JP7424574B2 - Method for producing a radioactive fluorine-labeled compound and method for producing a radiopharmaceutical composition - Google Patents

Description

The present invention relates to a method for producing a radioactive fluorine-labeled compound and a method for producing a radiopharmaceutical composition.

Positron emission tomography (hereinafter also referred to as "PET") is a method in which a compound labeled with a radionuclide that emits positrons is administered to a living body as a drug, and the specific distribution of the drug is determined by radioactivity concentration. By imaging the distribution, information regarding the physiological functions of the living body can be obtained. In this method, for example, fluorine-18 ([ ¹⁸ F], half-life: 109.8 min) is used as a radionuclide.

As a method for producing radioactive fluorine ([ ¹⁸ F])-labeled compounds, the production method described in Non-Patent Document 1 is generally performed. The document describes a purification step in which [ ¹⁸ F]fluoride ions supported on an anion exchange resin are eluted using an eluent containing a protic solvent, and a first solvent for removing the protic solvent in the eluate. a removal step, a fluorination step in which a labeled precursor compound solution is added to a container containing [ ¹⁸ F]fluoride ions and a [ ¹⁸ F] fluorination reaction is carried out in a closed system, and a solvent is removed after the fluorination reaction. It is described that the method includes a second solvent removal step, and each step is performed as a separate step.

Further, Patent Documents 1 and 2 and Non-Patent Document 2 describe a manufacturing method in which the first solvent removal step is not performed for the purpose of shortening the manufacturing time of a radioactive fluorine-labeled compound.

International Publication No. 2009/003251 pamphlet Special table 2013-529186 publication

K. Hamacher et al., J. Nucl. Med. , 1986, Volume 27, No. 2, p. 235-238 Kim HW et al., Appl. Radiat. Isot. , 2004, Volume 61, p. 1241-1246

Since radioactive fluorine has a short half-life, it is desired to further shorten the production time in order to improve the yield of the target labeled compound. The production methods described in Patent Documents 1 and 2 and Non-Patent Document 2 described above were able to shorten the production time of the labeled compound, but depending on the type of labeling precursor compound used, [ ¹⁸ F]fluorine In some cases, the conversion rate was significantly lowered, and as a result, the yield was significantly lower than in the conventional method.

Therefore, an object of the present invention is to provide a method for producing a radioactive fluorine-labeled compound that can achieve a [ ¹⁸ F] fluorination rate equivalent to or higher than that of conventional methods while reducing production time.

The present invention comprises a radiofluorination step in which a radioactive fluoride ion and a labeled precursor compound are reacted in the presence of a solvent,
The present invention provides a method for producing a radioactive fluorine-labeled compound, in which the radioactive fluorination step is performed while the solvent is evaporated.

The present invention also provides a method for producing a radioactive fluorine-labeled compound by the method for producing a radioactive fluorine-labeled compound, and then preparing a radiopharmaceutical composition containing the radioactive fluorine-labeled compound or a salt thereof as an active ingredient. A method for producing a composition is provided.

According to the present invention, a radioactive fluorine-labeled compound and a radioactive pharmaceutical composition containing the compound as an active ingredient can be produced in a shorter production time than the conventional method while achieving a [ ¹⁸ F]fluorination rate equivalent to or higher than that of the conventional method. can manufacture things.

FIG. 1 is a graph showing the results of Example 1 and Comparative Examples 1 and 2.

Hereinafter, the method for producing a radioactive fluorine-labeled compound of the present invention will be explained based on its preferred embodiment. In the following description, "radioactive fluorine" refers to a radioactive isotope of fluorine, and specifically refers to fluorine-18 (hereinafter also referred to as [ ¹⁸ F]).

The production method of the present invention includes a radiofluorination step in which a radioactive fluoride ion and a labeled precursor compound are reacted in the presence of a solvent. In this step, as long as the radioactive fluoride ion and the labeled precursor compound can react, the order of their addition is not important, and either one may be added to the other and reacted in the presence of a solvent. They may be mixed simultaneously and reacted in the presence of a solvent.

First, radioactive fluorine ([ ¹⁸ F]) is generated in order to obtain radioactive fluoride ions used in the radioactive fluorination step. Known methods can be used to generate radioactive fluorine, such as irradiating neon gas with deuterons accelerated by a cyclotron, or irradiating protons accelerated by a cyclotron with [ ¹⁸ O] water (H ₂ ¹⁸ O). ). Among these, from the viewpoint of efficiently obtaining radioactive fluoride ions having high specific radioactivity, it is preferable to employ a method of irradiating [ ¹⁸ O] water with protons. In the following explanation, a method using [ ¹⁸ O] water will be exemplified.

Next, the [ ¹⁸ O] aqueous solution containing radioactive fluorine produced by the above method is purified to obtain radioactive fluoride ions ([ ¹⁸ F] ions). This [ ¹⁸ O] aqueous solution contains the generated radioactive fluorine in the form of radioactive fluoride ions, so by separating the ions, the radioactive fluoride ions and [ ¹⁸ O] water are separated. Can be easily separated.

Radioactive fluoride ions were separated from [ ¹⁸ O] water using an anion exchange column in order to shorten the purification time and make it easier to carry the purified radioactive fluoride ions into the next step. It is preferable. As the anion exchange column, a known column such as a column comprising a resin having a basic functional group such as a quaternary ammonium group can be used.

A method for purifying radioactive fluoride ions using an anion exchange column is, for example, as follows. That is, an [ ¹⁸ O] aqueous solution containing radioactive fluoride ions is passed through an anion exchange column, and the radioactive fluoride ions are retained in the resin within the column (retention step). Thereafter, an eluent for eluting radioactive fluoride ions from the column is passed through the column to elute the retained radioactive fluoride ions from the column (elution step), and the eluate containing radioactive fluoride ions is (Hereinafter, this is also simply referred to as a [ ¹⁸ F] ion eluate.)

The eluent is not particularly limited as long as it has a composition that can elute radioactive fluoride ions and carry it into the next step. For example, a protic solvent may be used alone or in combination, and a protic solvent and a protic solvent may be used. A mixed solvent with an aprotic solvent may also be used. From the viewpoint of improving the elution properties of radioactive fluoride ions, the eluent preferably contains a base such as a carbonate or hydrogen carbonate of an alkali metal and quaternary ammonium. Examples of the alkali metal carbonate or hydrogen carbonate include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and the like. Examples of quaternary ammonium carbonates or hydrogencarbonates include tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, tetrapentylammonium, and tetrahexylammonium, which have a carbon number of 1 or more and 6 or less, and Straight-chain or branched tetraalkylammonium carbonates or hydrogen carbonates may be mentioned. The eluent may contain a labeled precursor compound. Details of the protic solvent and the aprotic solvent will be described later.

