JP4238353B2 - [11C] Method for producing CH3X - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing [ ¹¹ C] CH ₃ X and [ ¹¹ C] -labeled drugs.
[0002]
[Prior art]
In the fields of medicine, pharmacy, biochemistry, etc., PET (positron tomography diagnostic method) is useful as a means for obtaining quantitative physiological images of biological functions. ^This is because positron emitting nuclides such as ¹¹ C, ¹³ N, and ¹⁵ O can be introduced into biologically active tracers without affecting their chemical behavior. Of positron emitting nuclides used in PET, the labeling of the labeled compounds by ¹¹ C is usually used ¹¹ C methyl iodide as a labeling agent, ¹¹ since the half-life of C is a short 20.4 minutes, necessary Therefore, it is necessary to synthesize quickly at the site of use.
[0003]
Conventional, ^[11 C] labeled agents, for example, ^[11 C] CH ₃ as the starting material ^[11 C] CO ₂ in I synthesis was produced by the reaction of LiAlH ₄ / THF and HI ^[11 C] CH ₃ I Is most commonly obtained as a reaction intermediate (for example, Non-Patent Document 1). In this method, [ ¹¹ C] CH ₃ I can be stably obtained with high yield, but the difficulty is that preparation work is difficult, high specific activity is difficult to obtain, and it is not suitable for repeated production. It is a thing. On the other hand, the method of producing [ ¹¹ C] CH ₃ I directly from the reaction with I ₂ using [ ¹¹ C] CH ₄ as a starting material reduces the yield by about half, but is suitable for repeated production. In addition, there are advantages such as being easy to prepare and being suitable for high specific activity (for example, Non-Patent Document 2). However, this process generally produces [ ¹¹ C] CO ₂ in the first stage, which is then converted to [ ¹¹ C] CH ₄ by a catalyst, which is combined with I ₂ vapor in a quartz reaction tube. In which [ ¹¹ C] CH ₃ I is produced, collected and used. The difficulty of this method is that contamination with [ ¹¹ C] CO ₂ is unavoidable, and I ₂ vapor is circulated at a relatively high temperature, so that it is necessary to exchange I ₂ in 7 to 8 times. This is because I ₂ is easily clogged in the path. Furthermore, it takes time for operations such as circulation, and [ ¹¹ C] CH ₄ is easily attenuated and lost.
[0004]
On the other hand, a single-pass method that does not circulate has also been proposed, and this method automatically eliminates the above-mentioned difficulties associated with circulation, but naturally the yield decreases (Non-patent Document 3).
[0005]
Furthermore, a method for producing ¹¹ CH ₄ directly in the target by mixing hydrogen with the target gas is also known, and a method for producing ¹¹ CH ₃ I by combining this method with the single pass I ₂ method has also been studied. However, a specific method for achieving high specific activity has not been known (Non-patent Document 4).
[0006]
[Non-Patent Document 1]
Suzuki K. et al., Computer Controlled Large Scale Production of High Specific activity [ ¹¹ C] Ro15-1788 for PET Studies of Benzodiazepine Receptors. Int. J. Appl. Radiat. Isot. 36, 971-976, 1985
[Non-Patent Document 2]
Larsen P., et al., Synthesis of [ ¹¹ C] Iodomethan by Iodination of [ ¹¹ C] Methan. Appl. Radiat. Isot. 48, 153-157, 1997.
[Non-Patent Document 3]
Link MJ et al., Production of [ ¹¹ C] CH ₃ I by single Pass Re action of [ ¹¹ C] CH ₄ with I2. Nucl. Med. & Biol. 24, 93-97, 1 997.
[Non-Patent Document 4]
Noguchi J., Mutoh M., Suzuki K. Optimization of the single Pass I2 Method for [ ¹¹ C] CH ₃ I Synthesis and its application to [ ¹¹ C] Ro15-4513 Synthesis. J. Labelled Cpd. Radiopharm. 44 ( sup pl.1), S995-S996, 2001.
