KR101519425B1 - Method of preparing radiopharmaceutical products using cassette comprising reaction vessel preventing countercurrent - Google Patents

Abstract

The present invention relates to a method of manufacturing a radioactive pharmaceutical product using a cassette comprising a reaction vessel for preventing a countercurrent. According to the present invention, the method of manufacturing a radioactive pharmaceutical product using a cassette comprising a reaction vessel for preventing a countercurrent comprises the steps of: exsoluting [18F]fluoride in the reaction vessel preventing a countercurrent; drying an eluant in the reaction vessel preventing a countercurrent; and supplying a precursor and a reactant solvent of the radioactive pharmaceutical product in the reaction vessel for preventing a countercurrent, and reacting the dried [18F]fluoride and the precursor of the radioactive pharmaceutical product under the reactant solvent. An end point of a first line is located at least higher than the surface of a reagent used for composing the radioactive pharmaceutical product supplied in the reaction vessel for preventing a countercurrent.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a method of preparing a radiopharmaceutical using a cassette including a reaction-

The present invention relates to a method of manufacturing a radiopharmaceutical using a cassette including a backflow prevention reaction container.

While the quality of life improves with the development of modern civilization and the life span of human beings increases with the development of medicine, brain diseases such as Parkinson's disease, depression, schizophrenia and Alzheimer's disease; Heart disease due to stress and dietary changes; And the incidence of various cancers due to the exposure of human body to various toxic reagents is increasing. Therefore, the development of a diagnostic imaging method that can diagnose these diseases early was requested.

Positron Emission Tomography (PET) is a method that is readily applicable to clinical practice although various imaging methods are being commercialized. The positron emission tomography (PET) is a method in which an organic compound labeled with a radioactive isotope, Intravenous injection into the body of the radiopharmaceuticals in vivo can be visualized the process of biochemical changes and distribution. Therefore, it is possible to quantitatively measure the biochemical changes of the living body in the lesion site through positron emission tomography (CT), so that the degree of development of the disease can be measured and the degree of treatment can be predicted [ J. Agar, R. H. Slart, K. K. Thorp, A. W. Glaudemans, D. C. Cobben, L. B. Been, F. R. Burlage, P. H. Elsinga, R. A. Dierckx, E. Vellenga, J. L. Holter, Nucl. Med. Commun. 2011, 32, 14 .; N. Aide, K. Kinross, C. Cullinane, P. Roselt, K. Waldeck. O, Neels, D. Dorow, G. McArthur, R. J. Hicks, J. Nucl. Med. 2011, 51, 1559 .; A. Debucquoy, E. Devos, P. Vermaelen, W. Landuyt, S. De Weer, F. Van Den Heuvel, K. Haustermans, Int. J. Radiat. Biol. 2009, 85, 763.].

Radiopharmaceuticals are labeled with radioactive isotopes and administered to the human body for diagnosis or treatment of disease. Radioactive isotopes used in radiopharmaceuticals are unstable and emit radiation to become stable isotopes. The emitted radiation can then be used to diagnose or treat diseases. Radiation can be α-ray, β-ray, γ-ray, positron or β + -ray. On the other hand, a radioisotope used for positron emission tomography is fluoride ^([18 F] F), Carbon ^([15 C] C), nitrogen ^([13 N] N), oxygen ^([15 O] O) and and the like, gallium ^([68 Ga] Ga), double, ^[18 F] fluoride has a similar size and hydrogen to form carbon and stable binding of the organic compound, and its production is easy, the appropriate half-life (110 minutes ) Have been reported to be very suitable for positron emission tomography (Lasne, MC; Perrio, C .; Rouden, J .; Barre, L .; Roeda, D .; Dolle, F .; Crouzel, C. Contrast Agents II, Topics in Current Chemistry, Springer-Verlag, Berlin, 2002, 222, 201-258 .; Bolton, RJ Labeled Compd. Radiopharm. 2002, 45: 485-528].

At this time, Korea, etc. C-11 formulation as ^[11 C] Acetate, ^[11 C] methionine, and is widely used in the clinical case of F-18 Formulation ^{[18 F] FDG, [18} F] FLT, [18 F] FP- CIT, and [ ¹⁸ F] FDOPA have obtained approval from the Ministry of Food and Drug Administration, and [ ¹⁸ F] FDG has been manufactured in a large number of companies and large hospitals up to four times a day and has conducted 100 scans.