Next, the radioactive fluoride ion and the labeled precursor compound are reacted in the presence of a solvent to perform a radiofluorination reaction ([ ¹⁸ F] reaction) (radiofluorination step). As a method for starting the reaction, for example, after concentrating the eluate containing radioactive fluoride ions contained in a reaction container, a solution or dispersion of the labeled precursor compound is added and reacted (hereinafter, this is referred to as " (also referred to as "Method 1"), or a method in which a solid labeled precursor compound is stored in advance in a reaction container such as a vial or tube, and an eluate containing radioactive fluoride ions is added thereto and reacted (hereinafter referred to as "Method 1"). (This is also referred to as "Method 2." 3), elute radioactive fluoride ions from an anion exchange column using an eluent containing a labeled precursor compound, and then elute the eluate containing the obtained radioactive fluoride ions and labeled precursor compound. Examples include a method of accommodating and reacting in a reaction container (hereinafter also referred to as "Method 4"). Among these, it is preferable to employ the method 2, the method 3, and the method 4 because the radiofluorination reaction can be carried out in a shorter time and the operability is simple, especially the method 2. It is even more preferable to employ method 4, since the configuration of the synthesis apparatus can be simplified.

In the case of method 1, the solvent used in the solution or dispersion becomes the solvent in this step. In the case of Method 2 and Method 4, the solvent used in the eluent becomes the solvent in this step. In the case of method 3, a mixed solvent of the solvent used for the eluent and the solvent used for the solution or dispersion is the solvent in this step. In addition to these solvents, a protic solvent and an aprotic solvent may be further added to serve as the solvent in this step.

The radioactive fluorination step described above is carried out while evaporating the solvent present in the reaction system. By carrying out the reaction under such conditions, the radiofluorination reaction can be carried out in a short time and the reaction product can be obtained in high yield. In the present invention, it is particularly preferable to promote evaporation of the solvent. Examples of means for promoting transpiration include heating the reaction system, reducing the pressure of the reaction system, bubbling gas into the reaction system, and blowing gas onto the surface of the reaction liquid. In this specification, transpiration refers to vaporizing the solvent and removing it from the reaction system.

The present inventor believes that the reaction can be achieved in a short time and in high yield by performing the radioactive fluorination reaction while evaporating the solvent as follows. The radiofluorination reaction proceeds due to the nucleophilicity of radiofluoride ions. Generally, an eluate containing a protic solvent is used to elute radioactive fluoride ions, so if the eluate is mixed into the solvent in the radiofluoridation process, the radioactive fluoride ions and the protic solvent may be mixed together. The nucleophilicity of the radioactive fluoride ion decreases due to competition between the two, making it difficult for the desired radiofluorination reaction to proceed. In order to prevent such problems, for example, in the method described in Non-Patent Document 1, in order to reduce the amount of protic solvent present in the radiofluorination reaction system, the protic solvent used for elution of radioactive fluoride ions is It is removed in advance and then a radiofluorination reaction is performed. However, with the method described in Non-Patent Document 1, it is not easy to shorten production time or achieve high yield.

In this regard, in the production method of the present invention, by performing the process while evaporating the solvent, the radiofluorination reaction can proceed even when a protic solvent is present in the reaction system or the amount of solvent is large. . This method is particularly suitable when the eluate containing the protic solvent is used as it is in the radiofluorination reaction, as in Method 2 and Method 3. At the initial stage of the reaction in the production method of the present invention, radioactive fluoride ions are almost uniformly dispersed in the solvent due to the protic solvent in the solvent. As the solvent evaporates in this state, the concentration of the protic solvent in the solvent decreases, and accordingly, the reaction rate of the nucleophilic reaction by radioactive fluoride ions increases, and the reaction progresses. In the latter stage of the reaction, concentration occurs as the amount of solvent present in the reaction system decreases, and the molar concentrations of radioactive fluoride ions and labeled precursor compounds increase. As a result, the reaction rate of the nucleophilic reaction by radioactive fluoride ions further increases, and the radioactive fluorination reaction progresses further. Therefore, according to the production method of the present invention, unlike conventional methods, there is no need to perform the solvent removal step and the radiofluorination reaction step separately, and these steps can be integrated and performed at once. , the manufacturing process can be simplified. As a result, the production time of the radioactive fluorine-labeled compound can be shortened and a high yield can be achieved. Furthermore, due to the reduction in manufacturing time, there is also the advantage that the exposure of workers can be reduced.

From the viewpoint of increasing the dispersibility of the radioactive fluoride ion and the labeled precursor compound in the solvent and allowing the radiofluorination reaction to proceed efficiently, the solvent in the radiofluorination step should be a protic solvent and an aprotic solvent. It is preferable to include. Examples of the protic solvent used in the present invention include water, methanol, and ethanol. Examples of the aprotic solvent used in the present invention include dimethylformamide, acetonitrile (MeCN), tetrahydrofuran, dimethyl sulfoxide, and ethyl acetate.

From the viewpoint of increasing the evaporation efficiency of the solvent and increasing the reaction rate of the radiofluorination reaction, when the solvent contains a protic solvent and an aprotic solvent, it is preferable that the solvent has a composition having an azeotropic point. That is, the solvent is preferably an azeotrope. Examples of such solvent combinations include water and acetonitrile, water and ethyl acetate, methanol and acetonitrile, methanol and ethyl acetate, methanol and tetrahydrofuran, ethanol and acetonitrile, ethanol and ethyl acetate, and the like.

From the viewpoint of facilitating the progress of the radiofluorination reaction while maintaining the dispersibility of the radioactive fluoride ion and the labeled precursor compound in the solvent, the content of the protic solvent in the solvent should be adjusted to the total volume of the solvent. It is preferably 30% by volume or less, more preferably 20% by volume or less, even more preferably 15% by volume or less, even more preferably 10% by volume or less. Note that the above-mentioned content of the protic solvent in the solvent refers to the content in the solvent at the start of the reaction.