[0007]
[Problems to be solved by the invention]
The present invention provides a method for producing ¹¹ CH ₃ I that overcomes the difficulties of the conventional methods described above, can be expected to achieve high specific activity, and can maintain a high yield.
[0008]
[Means for Solving the Problems]
In the present invention, ¹¹ C generated by irradiating protons to nitrogen gas containing hydrogen gas is directly converted into [ ¹¹ C] CH ₄ in an irradiation container, and then reacted with halogen gas in a reaction tube. In the method of generating [ ¹¹ C] CH ₃ X (X represents a halogen atom), the irradiation container is preliminarily irradiated with protons in advance to remove mixed non-radioactive carbon, and then the main irradiation is performed. and the ^[11 C] CH ₃ X and the halogen gas, the single-pass method which does not circulate the reaction tube, passing the reaction tube, and to provide the optimum conditions, and wherein the ^[11 C The production method of CH ₃ X is summarized.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
In the production method of ^[11 C] CH ₃ X of the present invention, directly into a ^[11 C] CH ₄ to ¹¹ C generated by irradiating the protons nitrogen gas containing hydrogen gas in the irradiation chamber, Next, in the method of reacting this with a halogen gas in a reaction tube to generate [ ¹¹ C] CH ₃ X (X represents a halogen atom), the irradiation container is preliminarily irradiated with protons and mixed. After removing the non-radioactive carbon, the main irradiation is performed, and the [ ¹¹ C] CH ₃ X and the halogen gas are allowed to pass through the reaction tube by a single pass method that does not circulate in the reaction tube. It is preferable that the preliminary irradiation is performed for a relatively short time at a current value that is equal to or higher than that of the main irradiation. The hydrogen gas concentration in the inert gas containing hydrogen gas is usually about 2 to 20%, preferably about 3 to 10%. The halogen is usually iodine or bromine. The irradiation container is preferably made of aluminum or an aluminum alloy, and more preferably a lathe machined without using a fluid containing carbon such as cutting oil. Further, the reaction tube comprises a halogen reaction tube portion and a main reaction tube portion, and the main reaction tube portion is preferably made of quartz. And the temperature in a halogen reaction tube part is room temperature-90 degreeC normally, Preferably it is 40-70 degreeC. On the other hand, the temperature in the main reaction tube is usually 500 to 850 ° C, preferably 580 to 700 ° C. The gas flow rate in the reaction system is usually 10 to 300 mL / min, preferably 30 to 150 mL / min.
[0010]
Preferred embodiments of the present invention will be further described.
1) Direct production of [ ¹¹ C] CH _{4 in} an irradiation container:
For example, N ₂ gas containing about 5% H _2, for example, when irradiated with protons having an energy of about 14 MeV, 90% approximately of the resulting ¹¹ C is produced as a direct ^[11 C] CH ₄ at irradiation vessel. By using this [ ¹¹ C] CH ₄ as a starting material for the labeling reaction, subsequent contamination with CO ₂ occluded in the atmosphere and in the reagent can be avoided. In addition, since it is not necessary to collect [ ¹¹ C] CO ₂ and convert it to [ ¹¹ C] CH ₄ with a reducing agent, the synthesis route is simplified, the risk of contamination can be avoided, and no time is required. Therefore, loss due to time decay of ¹¹ C can be prevented, which is advantageous for high specific activity.
2) Adoption of single-pass iodine method:
Thus, a pump for circulating the generated ^[11 C] CH ₃ I for collecting trap, ^[11 C] CH ₃ I detaching the heater, also valves, etc. associated with these unnecessary and apparatus is extremely simple Can be realized. Furthermore, the synthesis time can be shortened. As a result, as in 1), isotope dilution with non-radioactive carbon is reduced, and loss of ¹¹ C due to time decay is also reduced. Further, these simplifications enable the apparatus to be miniaturized, which is advantageous for installation in a narrow hot cell.