In order to protect workers from radioactivity during the production of such radiopharmaceuticals, they are manufactured using an automated synthesizer in a hot-cell-shielded space called a hot cell. The automated synthesizer is a non-cassette type (TracerLab FXFN, GE Healthcar; Modular Lab, E & Z, etc.) and cassette type (TracerLab MX, GE Healthcare, FastLab, GE Healthcare, AIO module, Trasis, etc.).

In the case of a non-cassette-type automation synthesizer, the main purpose is to use it for research, and it is troublesome to clean the automation synthesizer after the use of the cassette type automation synthesizer. However, the cassette type automation synthesizer uses a disposable cassette, It can be used more than twice a day if the cassette is exchanged. Above all, it is easy to apply GMP (excellent medicine manufacturing management system). Therefore, the cassette-type automated synthesizer has many advantages over the non-cassette-type automated synthesizer in the case of radioactive pharmaceuticals having frequent manufacture.

However, in order to use such a cassette-type automated synthesizing apparatus, there is a problem that the manufacturing conditions (reaction solvent type, reaction temperature, reaction time) of the radiopharmaceuticals to be manufactured must be suitable for the cassette. Otherwise, And may fail to produce radiopharmaceuticals.

The reaction vessel (see FIG. 2 (A)) introduced into the cassette used in the cassette type automated synthesizer has a reagent supply line 11a for recovering the reaction product after the reaction. In order to increase the recovery rate, (See Fig. 2 (A)). In order to increase the recovery rate, the bottom is made into a round shape or a V shape. Accordingly, when the positive pressure is applied to the reaction vessel 10a due to the vaporization of the solution as the temperature in the reaction vessel 10a increases in the reaction step, the solvent flows back to the reagent supply line 11a reaching the bottom surface, The reaction solvent is filled in the cassette connected to the other end of the reaction tube 11a during the reaction time. At this time, when a cassette having no resistance to a reaction solvent is used, or when the reaction temperature is much higher than the boiling point of the reaction solvent, there is a problem that the cassette is broken by the pressure applied to the cassette, can do. In addition, since the solution reversely flowing into the reagent supply line 11a does not participate in the reaction, the reaction reagent does not participate in the entire reaction, and the reaction yield varies greatly. This makes it difficult to secure the stability of the yield. Making it impossible to manufacture.

In order to solve the above problems, cassettes having resistance to various solvents have been developed, but most of them have been developed in foreign countries. In the case of a cassette using a new material, the cost is too high for disposable use, There are economic difficulties in doing so. In addition, there is a method in which a pinch valve is installed in a line which flows back from the reactor to prevent the solution flowing backward from staying in the cassette, but this is not a fundamental prevention of the backflow phenomenon and is merely a temporary measure for preventing the backflow solution from staying in the cassette .

In the case of the reaction vessel 10a (see FIG. 2A) in which the conventional reagent supply line 11a is designed to reach the bottom surface of the reaction vessel 10a, the reagent supply line 11a When the reagent is supplied through the reaction vessel 10a, the reagent supplied to the entire wall of the reaction vessel 10a is ejected by the reagent supply speed. In addition, during the manufacturing process of the radioactive pharmaceutical agent labeled with F-18, the F-18 is eluted from the anion exchange cartridge and then dried to obtain reactivity. At this time, when nitrogen is supplied to the same line, Nitrogen is supplied into the filled solution, and bubbles are generated due to the supplied nitrogen, so that the reagent is sprayed over the entire wall to dry. When the solution containing the precursor is supplied again to the reaction vessel 10a through the reagent supply line 11a after drying the F-18, the precursor also splashes to the base wall of the reaction vessel 10a, Reaction participation of the dried reagent is inevitable every time, which leads to fluctuation of the yield of the radiopharmaceutical. In particular, radioactive pharmaceuticals that are sensitive to the amount of reagent have a problem in that it is difficult to synthesize stable radioactive pharmaceuticals due to frequent production failure beyond the yield fluctuation.

Korean Patent Publication No. 2011-0122941

Accordingly, it is an object of the present invention to provide a method of manufacturing a radiopharmaceutical using a cassette, which comprises a backflow prevention reaction vessel capable of stably supplying an amount intended for participation of a reagent used in the production of a radiopharmaceutical to the reaction vessel .

It is another object of the present invention to provide a method and apparatus for preventing backflow caused by vaporization during the labeling reaction at a high temperature and preventing the backflow of the cassette, And a method of manufacturing a radiopharmaceutical using a cassette including a reaction container.