In particular, in addition to the above-mentioned advantages, from the viewpoint of ease of handling in this process, the solvent in the radiofluorination process is a mixed solvent of water and acetonitrile as a combination of a protic solvent and an aprotic solvent. It is more preferable that In this case, the content of water in the solvent is preferably 30% by volume or less, more preferably 20% by volume or less, and preferably 15% by volume or less, based on the total volume of the solvent. More preferably, it is 10% by volume or less.

From the viewpoint of promoting the radiofluorination reaction, in the radiofluorination step, the radioactive fluoride ion, the labeled precursor compound, and a solvent are placed in a reaction container, and the radioactive fluoride ion and the labeled precursor compound are allowed to react. It is preferable that the evaporation of the solvent is promoted in a state where the evaporation is carried out, and the evaporated solvent can be flowed out of the reaction vessel or discharged, and it is more preferable to carry out a combination of these methods. By having such a configuration, the vapor-liquid equilibrium of the solvent can be tilted toward the gas side, and as a result, the concentration efficiency of the solvent can be further increased and the radioactive fluorination reaction can be promoted.

As a method for causing the evaporated gaseous solvent to flow out of the reaction vessel, it is preferable to react the radioactive fluoride ion and the labeled precursor compound in an open system. An open system refers to a non-sealed state in which the vaporized solvent can flow out of the reaction vessel. Specifically, the opening of the reaction vessel is not covered with a member such as a lid or a film, or the opening of the reaction vessel is covered with a member with a through hole that allows gas to flow inside and outside the reaction vessel. It can be in a state where With this configuration, it is possible to suppress an excessive increase in the internal pressure of the reaction vessel during the radiofluorination process, and as a result, it is possible to suppress damage to the reaction vessel and the scattering of radioactive substances caused by this. Can be done. Furthermore, the radioactive fluorination reaction can be carried out without considering the pressure resistance of the reaction vessel.

As a method for discharging the evaporated gaseous solvent out of the reaction container, a gas is introduced into the reaction container, or the radioactive fluoride ion and the labeled precursor compound are allowed to react with each other under reduced pressure inside the reaction container. is preferred. Specifically, the manner in which gas is introduced into the reaction container is to supply gas to the reaction container using a cylinder or pump to cause the solvent in the reaction container to bubble, or to increase the liquid level of the solvent in the reaction container. You can also spray gas onto the surface. Further, as a mode for reducing the pressure inside the reaction container, a suction pump and the reaction container may be connected to reduce the pressure inside the reaction container, and the gaseous solvent can be discharged to the outside of the reaction container. Examples of the gas to be introduced include active gases such as air, and inert gases such as nitrogen and argon.

From the viewpoint of accelerating evaporation of the solvent, it is preferable to perform the radioactive fluorination step by heating. The heating temperature in this step can be changed as appropriate depending on the total liquid amount and composition of the solvent, but is preferably at least the azeotropic point or boiling point of the solvent, more preferably at least 100°C. The upper limit of the heating temperature may be any temperature at which the labeled precursor compound does not decompose, and is preferably, for example, 150°C or lower, more preferably 120°C or lower. Similarly, the heating time in this step may be at least until it can be visually confirmed that all the solvent in the reaction vessel has evaporated. For example, assuming the above heating temperature, the heating time is 3 minutes or more and 20 minutes. It can be set to less than 1 minute (min).

In addition, from the viewpoint of promoting the release of radioactive fluoride ions in the solvent and obtaining a radioactive fluorine-labeled compound in high yield, this step is carried out in the presence of a base such as the above-mentioned potassium carbonate and potassium hydrogen carbonate. Preferably, in the presence of various phase transfer catalysts such as 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane (trade name: Kryptofix 222). It is also preferable to do so. From the same viewpoint, the molar ratio of the labeled precursor compound to the base in the reaction solution is expressed as the ratio of the number of moles of the labeled precursor compound (P) to the number of moles of the base (B) (P/B ratio). , is preferably 1.0 or more, more preferably 1.5 or more, and even more preferably 2.0 or more.

The amount of reaction liquid at the start of the radiofluorination step is not particularly limited, but from the viewpoint of practicality in the manufacturing process, it is realistically 1 μL or more and 5 mL or less. From the same viewpoint, at the start of the radiofluorination step, it is realistic that the concentration of the labeled precursor compound per mL of solvent is 0.1 μmol/mL or more and 100 μmol/mL or less. According to the method of the present invention, the volume of reaction liquid can be reduced during the radiofluorination step by evaporation of the solvent in the reaction vessel, and the molar concentration of the labeled precursor compound can be increased accordingly. Therefore, the reaction rate of the radiofluorination reaction can be sufficiently increased even with the above-mentioned reaction solution volume and labeled precursor compound concentration. As a result, a radiofluorination reaction can be achieved in a short time and with high yield.

The radiofluorination step described above can be terminated when all the solvent in the reaction vessel has evaporated. In this way, a [ ¹⁸ F]-ized intermediate in which radioactive fluorine is introduced into a labeled precursor compound can be obtained. After this, if necessary, the same or different solvent as used previously may be further introduced into the reaction vessel and the radiofluorination reaction may be carried out again, and the [ ¹⁸ F] intermediate which is the reaction product A dispersion liquid may be prepared by adding a solvent which is dispersible and the same as or different from that used previously, and the dispersion liquid may be subjected to subsequent steps.

The [ ¹⁸ F] intermediate obtained by the radiofluorination step may be used as it is as a radiofluorine-labeled compound; alternatively, the protecting group in the [ ¹⁸ F] intermediate may be removed. By further performing a step (deprotection step), the desired radioactive fluorine-labeled compound can also be obtained. In the deprotection step, for example, an acidic aqueous solution such as hydrochloric acid or a basic aqueous solution containing sodium hydroxide or the like is added to a solution of the [ ¹⁸ F] intermediate and heated to perform hydrolysis.

In order to increase purity by removing unreacted radioactive fluorine, labeled precursor compounds, and precipitates, membrane filters, columns packed with various packing materials, and high performance liquid chromatography (HPLC) are used after the production process of radioactive fluorine labeled compounds. ) etc. to purify the product.