3) Optimization of reaction conditions:
When the single pass method is adopted, a decrease in yield is expected. In order to prevent this, the iodine column temperature, reaction temperature, and gas flow rate can be optimized to achieve a reaction yield close to that of a circulation method. This makes it possible to greatly simplify the synthesis route, shorten the synthesis time, and avoid isotope dilution.
4) Adoption of preliminary irradiation:
Before the main irradiation, the irradiation container was irradiated for a short time under actual conditions, non-radioactive carbon mixed in the irradiation container or on the surface was baked out, the product was discarded, and the gas was filled again. This operation was repeated several times to remove residual non-radioactive carbon. At this time, since short-lived nuclides such as ¹¹ C and ¹³ N are generated at a high concentration, the gas cannot be discharged to the outside as it is. Therefore, the radioactivity can be attenuated by discarding the generated gas through, for example, a collection tube filled with molecular sieves and an exhaust tank of about 100 L with a baffle plate inside. In this way, contamination of non-radioactive carbon in the irradiation container that would normally be mixed can be prevented.
5) Clean processing of irradiation container:
As the irradiation container material, for example, aluminum or an aluminum alloy, preferably A5056 is used. Usually, these materials are turned using cutting oil, but it is preferable not to use cutting oil in the present invention. This is to prevent a minute amount of remaining oil from being decomposed by irradiation and mixed into the system as non-radioactive carbon. Furthermore, it is preferable to use a metal seal without using a rubber O-ring or the like during assembly.
[0011]
An example of the synthetic system diagram of the present invention is shown in FIG.
[0012]
This FIG. 1 shows one example of a systematic diagram of the synthesis of [ ¹¹ C] CH ₃ I and the production of a [ ¹¹ C] -labeled compound.
[0013]
V1 to V12; solenoid valves (in particular, V1 and V2 are for high pressure), PG-1 to PG-2; pressure sensors, RG; pressure regulators, RI-1 to RI-2; radioactivity sensors, FM / FC; / Controller, 1; Irradiation vessel made of aluminum or aluminum alloy, 2; Iodine reaction part, filled with several grams of iodine crystals in a quartz tube and sandwiched between front and back by quartz wool. The surroundings are surrounded by an electric furnace 1 and the temperature can be adjusted. 3. Quartz main reaction tube section; a quartz empty column surrounded by an electric furnace 2 so that the temperature can be adjusted to 800 ° C .;
[0014]
High purity nitrogen gas containing 5% hydrogen is filled in the irradiation container until V1 is opened and PG-1 reaches 15 atm, and V1 is closed. Irradiate with 18 MeV proton 20 μA for about 30 minutes, and let the irradiation gas flow through V2, V3, V5, V6 and V7. At this time, [ ¹¹ C] CH ₄ produced by the ¹⁴ N (p, α) ¹¹ C reaction is collected in a Porapak Q ™ trap at the liquid Ar temperature in the irradiation container. After the completion of collection, He gas is supplied at a predetermined flow rate via V4, V5, V6, reaction tubes, V8, V9, V10, and V11 to a reaction tube that is maintained at a predetermined temperature while heating the trap except for the liquid Ar. Then, [ ¹¹ C] CH ₄ is converted to [ ¹¹ C] CH ₃ I and collected in a reaction vessel. At this time, impurities are removed by Ascarite (trademark) at the outlet of the reaction tube and Ascarite inserted in the middle. If the reaction vessel is pre-filled with a solvent containing the reaction substrate and cooled with cold air, the collection efficiency of [ ¹¹ C] CH ₃ I will be improved and the time will be shortened, which is effective in improving the yield. It is. After completion of the reaction, the reaction mixture is sent to HPLC (High Performance Liquid Chromatograph), purified, and subjected to a dispensing treatment, and then becomes a drug.