This object is solved according to the present invention by a method for producing a radiopharmaceutical using a cassette comprising a non-backflow reaction vessel, comprising the steps of: eluting [ ¹⁸ F] fluoride in a backflow prevention reaction vessel; Drying the eluent in the reflux preventing reaction vessel; Reacting the dried [ ¹⁸ F] fluoride with a precursor of the radiopharmaceutical in the reaction solvent by supplying a precursor of the radiopharmaceutical and a reaction solvent into the backflow prevention reaction vessel, and reacting the dried [ ¹⁸ F] fluoride with the precursor of the radiopharmaceutical, A first line for supplying a reagent used for synthesis of the radiopharmaceutical and a second line for providing a vacuum state, wherein the end point of the first line is at least composed of the radioactive drug Which is higher than the surface of the reagent used in the above-mentioned reagent, is provided.

The distance between the endpoint of the first line and the surface of the reagent may be up to 5 cm.

The cassette including the backflow prevention reaction vessel may include a cassette in the form of a manifold.

The reaction solvent may include any one of an aprotic solvent, a protonic solvent and a polyfunctional solvent.

The aprotic solvent may include any one selected from acetonitrile, dimethylformamide, and dimethysulfoxide.

Wherein the protonic solvent is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, primary alcohol comprising n-octanol, isopropanol, Amyl alcohol, secondary alcohol containing 3-pentanol, t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol, 2- (trifluoromethyl) -2- propanol, Pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl- 2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-ethylcyclopentanol, 1-methylcyclopentanol, 1-methylcyclopentanol, -Propyl cyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, and tertiary alcohols including 1-methylcycloheptanol.

The polyfunctional solvent may include a compound represented by the following formula (1): < EMI ID =

[Chemical Formula 1]

(1)

R ₁ and R ₂ are each independently hydrogen, a C ₁ -C ₁₀ alkyl group or a functional group same as X,

Ln is a C ₁ ~ C ₁₀ alkyl group or a polyethylene glycol (OCH ₂ CH ₂₎ in a n n = 1 ~ 10,

X is a polar group, and is selected from an alkoxy group (OR ₃ ), a nitrile group (CN) and a halide).

R ₃ is a C ₁ -C ₁₀ alkyl group, and the halide may include any one selected from chloride (Cl), bromide (Br), and iodide (I).

The polyfunctional solvent is selected from the group consisting of 1-methoxy-2-methyl-2-propanol, 1-ethoxy-2-methyl- Methyl-2-propanol, 1-t-butoxy-2-methyl-2-propanol, Bromo-2-methyl-2-propanol, and 1-iodo-2-methyl-2-propanol.

As described above, according to the present invention, it is possible to stably supply the reagent used in the production of a radiopharmaceutical drug to the reaction container without loss in an amount intended to participate in the reaction, A method for manufacturing a radiopharmaceutical using a cassette including an anti-reaction container is provided.

In addition, according to the present invention, it is possible to prevent the backflow of the reaction solvent due to vaporization or the like during the labeling reaction at a high temperature so as not to break the cassette and to prevent the backflow prevention reaction A method of manufacturing a radiopharmaceutical using a cassette including a container is provided.

As a result, all of the reagents used in the production of radiopharmaceuticals can be stably participated in the reaction, and the radioactive pharmaceuticals can be produced with high yield, stable, less variation in synthesis yield and without fail, (GMP), which will be introduced in the future. In addition, since the backflow phenomenon of the reaction solvent does not occur, the cassette need not be resistant to the reaction solvent, so that the radiopharmaceuticals can be economically produced.

1 is a schematic view of a process for manufacturing a radiopharmaceutical using a cassette including a counterflow prevention reaction container according to an embodiment of the present invention
2 is a schematic view of a process for manufacturing a radiopharmaceutical using a cassette including a conventional reaction vessel.

Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings, which will be readily apparent to those skilled in the art to which the present invention pertains. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. In order to clearly illustrate the present invention, parts not related to the description are omitted, and the same or similar components are denoted by the same reference numerals throughout the specification.

FIG. 1 is a schematic view of a process for manufacturing a radiopharmaceutical using a cassette including a counterflow prevention reaction container according to an embodiment of the present invention.