The labeling precursor compound used in the present invention can be used without particular limitations as long as it is a compound that can produce the desired radioactive fluorine labeled compound and is stable in proton solvents such as water. For example, various radioactive fluorine-labeled compounds ( [ ¹⁸ F]fluorodeoxyglucose ([ ¹⁸ F]FDG), O-(2-[ ¹⁸ F]fluoroethyl-L-tyrosine ([ ¹⁸ F]FET), 3'-deoxy-3'-[ ¹⁸ F] Fluorothymidine ([ ¹⁸ F]FLT), 16α-[ ¹⁸ F]fluoro-17β-estradiol ([ ¹⁸ F]FES), [ ¹⁸ F]AV-45, [ ¹⁸ F]fluoromisonidazole ([ ¹⁸ F] FMISO), [ ¹⁸ F]FRP-170, [ ¹⁸ F]fluoroazomycin arabinoside ([ ¹⁸ F]FAZA)) labeled precursor compounds, and anti- Labeled precursor compound of 1-amino-3-[ ¹⁸ F]fluorocyclobutane-1-carboxylic acid ([ ¹⁸ F]FACBC), labeled precursor of radioactive fluorine-labeled compound described in International Publication No. 2013/042668 pamphlet Compounds, labeled precursor compounds of radioactive fluorine-labeled compounds described in International Publication No. 2015/199205 pamphlet, radioactive fluorine-labeled compounds described in International Publication No. 2017/054907 pamphlet (for example, [ ¹⁸ F]PSMA-1007 ) labeled precursor compounds.

Specifically, if the target radioactive fluorine-labeled compound is [ ¹⁸ F]FMISO, 1-(2'-nitro-1'-imidazolyl)-2-O-tetrahydropropanyl-3 is used as the labeling precursor compound. -O-osyl-propanediol (NITTP) can be used. In addition, if the target radioactive fluorine-labeled compound is 1-(2,2-dihydroxymethyl-3-[ ¹⁸ F]fluoropropyl)-2-nitroimidazole ([ ¹⁸ F]DiFA), the labeled precursor compound 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane can be used as the dioxane. In addition, the target radioactive fluorine-labeled compound is 6-chloro-5-fluoro-1-(2-[ ¹⁸ F]fluoroethyl)-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl] In the case of benzimidazole ([ ¹⁸ F]CDP2230), 6-chloro-5-fluoro-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl]-1-[2- (p-Toluenesulfonyloxy)ethyl]benzimidazole can be used. In addition, if the target radioactive fluorine-labeled compound is [ ¹⁸ F]FLT, 5'-O-(4,4'-dimethoxytrityl)-2,3'-anhydrothymidine or 3 -N-Boc-5'-O-dimethoxytrityl-3'-O-nosyl-thymidine and 5'-O-(benzoyl)-2,3'-anhydrothymidine can be used.

The method for producing a radioactive fluorine-labeled compound described above may be performed manually, for example, or with a synthesis apparatus equipped with a reaction vessel. From the perspective of reducing radiation exposure, it is preferable to carry out this manufacturing method with a shield such as lead placed between the worker and the manufacturing site, and all processes are automated using an automatic synthesis device. It is also preferable to do as little work as possible.

The radioactive fluorine-labeled compound thus produced can also be used to prepare a radiopharmaceutical composition containing the compound as it is or a salt of the compound as an active ingredient. A radiopharmaceutical composition refers to a formulation containing a radioactive fluorine-labeled compound or a salt thereof in a form suitable for in vivo administration. A radiopharmaceutical composition is prepared by, for example, producing a radioactive fluorine-labeled compound by the method described above, and then mixing the obtained radioactive fluorine-labeled compound with the components to be incorporated into the target radiopharmaceutical composition. It can be manufactured by Components to be mixed include, for example, a solvent that is suitable for administration into a living body and can dissolve the radioactive fluorine-labeled compound, and other components described below. Examples of such solvents include solvents mainly composed of water.

The radiopharmaceutical composition may be administered orally or parenterally (e.g., intravenously, subcutaneously, intramuscularly, intrathecally, topically, rectally, transdermally, nasally or pulmonary). Can be done. Dosage forms for oral administration include, for example, tablets, capsules, pills, granules, fine granules, powders, solutions, syrups, suspensions, and the like. In addition, dosage forms for parenteral administration include, for example, aqueous injections, oil-based injections, suppositories, nasal preparations, and transdermal absorption preparations (lotions, emulsions, ointments, creams, and jellies). Forms include agents, gels, patches (tapes, transdermal patch preparations, poultices, etc.), external powders, etc. Among these, from the viewpoint of suppressing a decline in diagnostic ability due to attenuation of radioactivity, it is preferable to administer parenterally, and it is more preferable to administer in vivo by injection. In this case, the radiopharmaceutical composition is preferably in the form of an aqueous solution.

The radiopharmaceutical composition may contain other pharmaceutically acceptable components that do not react with the radioactive fluorine-labeled compound or its salt, as necessary. Other ingredients include, for example, pharmaceutically acceptable salts, excipients, binders, lubricants, stabilizers, disintegrants, buffers, solubilizers, isotonic agents, solubilizers, and pH adjusters. agents, surfactants, emulsifiers, suspending agents, dispersants, suspending agents, thickeners, viscosity modifiers, gelling agents, soothing agents, preservatives, plasticizers, transdermal absorption enhancers, anti-aging agents Other ingredients such as agents, humectants, preservatives, fragrances, etc. can be used. These other components can be used alone or in combination of two or more.

When using a radioactive fluorine-labeled compound as a radiopharmaceutical composition, the composition is further processed using a membrane filter, a column packed with various packing materials, HPLC, etc., in order to remove precipitates caused by the addition of other components. Purification is also preferred.

A radiopharmaceutical composition containing a radioactive fluorine-labeled compound or a salt thereof is introduced into an organism, and then the radiation emitted from the organism is detected using a radioactivity detector, a single photon tomography scanner, a positron emission tomography scanner, or a scintillator. The distribution of radiation can be visualized by non-invasively detecting it from outside the living body using a detection device such as a radiograph. In other words, a radiopharmaceutical composition containing a radioactive fluorine-labeled compound or a salt thereof can be used as an imaging diagnostic agent for nuclear medicine examinations such as single photon tomography and positron emission tomography, preferably for positron emission tomography. It can be used as an imaging diagnostic agent.