[0015]
As shown in FIG. 1, the irradiation container (1) is preliminarily filled with nitrogen gas containing 5% hydrogen gas at about 15 atm, irradiated with 18 MeV protons accelerated by a cyclotron at about 20 μA for several minutes, and then exhausted. This procedure is repeated 2-3 times. Thereafter, the main irradiation is performed for about 30 minutes under the same conditions. As a result, ¹¹ C was produced by the ¹⁴ N (p, α) ¹¹ C reaction in the irradiation container (1) and simultaneously converted to [ ¹¹ C] CH ₄ . After irradiation completion, was collected ^[11 C] CH ₄ by passing immediately ^[11 C] Porapak-Q (TM) trap cooled to CH ₄ in liquid argon with the target gas. [ ¹¹ C] CH ₄ produced in the irradiation container (1) is collected in Porapak Q (trademark) cooled with liquid argon, and other gases are exhausted via a waste line. Confirm the end of collection with RI-1 and remove liquid argon. He gas is flowed through the Porapak Q column while controlling it preferably at 50 mL / min with a mass flow controller / monitor (FM / FC in the figure), and [ ¹¹ C] CH ₄ is supplied to the reaction tube (iodine reaction tube part (2), quartz) Transport to main reaction column (3)). When passing through the iodine reaction tube part (2) filled with iodine (2) (50 ° C) and the main reaction tube part made of quartz (3) (630 ° C) not filled with anything, [ ¹¹ C] CH ₄ becomes [ ¹¹ C ] Converted to CH ₃ I and collected in a cooled container such as by spraying solid carbon dioxide (“dry ice”) or liquid nitrogen. At this time, iodine introduced in the vicinity of the reaction tube outlet and in the purification tube inserted in the middle is removed. At this time, it is preferable to fill Ascalite (trademark) (sodium hydroxide-based carbon dioxide absorbent), since the efficiency is further improved. Further, after removing the iodine, [ ¹¹ C] CH ₃ I is collected in a solvent previously placed in the reaction vessel. At this time, a reaction substrate is put in the solvent in advance, and a predetermined reaction is performed. Then, various ¹¹ C-labeled drugs can be obtained by separation and purification using a high performance liquid chromatograph (HPLC) or the like, and by applying a dispensing treatment.
[0016]
According to the method of the present invention, the direct production of [ ¹¹ C] CH ₄ in the irradiation container can provide a very high yield of about 98% at a weak current value of about several μA. The yield gradually decreased and decreased to about 90% at 20 μA (about), but the yield is practically sufficient.
[0017]
On the other hand, with respect to the conversion from [ ¹¹ C] CH ₄ to [ ¹¹ C] CH ₃ I, the iodine reaction tube temperature, the quartz main reaction tube temperature, and the He gas flow rate were optimized. In order to obtain the optimum conditions for conversion from [ ¹¹ C] CH ₄ to [ ¹¹ C] CH ₃ I, an experiment was conducted using iodine reaction tube temperature, main reaction tube temperature, and He gas flow rate as parameters.
[0018]
(A) Influence of iodine reaction tube temperature: The main reaction tube temperature was fixed at 660 ° C., the He gas flow rate was fixed at 50 mL / min, the iodine reaction tube temperature was changed from 40 ° C. to 70 ° C., and the change in yield was measured. As a result, the maximum yield was obtained at 50 ° C. Further, it was speculated that [ ¹¹ C] CH ₃ I would be produced even though the yield decreased even if the iodine reaction tube temperature was outside the measurement range temperature of this time.
[0019]
(B) Effect of main reaction tube temperature: The iodine reaction tube temperature was fixed at 50 ° C., the He gas flow rate was fixed at 50 mL / min, the main reaction tube temperature was changed from 580 ° C. to 700 ° C., and [ ¹¹ C] CH ₃ I The effect on the yield was investigated. As a result, the maximum yield was obtained at 630 ° C. It was also speculated that [ ¹¹ C] CH ₃ I would be produced even though the yield decreased even when the main reaction tube temperature was outside the current measurement range temperature.