The backflow prevention reaction container 10 according to an embodiment of the present invention includes a first line 11 to which a reagent used for synthesizing a radiopharmaceutical is supplied and a second line 11 to provide a vacuum state in the backflow prevention reaction container 10. [ Line [13], wherein said first line (11) comprises a reagent used in the synthesis of a radiopharmaceutical, such as a [ ¹⁸ F] fluoride providing solution, a precursor of a radiopharmaceutical, [ ¹⁸ F] fluoride A reaction solvent used for labeling the precursor, and a nitrogen or air supply unit connected to each other in the form of a manifold to form one cassette. Therefore, the cassette may be composed of a single manifold or a plurality of manifolds, and the cassette of the radiopharmaceuticals may have a configuration other than the backflow prevention reaction vessel 10 according to the present invention, ≪ / RTI >

The end point E of the first line 11 is located at a predetermined height from the bottom surface of the backflow preventive reaction vessel 10. Preferably, The end point E of the first line 11 and the end point E of the backflow preventive reaction vessel 10 are positioned at a predetermined height h from the surface of the material supplied into the backflow prevention reaction vessel 10, Lt; RTI ID = 0.0 > 5 cm. ≪ / RTI > That is, the end point E of the first line 11 may be located at a position at least 0 cm to a maximum of 5 cm from the surface of the reagent used for synthesis of all the radiopharmaceuticals supplied into the anti- have.

1, the end point E of the first line 11 is located at a predetermined height from the bottom surface of the backflow prevention reaction vessel 10, and the F-18 solution The end point E of the first line 11 is located at a position spaced apart from the bottom surface of the backflow prevention reaction vessel 10 by a predetermined distance and the F-18 solution 20 (FIG. 1 (A) (FIG. 1 (B)), the solution is stably supplied to the bottom of the backflow prevention reaction vessel 10 (FIG. 1 (C)). Even if nitrogen or air is supplied through the first line 11 to dry the supplied F-18 solution (FIG. 1 (D)), the end point E of the first line 11 is prevented from flowing backward A phenomenon in which the F-18 solution 20 does not form bubbles due to the supplied nitrogen or air and splashes to the wall of the anti-reverse flow reaction vessel 10 due to the fact that the F-18 solution 20 is located at a position spaced apart from the bottom surface of the reaction vessel 10 (Fig. 1 (E)). After the F-18 solution 20 is dried, the precursor 30 of the radiopharmaceutical is supplied through the first line 11. Similarly, the radiopharmaceuticals 30 are stably injected onto the F-18 solution 20, (Fig. 1 (F) and (G)). The reaction solvent 40 is supplied through the first line 11 to perform a reaction in which the f-18 is labeled on the precursor of the radiopharmaceutical. In this case, the end point of the first line 11 (E) is located at a high position (h), which is a predetermined distance from the surface of all the reagents supplied in the backflow prevention reaction vessel (10), the reaction solvent (40) It is possible to stably participate in the labeling reaction in the backflow preventive reaction vessel 10 stably by an amount not supplied back to the first line 11 and to produce the radioactive pharmaceutical product stably. And the reaction solvent 40 does not flow back through the first line 11 and therefore the end point E of the first line 11 is not provided There is associated with the set is not in reaction No solvent 40 does not flow back to the cassette is also occur problems such as damaged cassette.

For comparison with the present invention, a case where a radiopharmaceutical is manufactured using a cassette including a conventional reaction container will be described with reference to FIG. 2 is a schematic view of a process for manufacturing a radiopharmaceutical using a cassette including a conventional reaction vessel. 2, an end point Ea of the reagent supply line 11a is provided so as to contact the bottom surface of the reaction container 10a in order to increase the recovery rate, which is provided for supply and recovery of the reagent )). Therefore, when the F-18 solution 20a is supplied through the reagent supply line 11a, the F-18 solution splashes to the wall of the reaction vessel 10a (FIG. 2 (B) The solution 20a is deposited on the wall of the reaction vessel 10a (Fig. 2 (C)). When nitrogen or air is supplied through the reagent supply line 11a to dry the supplied F-18 solution 20a, nitrogen or air is supplied into the F-18 solution 20a, (FIG. 2 (D)). As a result, a larger amount of the F-18 solution splashes onto the wall of the reaction vessel 10a (FIG. 2 (E)). The precursor of the radiopharmaceutical is supplied through the reagent supply line 11a (FIG. 2 (F)). Like the F-18 solution 20a, the precursor 30a of the radiopharmaceutical is also supplied to the reaction vessel 10a 2 (G)), a predetermined amount of the precursor of the radiopharmaceutical also remains as a droplet on the wall (FIG. 2 (H)), because the reagent supply line 11a is in contact with the reaction vessel And is positioned in contact with the bottom surface of the base 10a. Thereafter, a reaction solvent 40a is injected through the reagent supply line 11a to label the precursor of the radiopharmaceutical with F-18. The labeling reaction is generally performed at 100 to 140 ° C, The boiling point of the solvent 40a is exceeded and vaporization of the reaction solvent 40a occurs and a positive pressure is applied to the reaction solvent 40a. Due to the positive pressure, the reaction solvent 40a flows back to the reagent supply line 11a, (Fig. 2 (I)). Accordingly, the other end of the reagent supply line 11a, which is not provided with the end point Ea, is connected to the cassette. If there is no resistance of the cassette depending on the type of material of the reaction solvent 40a used, There is a possibility that breakage may occur and thus the reaction material can not be recovered, thereby failing to manufacture the radiopharmaceuticals.