Specifically, when a radiopharmaceutical composition containing a radioactive fluorine-labeled compound or a salt thereof is introduced into an organism, it can exhibit diagnostic ability according to the specific accumulation ability of the compound. For example, in the case of a radiopharmaceutical composition containing [ ¹⁸ F]FMISO or [ ¹⁸ F]DiFA as a radioactive fluorine-labeled compound, these compounds accumulate in hypoxic tissues and lesions. Therefore, by using positron emission tomography (PET), this pharmaceutical composition can image the extent of hypoxic tissue and the degree of hypoxic state according to the distribution of detected radiation. can.

Furthermore, when a radiopharmaceutical composition containing [ ¹⁸ F]CDP2230 as a radioactive fluorine-labeled compound is used, the compound accumulates at the expression site of aldosterone synthase (CYP11B2). Therefore, this pharmaceutical composition can detect and diagnose aldosterone-producing tumors by using PET.

Furthermore, when a radiopharmaceutical composition containing [ ¹⁸ F]FLT as a radioactive fluorine-labeled compound is used, the compound accumulates in sites where DNA synthesis is active. Therefore, this pharmaceutical composition can detect and diagnose sites where DNA synthesis is active, such as cancer, by using PET.

Although the present invention has been described above based on its preferred embodiments, the present invention is not limited to the above-described embodiments. For example, elution of radioactive fluoride ions was performed with an eluate that did not contain a phase transfer catalyst and a labeled precursor compound, but instead, an eluate containing at least one of a phase transfer catalyst and a labeled precursor compound was used to The fluoride ions may be eluted from the anion exchange column, and the radioactive fluoride ions in the eluate may be reacted with the labeled precursor compound in a solvent. Even with this method, the effects of the present invention can be sufficiently achieved.

Hereinafter, the present invention will be explained in more detail with reference to Examples. However, the scope of the invention is not limited to such examples. In the table below, the "-" column indicates that it was not implemented or added.

<Experiment 1. Time-dependent change in yield of radiofluorination reaction>
[Example 1]
[ ¹⁸ O] water was irradiated with protons using a cyclotron to obtain [ ¹⁸ F] ion-containing [ ¹⁸ O] water (radioactivity amount: 1.6 GBq). Next, [ ¹⁸ O] water containing [ ¹⁸ F] ions was passed through an anion exchange column (Sep-Pak (registered trademark) Accell Plus QMA Carbonate Plus Light, manufactured by Nippon Waters Co., Ltd.) which had previously been made into a carbonate foam. [ ¹⁸ F] ions were adsorbed and collected on the column. Next, 0.5 mL of an aqueous solution containing 50% by volume of acetonitrile containing the potassium carbonate and Kryptofix 222 was passed through the column to elute [ ¹⁸ F] ions to obtain a [ ¹⁸ F] ion eluate.

0.02 mL (35.9-38.3 MBq) of the obtained [ ¹⁸ F] ion eluate was placed in a glass vial, and 0.02 mL (0.34 mg, equivalent to 0.8 μmol) of an acetonitrile solution of NITTP was added as a labeled precursor compound; ABX) and 0.96 mL of acetonitrile (water content 2.85%) were added to the eluate to make the total volume of the reaction solution 1 mL (water content 2.85 ^volume %). The reaction started. This reaction was conducted in an open system (non-sealed state) while introducing nitrogen into the reaction vessel by blowing nitrogen onto the surface of the reaction solution. The reaction time was 3, 4, 5, 6, 7, and 10 minutes, and the heating temperature was 100°C. Each of these reactions was performed independently three times. All other reaction conditions were as shown in Table 1 below.

After reacting for a predetermined time, the reaction vessel was immediately cooled with ice to stop the [ ¹⁸ F] conversion reaction. Then, 0.1 mL of an aqueous solution containing 50% by volume of acetonitrile was added. This solution was introduced into high performance liquid chromatography, and the abundance ratio of the [ ¹⁸ F] intermediate in the solution was analyzed under Condition 1 below.

(High performance liquid chromatography conditions 1)
Device: LC-20AD (manufactured by Shimadzu Corporation)
Detector 1 (ultraviolet-visible light (UV-vis) detection): SPD-20A (manufactured by Shimadzu Corporation), measurement wavelengths 210 nm and 325 nm
Detector 2 (gamma ray (RI) detection): RLC-700 (manufactured by Aloka)
Column: XBridge C18 (inner diameter 4.6 mm x length 150 mm, 5 μm; manufactured by Nippon Waters)
Column temperature: room temperature Eluent composition (mobile phase): 10mM ( _NH4 ) _2HPO4 and _MeCN
(From 0 to 1.5 min, 10 mM (NH ₄ ) ₂ HPO ₄ :MeCN = 88 volume %: constant at 12 volume %, and from 1.5 to 10 min, 10 mM (NH ₄ ) ₂ HPO ₄ and MeCN = 88 volume % %: 12 volume % to 30 volume %: 70 volume % gradient analysis.)
Eluent flow rate: 1.0mL/min
Injection volume: 10μL

The yield (%) of the [ ¹⁸ F]-formed intermediate is calculated as “100×[radioactivity (count) of [ ¹⁸ F]-formed intermediate]/[total detected radioactivity (count)]” for each reaction. Calculated for each hour. The yield of the [ ¹⁸ F] intermediate was calculated using a peak detected around 7.6 min with a gamma ray detector. These results are shown in FIG. 1 and Table 2 as the mean value±standard error (hereinafter also referred to as "mean±SE").

[Comparative example 1]
In this comparative example, the [ ¹⁸ F] conversion reaction was carried out under conditions where water was not present in the reaction system (non-aqueous conditions) and in a closed state. Specifically, in the same manner as in Example 1, an aqueous solution containing 50% by volume of acetonitrile containing potassium carbonate and Cryptofix 222 was passed through to obtain a [ ^18F ] ion eluate, which was then heated at 100°C under nitrogen gas introduction. The mixture was heated for 5 minutes to evaporate water to obtain a dry product containing [ ¹⁸ F]. Acetonitrile was added to this dried product (2 GBq) to form a solution of the [ ¹⁸ F]-containing dried product. To 20 μL (16.1 to 19.9 MBq) of the dissolved [ ¹⁸ F]-containing solution (water content 0 volume %), 20 μL (water content 0 volume %) of an acetonitrile solution containing NITTP (0.34 mg) and 960 μL acetonitrile ( The total volume of the reaction solution was 1 mL (water content: 0 volume %), and the [ ¹⁸ F] conversion reaction was started. This reaction was conducted in a closed state. The reaction times were 3, 5, 7, and 10 minutes, and each of these reactions was performed independently three times. All other reaction conditions were as shown in Table 1 below.

