound and its packaging
It is related to the location.

[0002]

2. Description of the Related Art A labeling agent conventionally used in the field of nuclear medicine is a compound labeled with a radioisotope (RI), and emits only γ-rays or X-rays as radioisotopes. However, it is said that it is desirable to have an appropriate energy and a physical half-life of several hours to about one day.

Further, a compound labeled with a radioisotope is
Positron emitting element¹¹C,¹⁸F, ¹³N,^FifteenMark with O
Is gaining attention in the application to positron CT
ing. Because these positron emitting elements
of,¹¹C,¹⁸F,¹³N,^FifteenO etc. are physiological substances,
This is because the properties of the compound do not change even after labeling.
Positron CT, which makes good use of such properties,
For example,¹¹C has a relatively long half-life of 20 minutes
Are often used.

However, on the other hand, ¹³ N is also expected to be useful as a label for various physiological compounds. At present, however, since ¹³ N has a half-life of 10 minutes, an enzymatic reaction with ¹³ NH ₃ aqueous solution is not possible. The fact is that the use is limited to the used ¹³ N-labeled amino acid. Also, since there are many non-radioactive NH ₃ in the environment, the production of high specific activity ¹³ N-labeled compound is very difficult, a high degree available for receptor studies specific activity (> 1C: 1μmol) ¹³ having a N
There are no production reports of labeled radiopharmaceuticals.

As for ¹³ N, as described above, an aqueous solution of ¹³ NH ₃ is used as a reaction precursor. However, in aqueous solution, ¹³ NH ₄ ⁺ generally has a low reactivity, and a hydrolysis reaction with water is used. And it cannot be used for reaction raw materials and products that are unstable in aqueous alkaline solutions.

[0006] Therefore, ¹³ NH for which the manufacturing technology has been established has been established.
Starting from an aqueous solution of _3, it is possible to produce an anhydrous ¹³ NH ₃ solution having high reactivity and a wide range of applications, and from this anhydrous ¹³ NH _3, various high specific activities of ¹³ N which can be used for receptor studies. It has been desired to develop a method for easily and easily producing a labeled compound in a high yield, and an apparatus for the method.

In such a situation, Tominaga, Suzu
ki et al. (Appl. Radiat, Isot., 38, 437-445, 19)
87) examined the method of producing anhydrous ¹³ NH ₃ and its reactivity. However, the use of a large amount of a dehydrating agent at a high temperature (about 10 g of ascalite, 200 ° C.) included labeling reaction, separation and purification, and preparation treatment. for such that automation not been hundreds contamination μg about moisture can not be avoided, it is difficult high specific activity of, short preparation time is difficult, utility-scale PET diagnostic ¹³ N-labeled drugs There was a problem that it was difficult to manufacture.

[0008] Therefore the present invention has been made in light of the circumstances described above, ¹³ as a conventional labeling agent
An object of the present invention is to provide a method for producing various ¹³ N-labeled drugs capable of overcoming the limitation of N and increasing the specific radioactivity, and an apparatus therefor.

[0009]

In order to solve the above-mentioned problems, the present invention comprises the following steps: a) generation of anhydrous ¹³ NH ₃ by cation ion exchange treatment of ¹³ NH ₃ aqueous solution and dehydration drying b) anhydrous ¹³ NH providing a high specific manufacturing method of the radioactivity corresponding type ¹³ N-labeled compound characterized in that it comprises dissolving a ¹³ N-labeled reaction ₃ to the organic solvent or reaction substrate laden organic solvent (claim 1).

[0010] Then, the present invention is in the above method, performing the alkaline elution in a cation ion exchange treatment (claim 2) or be a physiological formulation was purified ¹³ N-labeled compound (Claim 3) And the like are also the modes.
In addition, the present invention comprises the following steps: a) a cation ion exchange treatment section of ¹³ NH ₃ aqueous solution and a dehydration drying section; b) a dissolution section of anhydrous ¹³ NH _{3 in} an organic solvent and a reaction section with a reaction substrate. Characterized by high specific activity ¹³
There is also provided an apparatus for producing an N-labeled compound (Claim 4) and a production apparatus comprising a detecting means and a control means and capable of automatically synthesizing the same (Claim 5).