[0020]
(C) Effect of He gas flow rate: The iodine reaction tube temperature was fixed at 50 ° C., the main reaction tube temperature was fixed at 630 ° C., the He gas flow rate was changed from 30 to 100 mL / min, and the yield of [ ¹¹ C] CH ₃ I The effect on rate was investigated. As a result, the maximum yield was obtained at 50 mL / min. Further, it was speculated that [ ¹¹ C] CH ₃ I would be produced even though the yield decreased even when the He gas flow rate was outside the current measurement range flow rate.
[0021]
The result is shown in FIG. In FIG. 2, that is, when the iodine reaction tube temperature is 50 ° C., the quartz main reaction tube temperature is 630 ° C., and the He gas flow rate is 50 mL / min, [ ¹¹ C] CH _{4 is} converted to [ ¹¹ C] CH ₃ I. The conversion yield reached the highest 43%.
[0022]
Using [ ¹¹ C] CH ₃ I synthesized in this way, [ ¹¹ C] Ro15-4513, which is a partial inverse antagonist of benzodiazepine receptor, is used as a specific activity 127 +/− 69 Ci / μmol, A yield of 41 +/- 13 mCi at the end of the synthesis could be obtained. This level was about 10 times higher than the conventional highest level in specific activity, and the yield was about 1/2 to 1/3. Although the yield was small, it was sufficient for two PET examinations.
[0023]
【The invention's effect】
According to the present invention, it is possible to provide a production method capable of stably producing high specific activity [ ¹¹ C] CH ₃ I and the like stably at a relatively high yield and, for example, 30 times or more in the same set. Therefore, in vivo behavior of ultra-high physiologically active substances that express a strong physiological activity in a very small amount, such as quantification of neuroreceptors that are present in a very small amount in the brain, such as extremely low concentration regions that have been unexplored in the past It is expected to contribute to the development of research. This is expected to be applied not only to the fields of medicine and physiology, but also to general areas that require ultrasensitive measurement and require noninvasive external measurement.
[Brief description of the drawings]
FIG. 1 shows an example of a synthetic system diagram of the present invention.
FIG. 2 shows the results of reactions performed under various conditions in order to optimize the reaction conditions.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 ... Irradiation container 2 ... Iodine reaction tube part 3 ... Quartz main reaction tube part

Claims (12)

¹¹ C produced by irradiating protons to nitrogen gas containing hydrogen gas is directly converted into [ ¹¹ C] CH ₄ in the irradiation container, and then reacted with halogen gas in a reaction tube to produce [ ¹¹ C]. a method of CH ₃ X (X is a halogen atom) to produce, and pre-irradiation in advance by protons the irradiation vessel, that the main irradiation after removing the non-radioactive carbon are mixed, and the ^[11 A method for producing [ ¹¹ C] CH ₃ X, wherein C] CH ₃ X and the halogen gas are allowed to pass through the reaction tube by a single pass method in which the gas is not circulated in the reaction tube. 2. The production method according to claim 1, wherein the preliminary irradiation is performed at a current value that is equal to or greater than that of the main irradiation. The method according to claim 1 or 2, wherein the hydrogen gas concentration in the nitrogen gas containing hydrogen gas is 2 to 20%. The production method according to claim 1, wherein the halogen is iodine or bromine. The manufacturing method according to claim 1, wherein the irradiation container is made of aluminum or an aluminum alloy. The manufacturing method according to claim 1, wherein the irradiation container is turned without using cutting oil. The production method according to any one of claims 1 to 6, wherein the reaction tube comprises a halogen reaction tube portion and a main reaction tube portion. The production method according to claim 7, wherein the main reaction tube portion is made of quartz. The process according to claim 7, wherein the temperature of the halogen reaction tube part is from room temperature to 90 ° C. The production method according to claim 7, wherein the temperature of the main reaction tube portion is 500 to 850 ° C. The gas flow rate in a reaction system is 10-300 mL / min, The manufacturing method in any one of Claims 1-10 Manufacturing method of ^[11 C] labeled agents, characterized in that the production of ^[11 C] labeled agents using ^[11 C] CH ₃ X obtained by the production method according to any one of claims 1 to 11.

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