After the reaction, the reaction was stopped in the same manner as in Example 1, and the reaction solution was introduced into high performance liquid chromatography under the above conditions, and the proportion of the [ ¹⁸ F] conversion intermediate in the solution was analyzed to determine the yield. Calculated. These results are shown in FIG. 1 and Table 2 as mean ± standard error.

[Comparative example 2]
In this comparative example, the [ ¹⁸ F] conversion reaction was carried out under conditions where water was present in the reaction system (hydrous conditions) and in a closed state. Specifically, a [ ¹⁸ F] ion eluate was obtained in the same manner as in the example. Next, 20 μL (28.3 to 34.5 MBq) of [ ¹⁸ F] ion eluate and 20 μL (water content 0 volume %) of an acetonitrile solution containing NITTP (0.34 mg) and 960 μL (water content 0 volume %) of acetonitrile were added. Then, the total volume of the reaction solution was set to 1 mL (water content: 2.85% by volume), and the [ ¹⁸ F] conversion reaction was started. This reaction was conducted in a closed state. The reaction time was 10 minutes, and each reaction was carried out three times. Other reaction conditions were as shown in Table 1 below. The results are shown in FIG. 1 and Table 2 as mean value±standard error.

As shown in FIG. 1 and Table 2, the [ ¹⁸ F] conversion reaction in Example 1, which was carried out under aqueous conditions and in an open system, was faster after 6 minutes than in Comparative Example 1, which was carried out under non-aqueous conditions and in a closed system. It can be seen that equivalent yields can be achieved with It can also be seen that the [ ¹⁸ F] conversion reaction in Comparative Example 2, which was carried out under water-containing conditions and in a closed state, did not proceed at all, and no [ ¹⁸ F] conversion intermediate was obtained.

In particular, as shown in FIG. 1, when comparing the reaction rate in 3 to 6 minutes in Example 1 and the reaction rate in 3 to 5 minutes in Comparative Example 1, the reaction rate in Example 1 was 32.5%/min. , 20.0%/min. Therefore, in Example 1, an increase in the reaction rate due to the evaporation of the solvent can be observed compared to Comparative Example 1, and it can also be seen that the reaction rate is about 1.6 times higher.

<Experiment 2. Change in yield of fluorination reaction due to difference in water content>
[Example 2]
In this example, the total liquid volume in the [ ^18F ] conversion reaction was 40 μL, and the water content in the reaction solution in the [ ^18F ] conversion reaction was 2.85% by volume, 10.0% by volume, and 15.0% by volume. The [ ¹⁸ F] conversion reaction was carried out three times in an open system in the same manner as in Example 1, except that the yields of the obtained [ ¹⁸ F] intermediates were calculated as follows: Calculated. The reaction conditions were as follows: the molar ratio (P/B ratio) of the labeled precursor compound (NITTP) to the base (potassium carbonate; K ₂ CO ₃ ) was 2.0, and the reaction temperature and time were 100°C and 10 minutes. did. These results are shown in Table 3 as mean ± standard error.

[Example 3]
In this example, the total liquid volume in the [ ^18F ] conversion reaction is 1 mL, and the water content in the reaction solution in the [ ^18F ] conversion reaction is 2.85% by volume, 6.0% by volume, and 10.0% by volume. The [ ¹⁸ F] conversion reaction was carried out three times in an open system in the same manner as in Example 2, except that the yields of the obtained [ ¹⁸ F] intermediates were calculated as follows: Calculated. These results are shown in Table 3 as mean ± standard error.

As shown in Table 3, it can be seen that in both Examples 2 and 3, which were carried out under water-containing conditions and in an open system, the [ ¹⁸ F]-formation reaction proceeded, and a [ ¹⁸ F]-formation intermediate was obtained. In particular, it can be seen that in Example 2, where the total volume of the reaction solution is small, the reaction proceeds satisfactorily even when the water content is 20% by volume.

<Experiment 3. Comparison of synthesis time and yield of radioactive fluorine-labeled compounds>
[Example 4]
In this example, a radioactive fluorine-labeled compound was synthesized under aqueous conditions and in an open system using an automatic synthesizer (COSMiC-Compact 2424, manufactured by NMP Business Support). Specifically, 1 mL of the reaction solution mixed in the same manner as in Example 1 was subjected to a [ ¹⁸ F] conversion reaction in a polypropylene tube to obtain a [ ¹⁸ F] conversion intermediate. The reaction conditions for this reaction were 115° C. for 12 minutes. Next, 0.3 mL of 1 mol/L hydrochloric acid was added into the tube, and the mixture was reacted at 110° C. for 3 minutes to perform a deprotection reaction of the [ ¹⁸ F] intermediate. Through this reaction, [ ¹⁸ F]FMISO was obtained as the target radioactive fluorine-labeled compound. The synthesis of [ ¹⁸ F]FMISO was performed independently three times.

The radiochemical purity of [ ¹⁸ F]FMISO was measured using HPLC under Condition 2 below. The radiochemical purity (%) of [ ¹⁸ F]FMISO is determined by using the peak around 4.0 min on a gamma ray detector as [ ¹⁸ F]FMISO, and calculating the radioactivity (count) of [ ¹⁸ F]FMISO by )/(Total detected radioactivity (counts)). Further, the total radioactivity (GBq) of the obtained [ ¹⁸ F]FMISO was measured using a dose meter (manufactured by Capintec, model number: CRC-55t PET Dose Calibrator). Furthermore, the radiochemical yield (End of bombardment: EOB, unit: %) when attenuation correction is performed based on the synthesis start time, and the radiochemical yield (End of synthesis) when attenuation correction is not performed. EOS (unit: %) was calculated. These results are shown in Table 4 as mean ± standard error.