[0011]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the method and apparatus of the present invention having the above-described structure, the non-radioactive ion species such as non-radioactive NO _x ^- ions and NH ₄ ⁺ ions which cause a decrease in specific activity are obtained. The first goal is to reduce contamination. Therefore, in the present invention, the use of the cation ion conversion resin to be used and the solution for elution is minimized,
In addition, the cation ion exchange resin and the concentration treatment by alkali elution are performed by making the dehydration and drying treatment inseparable.

It is preferable to use a small amount of the cation ion exchange resin up to about 30 mg. The cation ion exchange is preferably performed using He (helium), Ar
(Argon) or the like in a closed system in an inert gas atmosphere. Of course, the type of the resin may be appropriately determined. For elution from the cation ion exchange resin, it is preferable to use an aqueous alkali solution, for example, an aqueous NaOH solution in a trace amount of up to about 30 μl.
In the dehydration drying, it is preferable to use a small amount of a desiccant, for example, CaO, and to heat the heater as necessary.

[0013] Then, the anhydrous product obtained from the dehydration and drying process is obtained.
of¹³NH_ThreeIs NO as above_x ^-Ions and NH_Four ⁺
Non-radioactive nitrogen ion species such as ions
You. In addition, this anhydrous¹³NH_ThreeIs completely anhydrous
The water content is much lower than before,
Including those with high Such anhydrous¹³
NH_ThreeIs then dissolved in an organic solvent and
It will be used for reaction with quality. The organic solvent in this case
As a medium, hexane, cyclohexane, benzene, etc.
Hydrocarbons, ethers such as THF and diethyl ether
And the like are considered. These series of steps
Therefore, pollution from the environment can be suppressed.

After completion of the reaction, the product is purified and mixed with, for example, a physiological saline solution to prepare a physiological prescription agent. Such an apparatus for the method of the invention comprises:
The entire system is a closed system, and by arranging the detection means and the control means, an apparatus capable of automatic synthesis can be configured.

FIG. 1 is a configuration diagram showing an example of such a device configuration. Here, since ¹³ NH ₃ / He gas is used, it is important to reduce the loss of adsorption to the inner surface of the vessel or tube as well as to shorten the synthesis time. Therefore, miniaturization of the column, adoption of a 0.5 mm inner diameter tube, adoption of joints, filters, valves, etc. with a small dead volume are performed, and the quantity used is also reduced. As a whole, the volume and surface area in the passage are reduced, and the retention loss of gas and liquid is reduced. In addition, since ¹³ NH ₃ causes adsorption loss with a very small amount of water, drying is sufficiently performed.

[0016] Furthermore, by going online from the production of anhydrous ¹³ NH ₃ to the synthesis of labels, separation and purification, and the preparation process, by integrating the entire apparatus and making it computer-controllable,
Manufacturing time is being shortened. Further, the present apparatus can be connected almost directly to an existing commercially available ¹³ NH ₃ aqueous solution producing apparatus (titanium trichloride method, devarda alloy method, hydrogen method, ethanol method), and is versatile.

The manufacturing apparatus of the present invention having the above requirements realizes the following features. ¹³ NH ₃ aqueous solution produced by various methods (titanium trichloride method, Devarda alloy method, hydrogen method, etc.) can be used. ¹³ Starting from an aqueous NH ₃ solution, ¹³
An NH ₃ solution can be produced.

Various labeling synthesis reactions using an anhydrous ¹³ NH ₃ solution as a reaction precursor become possible. Until final drug becomes possible automatically produced in (injectable various ¹³ N-labeled drugs) within a short time. High specific activity is possible, PET (positron CT)
It can also be used for receptor research in Japan.

[0019] Thus, by high anhydrous degree ¹³ NH as a reaction precursor versatile ₃ solution preparation is established, is expected to spread further scope of applicability of the future. Then, by purely chemical practical scale of ¹³ N-labeled agent can be synthesized, conventional positron emitting nuclides ¹¹ C, ¹⁸ F, two ¹³
N-labeled drug can be added. Hereinafter, the present invention will be described in more detail with reference to Examples.