Therefore, when the radiopharmaceutical is manufactured using the cassette including the anti-reverse reaction container 10 according to the present invention, the reaction solvent does not flow back to the first line 11 during the labeling reaction, Since the problem is solved, it is necessary to develop a cassette having resistance to the reaction solvent, so that the manufacturing cost can be lowered and the supplied reaction solvent (40) can participate almost all in the labeling reaction, so that the synthesis yield of the radiopharmaceutical is improved And it is possible to manufacture radiopharmaceuticals suitable for GMP (excellent pharmaceutical manufacturing management system).

Referring again to FIG. 1, the reaction solvent used in the method of manufacturing a radiopharmaceutical using a cassette including the anti-reflux reaction vessel 10 according to the present invention may be any of an aprotic solvent, a protic solvent and a polyfunctional solvent One can be included.

The aprotic solvent may include any one selected from acetonitrile, dimethylformamide, and dimethysulfoxide.

Wherein the protonic solvent is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, primary alcohol comprising n-octanol, isopropanol, Amyl alcohol, secondary alcohol containing 3-pentanol, t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol, 2- (trifluoromethyl) -2- propanol, Pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl- 2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-ethylcyclopentanol, 1-methylcyclopentanol, 1-methylcyclopentanol, -Propyl cyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, and tertiary alcohols including 1-methylcycloheptanol.

The polyfunctional solvent is a compound represented by the following formula (1): < EMI ID =

[Chemical Formula 1]

(1)

R ₁ and R ₂ are each independently hydrogen, a C ₁ -C ₁₀ alkyl group or a functional group same as X,

Ln is a C ₁ ~ C ₁₀ alkyl group or a polyethylene glycol (OCH ₂ CH ₂₎ in a n n = 1 ~ 10,

X is a polar group, and is selected from an alkoxy group (OR ₃ ), a nitrile group (CN), and a halide.

Here, Ln is preferably a methyl group.

Here, R ₃ is preferably a C ₁ -C ₁₀ alkyl group, and more preferably, R ₃ is any one selected from methoxy, ethoxy, propoxy, isopropoxy and t-butoxy.

Here, the halide is preferably selected from among chloride (Cl), bromide (Br) and iodide (I).

Here, R ₁ and R ₂ are preferably a methyl group or an ethyl group.

Here, the polyfunctional solvent of Formula 1 is preferably 1-methoxy-2-methyl-2-propanol, 1-ethoxy-2-methyl- Propanol, 1-isopropoxy-2-methyl-2-propanol, 1-t-butoxy- -2-methyl-2-propanol, 1-bromo-2-methyl-2-propanol and 1-iodo-2-methyl-2-propanol.

Accordingly, a method of manufacturing a radiopharmaceutical using a cassette including a backflow prevention reaction vessel 10 according to the present invention includes the steps of eluting [ ¹⁸ F] fluoride in the backflow prevention reaction vessel 10 A) to C); Drying the eluant in the reflux preventing reaction vessel (Figs. 1 (D) to (E)); Reacting the dried [ ¹⁸ F] fluoride with the precursor of the radiopharmaceutical in the reaction solvent by supplying a precursor of the radiopharmaceutical and a reaction solvent into the backflow prevention reaction vessel (FIG. 1 (F) to (H) ). The eluted phase, for example, quaternary ammonium salts support (Chromafix or QMA) in the ^[18 F] The adsorbed ^[18 F] fluoride with a method for exchanging the anions to pass through the fluoride and the pH is adjusted KOMs And [ ¹⁸ F] fluoride adsorbed on the quaternary ammonium support with the mixed solution is eluted into the anti-reflux reaction vessel 10. The drying step is a step of drying the eluent through nitrogen or air at a predetermined temperature, for example, 100 to 140 캜, through the first line 11. In the reaction step, the precursor of the radiopharmaceutical and the reaction solvent are injected into the first line 11, reacted at about 100 to 140 ° C, and F-18 is labeled on the precursor of the radiopharmaceutical to synthesize the radiopharmaceutical to be. After the synthesis step, it may further include a step of dissolving in water and performing purification using a solid phase extraction (SPE) method or HPLC purification method. It is a matter of course that the elution step, the drying step, the synthesis step, and the purification step may utilize a method generally used in the production of radiopharmaceuticals.