(High performance liquid chromatography conditions 2)
Device: LC-20AD (manufactured by Shimadzu Corporation)
Detector 1 (ultraviolet-visible light (UV-vis) detection): SPD-20A (manufactured by Shimadzu Corporation), measurement wavelengths 210 nm and 325 nm
Detector 2 (gamma ray (RI) detection): RLC-700 (manufactured by Aloka)
Column: XBridge C18 (inner diameter 4.6 mm x length 150 mm, 5 μm; manufactured by Nippon Waters)
Column temperature: room temperature Eluent composition (mobile phase): 10mM ( _NH4 ) _2HPO4 and _MeCN
(From 0 to 1.5 min, 10 mM (NH ₄ ) ₂ HPO ₄ :MeCN = 88 volume %: constant at 12 volume %, and from 1.5 to 10 min, 10 mM (NH ₄ ) ₂ HPO ₄ and MeCN = 88 volume % %: 12 volume % to 30 volume %: 70 volume % gradient analysis.)
Eluent flow rate: 1.0mL/min
Injection volume: 10μL

[Comparative example 3]
In this comparative example, a radioactive fluorine-labeled compound was synthesized using an automatic synthesizer under nonaqueous conditions and in a closed state. Specifically, 1 mL of the reaction solution mixed in the same manner as in Comparative Example 1 was subjected to a [ ¹⁸ F] conversion reaction in a glass vial to obtain a [ ¹⁸ F] conversion intermediate. The reaction conditions for this reaction were 115° C. for 10 minutes. Next, 0.3 mL of 1 mol/L hydrochloric acid was added into the vial, and the reaction was carried out at 110° C. for 3 minutes to perform a deprotection reaction of the [ ¹⁸ F] intermediate. Through this reaction, [ ¹⁸ F]FMISO was obtained as the target radioactive fluorine-labeled compound. The synthesis of [ ¹⁸ F]FMISO was performed independently three times. The radiochemical purity, radioactivity amount, and yield of [ ¹⁸ F]FMISO were measured and calculated in the same manner as in Example 4. The results are shown in Table 4 below.

As shown in Table 4, Example 4, which was carried out under aqueous conditions and in an open system, had a shorter total synthesis time and a lower radiochemical yield than Comparative Example 3, which was carried out under non-aqueous conditions and in a closed system. It turns out that it is expensive.

<Experiment 4. Study of radiofluorination using various labeled precursor compounds>
[Example 5]
In this example, a [ ¹⁸ F] conversion intermediate of [ ¹⁸ F]FMISO was produced in an open system using NITTP as the labeled precursor compound A. The reaction was carried out in the same manner as in Example 1, except that the amount of [ ¹⁸ F] charged was 37.1 to 39.6 MBq, K ₂ CO ₃ was used as the base, and the reaction conditions were as shown in Table 5. The yield (%) of the [ ¹⁸ F] intermediate produced three times independently is shown in Table 5 as mean ± standard deviation (mean ± SD).

[Example 6]
In this example, the labeled precursor compound B was 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3 - A [ ¹⁸ F] conversion intermediate of [ ¹⁸ F]DiFA was produced in an open system using dioxane. Specifically, [ ¹⁸ F] ion-containing [ ¹⁸ O] water was passed through an anion exchange column that had been made into carbonate foam in advance, and [ ¹⁸ F] ions were adsorbed and collected on the column. Next, 0.5 mL of the above potassium bicarbonate Cryptofix 222 solution was passed through the column to elute [ ¹⁸ F] ions to obtain a [ ¹⁸ F] ion eluate.

20 μL (9.5 to 26.8 MBq) of the obtained [ ¹⁸ F] ion eluate was placed in a reaction container (polypropylene tube), and then 20 μL (0.2 mg, 0.47 μmol) of the labeled precursor compound B solution in acetonitrile was added. equivalent) and 960 μL of acetonitrile (water content 2.9 volume % or 10.0 volume %) were added to make the total volume of the reaction solution 1 mL (water content 2.9 volume % or 10.0 volume %) [ ¹⁸ F] conversion reaction was started. This reaction was conducted in an open system (non-sealed state) while introducing nitrogen into the reaction vessel by blowing nitrogen onto the surface of the reaction solution. The reaction time was 13 or 15 minutes. Other reaction conditions were as shown in Table 5 below.

After the reaction for a predetermined period of time, the reaction vessel was immediately ice-cooled to stop the [ ¹⁸ F] conversion reaction. Next, 0.1 mL of an aqueous solution containing 50% by volume of acetonitrile was added to dissolve the compound present in the reaction vessel. This solution was introduced into high performance liquid chromatography, and the abundance ratio of the [ ¹⁸ F] intermediate in the solution was analyzed under Condition 3 below. The yield (%) of the [ ¹⁸ F] conversion intermediate of this example calculated based on the peak around 7.4 min in the gamma ray detector is the average value ± standard deviation of the yield of three independent productions. It is shown in Table 5.

(High performance liquid chromatography conditions 3)
Device: LC-20AD (manufactured by Shimadzu Corporation)
Detector 1 (ultraviolet-visible light (UV-vis) detection): SPD-20A (manufactured by Shimadzu Corporation), measurement wavelengths 210 nm and 325 nm
Detector 2 (gamma ray (RI) detection): RLC-700 (manufactured by Aloka)
Column: XBridge C18 (inner diameter 4.6 mm x length 150 mm, 5 μm; manufactured by Nippon Waters)
Column temperature: room temperature Eluent composition (mobile phase): 10mM ( _NH4 ) _2HPO4 and _MeCN
(From 0 to 1.5 min, 10 mM (NH ₄ ) ₂ HPO ₄ :MeCN = 88 volume %: constant at 12 volume %, and from 1.5 to 10 min, 10 mM (NH ₄ ) ₂ HPO ₄ and MeCN = 88 volume % %: 12 volume % to 30 volume %: 70 volume % gradient analysis.)
Eluent flow rate: 1.0mL/min
Injection volume: 10μL

[Example 7]
In this example, the labeled precursor compound C was 6-chloro-5-fluoro-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl]-1-[2-(p-toluenesulfonyloxy) A [ ¹⁸ F]-formed intermediate of [ ¹⁸ F]CDP2230 was produced in an open system using ethyl]benzimidazole. Specifically, 0.5 mL (284 to 681 MBq) of the [ ¹⁸ F] ion solution was retained in the anion exchange column, and then the inside of the column was washed with 2.0 mL of water for injection. Next, 20 μmol/mL potassium hydrogen carbonate and 25 μmol/mL (1.0 mg, equivalent to 10.0 μmol; manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) Cryptofix 222 (4.7 mg, equivalent to 12.5 μmol; manufactured by Merck & Co., Ltd.) were added. Using 0.5 mL of an aqueous solution containing 90% by volume of acetonitrile, the [ ¹⁸ F] ions were eluted from the column into a glass vial. Next, 1.0 mL (10.5 mg, equivalent to 20 μmol) of the acetonitrile solution of the labeled precursor compound C was added to the eluate in the same vial to bring the total volume of the reaction solution to 1.5 mL (water content: 16.0 μmol). 7% by volume), and the [ ¹⁸ F] conversion reaction was started. This reaction was carried out in an open system (non-sealed state) while introducing air into the reaction vessel by blowing the air onto the surface of the reaction liquid. Other reaction conditions were as shown in Table 5 below.