[0020]

As the examples, the device structure of FIG. 1, the conventional manufacturing acetylcholinesterase activity measurement which was difficult ^[13 N] NPC ⁽¹³ N-labeled p-nitrophenylcarbama
te) was synthesized. Fig. 2 shows ¹³ NH ₃ and p-nitrop
1 shows a reaction formula for synthesizing [ ¹³ N] NPC from henyl chloroformate. ^As an example, the ¹³ NH ₃ aqueous solution is produced by an existing Devarda's alloy method, and a cation ion exchange column (resin) (AG50W-
X8, 100-200 mesh, 、 30 mg) through He
Elution was performed with 30 μl of 1N NaOH in a gas flowing atmosphere. The eluted [ ¹³ N] ammonium
The mixture was dehydrated through an aO (0.5 g) column, and trapped in 1 ml of anhydrous THF containing p-nitrophenyl chloroformate (ca. ₂ mg) and 5 mg of Na ₂ CO ₃ at a temperature of -10 ° C. or lower. The reaction was performed at 50 ° C. for 1 minute. The reaction mixture was n-hexane / acetic acid (99 /
1) After dilution with 10 ml, the solution was passed through a SEP-PAK silica cartridge. After washing with a 7 ml solution of n-hexane / ethyl acetate / acetic acid (85/13/2), the mixture was eluted with 4 ml of ethyl acetate, placed in a flask, and evaporated to dryness at 60 ° C. under reduced pressure. It was dissolved in 5-10 ml of physiological saline and filtered through a sterile bottle with a 0.22 μm Millex filter to obtain a [ ¹³ N] NPC physiological saline solution. The radiochemical purity analyzed by Radio-HPLC was as shown in FIG. <1>products; ^[13 N] NPC ⁽¹³ N-labeled p-nitropheny
lcarbamate) in physiological saline (intravenous drug) Yield; 1.5 +/- 0.03 Radiochemical yield; 30.2 +/- 3.3% (total ¹³ N) 41% ( ¹³ NH) ₃ with respect to the aqueous solution) radiochemical purity; 98.9 +/- 0.1% specific activity; 62.9 +/- 2.4 GBg / μmol synthesis time; 9.5 +/- 0.5 minutes ( From the end of irradiation to the final product) ５5 minutes ( ¹³ NH ₃ aqueous solution or later) Water content: From the measurement results by the gravimetric method, the weight change was below the detection limit (several 100 μg or less). <2> dry [ ¹³ N] -NH ₃ yield; 62.2 +/- 2.8 water content; <1 synthesis time; 4.7 +/- 0.2 min

[0021]

As described above in detail, according to the present invention, it is possible to achieve a high specific activity by overcoming the limitation of ¹³ N as a conventional labeling agent by producing a ¹³ NH ₃ solution having a high degree of anhydrousness. , available in receptor research in PET, also enables the automatic synthesis of production of new variety ¹³ N labeling agent.

[Brief description of the drawings]

FIG. 1 is a configuration diagram showing an example of an apparatus configuration of the present invention.

FIG. 2 is a synthesis reaction diagram of an example of the present invention.

FIG. 3 is a diagram showing radiochemical purity in an example of the present invention.

Claims (5)

(57) [Claims] 1. Next step: a) cation ion exchange treatment of ¹³ NH ₃ aqueous solution and formation of anhydrous ¹³ NH ₃ by dehydration drying b) dissolution of anhydrous ¹³ NH _{3 in} an organic solvent or an organic solvent containing a reaction substrate ^A method for producing a ¹³ N-labeled compound corresponding to high specific activity, characterized by a ¹³ N-labeling reaction. 2. The method according to claim 1, wherein alkaline leaching is performed in the cation ion exchange treatment. 3. A method according to claim 1, ¹³ manufacturing method of N-labeled compound was purified ¹³ N-labeled compound characterized in that the physiological formulation. 4. The following process section: a) a cation ion exchange treatment section of ¹³ NH ₃ aqueous solution and a dehydration drying section; b) a step of dissolving anhydrous ¹³ NH _{3 in} an organic solvent and having a reaction section with a reaction substrate. Characteristic high specific activity type ¹³
An apparatus for producing an N-labeled compound. 5. The manufacturing apparatus according to claim 4, wherein said apparatus is provided with a detecting means and a control means and capable of automatic synthesis.