After the reaction for a predetermined period of time, the reaction vessel was immediately ice-cooled to stop the [ ¹⁸ F] conversion reaction. Next, 1.0 mL of an aqueous solution containing 50% by volume of ethanol was added. This solution was analyzed by thin layer chromatography (TLC), and the abundance ratio of the [ ¹⁸ F] intermediate in the solution was analyzed under the following conditions. The yield (%) of the [ ¹⁸ F] intermediate of this example calculated based on the peak near Rf = 0.5 detected by the TLC scanner is the average value of the yield of three independent productions. It is shown in Table 5 as ± standard deviation.

(Thin layer chromatography conditions)
TLC plate: Silica gel 60F254 (manufactured by Merck & Co.)
Developing solvent: acetonitrile/water/diethylamine mixed solution (acetonitrile:water:diethylamine=10:1:1)
TLC scanner: Gita star: PS (manufactured by raytest)

[Example 8]
In this example, 3-N-Boc-5'-O-dimethoxytrityl-3'-O-nosyl-thymidine was used as the labeled precursor compound D to convert [ ¹⁸ F]-formed intermediate of [ ¹⁸ F]FLT. was produced in an open system. Specifically, 20 μL of the [ ¹⁸ F] ion eluate (equivalent to 284 to 681 MBq) obtained in the same manner as in Example 5 was put into a polypropylene tube, and then 20 μL of the acetonitrile solution (45.9 mM ) and 960 μL of acetonitrile (water content: 3% by volume) were added to bring the total volume of the reaction solution to 1 mL (water content: 3.0% by volume) with acetonitrile, and the [ ¹⁸ F] conversion reaction was started. This reaction was conducted in an open system (non-sealed state) while introducing nitrogen into the reaction vessel by blowing nitrogen onto the surface of the reaction solution. Other reaction conditions were as shown in Table 5 below.

After the reaction for a predetermined period of time, the reaction vessel was immediately ice-cooled to stop the [ ¹⁸ F] conversion reaction. Then, 0.1 mL of an aqueous solution containing 50% by volume of acetonitrile was added. This solution was introduced into high performance liquid chromatography, and the abundance ratio of the [ ¹⁸ F] intermediate in the solution was analyzed under Condition 4 below. The yield (%) of the [ ¹⁸ F]-formed intermediate of this example calculated based on the peak around 4.0 min in the gamma ray detector is shown in Table 5 as the average value ± standard deviation.

(High performance liquid chromatography conditions 4)
Device: LC-20AD (manufactured by Shimadzu Corporation)
Detector 1 (ultraviolet-visible light (UV-vis) detection): SPD-20A (manufactured by Shimadzu Corporation), measurement wavelengths 210 nm and 225 nm
Detector 2 (gamma ray (RI) detection): RLC-700 (manufactured by Aloka)
Column: XBridge C18 (inner diameter 4.6 mm x length 150 mm, 5 μm; manufactured by Nippon Waters)
Column temperature: room temperature Eluent composition (mobile phase): MeCN:H ₂ O = 88% by volume: 12% by volume
Retention time: 4 minutes Eluent flow rate: 1.0 mL/min
Injection volume: 10μL

As shown in Table 5, in Examples 5 to 8, which were carried out under water-containing conditions and in an open system, the radiofluorination reaction proceeded and the yield was high regardless of which labeled precursor compound was used. It turns out that there is something.

Therefore, the method for producing a radioactive fluorine-labeled compound of the present invention shortens the production time and provides a high synthesis yield compared to conventional methods. In addition, this method is a highly convenient method, as the radiofluorination reaction proceeds even with various labeled precursor compounds.

Claims (9)

a retention step of retaining radioactive fluoride ions in an anion exchange column;
an elution step of eluting the retained radioactive fluoride ions from the anion exchange column using an eluent containing a solvent;
a radiofluorination step in which the radioactive fluoride ion and the labeled precursor compound are reacted in the presence of a solvent including the solvent,
A method for producing a radioactive fluorine-labeled compound, wherein the radioactive fluorination step is performed while evaporating the solvent. The method for producing a radioactive fluorine-labeled compound according to claim 1, wherein the solvent includes a protic solvent and an aprotic solvent. The method for producing a radioactive fluorine-labeled compound according to claim 2 , wherein in the radioactive fluorination step, the content of the protic solvent in the solvent at the start of the reaction is 30% by volume or less. The method for producing a radioactive fluorine-labeled compound according to any one of claims 1 to 3, wherein in the radioactive fluorination step, the radioactive fluoride ion and the labeled precursor compound are reacted in an open system. The method for producing a radioactive fluorine-labeled compound according to any one of claims 1 to 4, wherein the radioactive fluoride ion is separated from [ ¹⁸ O] water using the anion exchange column. According to any one of claims 1 to 5, wherein in the elution step, the radioactive fluoride ion is eluted into a reaction vessel containing the labeled precursor compound , and then the radiofluorination step is performed. A method for producing the radiofluorine-labeled compound described. 2. The radiofluorination step is performed after the elution step includes eluting the radioactive fluoride ions from the anion exchange column using the eluent containing the labeled precursor compound and the solvent. 6. A method for producing a radioactive fluorine-labeled compound according to any one of 1 to 5. In the radiofluorination step, the radioactive fluoride ions, the labeled precursor compound, and the solvent are placed in a reaction container, the radioactive fluoride ions and the labeled precursor compound are reacted, and under this condition,
The radioactive fluorine label according to any one of claims 1 to 7, wherein the evaporated solvent is discharged outside the reaction container by introducing a gas into the reaction container or by reducing the pressure inside the reaction container. Method of manufacturing the compound. A radioactive pharmaceutical composition comprising a radioactive fluorine-labeled compound produced by the method for producing a radioactive fluorine-labeled compound according to any one of claims 1 to 8, and then containing the radioactive fluorine-labeled compound or a salt thereof as an active ingredient. A method of manufacturing a radiopharmaceutical composition.