Such a method for producing a radiopharmaceutical drug using a cassette including the anti-reflux reaction vessel 10 according to the present invention can be used for the synthesis of any kind of F-18 labeled organic compound under the reaction solvent described above.

Thus, the fluorine salt that is the source of F-18 fluoride used in the process of the present invention may preferably comprise a compound comprising fluorine-18, and is preferably selected from the group consisting of lithium, sodium, potassium, rubidium and cesium An alkali metal fluoride comprising an alkali metal selected from the group consisting of: An alkaline earth metal fluoride comprising an alkaline earth metal selected from the group consisting of magnesium, calcium, strontium and barium; And ammonium fluoride, but more preferably potassium fluoride or ammonium fluoride. The alkali metal fluoride or tetraalkylammonium fluoride including potassium is preferably adsorbed by any one support selected from Celite, Molecular Seiva, alumina and silica gel. The ammonium fluoride is preferably a quaternary ammonium fluoride comprising tetrabutylammonium fluoride and benzyltrimethylammonium fluoride; Tertiary ammonium fluoride including triethylammonium fluoride, tributylammonium fluoride; Secondary ammonium fluoride including dibutyl ammonium fluoride, dihexyl ammonium fluoride; Butylammonium fluoride, butylammonium fluoride, and primary ammonium fluoride including hexylammonium fluoride, but is more preferably tetrabutylammonium fluoride. The fluorine salt may be used in an amount of 1 pg to 100 ng of [ ¹⁸ F] fluoride per 1 mg of the precursor of the radiopharmaceutical described below

The precursor of the radiopharmaceutical used in the present invention is preferably an alkyl halide or an alkyl sulfonate. In the alkyl halide or alkyl sulfonate, the halide is selected from the group consisting of Cl, Br and I except F, is -SO ₃ R ¹² and R ¹² represent an alkyl group or an aryl group, and more specifically, the alkyl group is C ₁ ~ C ₁₂ alkyl sulfonate, or a halo-C ₁ ~ C ₁₂ alkyl group are preferable, and in his examples are methane sulfonate, ethane Sulfonate, sulfonate, isopropane sulfonate, chloromethane sulfonate, trifluoromethane sulfonate, and chloroethanesulfonate. The aryl group is preferably selected from a phenyl group, a C ₁ to C ₄ alkylphenyl group, a halophenyl group, a C ₁ to C ₄ alkoxyphenyl group, or a nitrophenyl group, and preferable examples thereof include methylphenylsulfonate; Ethyl phenyl sulfonate; Chlorophenylsulfonate, bromophenylsulfonate, methoxyphenylsulfonate or nitrophenylsulfonyl.

For example, a radiopharmaceutical which can be produced by a method of manufacturing a radiopharmaceutical using a cassette including the reaction container 10 of the present invention is a [ ¹⁸ F] fluoropropyl carbomethoxysilane represented by the following formula (2) . ≪ / RTI >

(2)

In addition, the radiopharmaceutical obtained according to the production method of the present invention may also contain [ ¹⁸ F] fluoromonidazole represented by the following formula (3)

(3)

In addition, the radiopharmaceutical obtained according to the production method of the present invention may include [ ¹⁸ F] fluorothymidine represented by the following formula (4)

[Chemical Formula 4]

In addition, the radiopharmaceutical obtained according to the production method of the present invention may comprise [ ¹⁸ F] fluoroestradiol represented by the following formula (5)

[Chemical Formula 5]

In addition, the radiopharmaceutical obtained according to the production method of the present invention may comprise [ ¹⁸ F] fluorodeoxyglucose represented by the following formula (6)

[Chemical Formula 6]

In addition, the radiopharmaceutical obtained according to the production method of the present invention may include [ ¹⁸ F] fluorodifenepine represented by the following formula (7)

(7)

In addition, the radiopharmaceutical obtained according to the production method of the present invention may include [ ¹⁸ F] fluorobetaine represented by the following formula (8)

[Chemical Formula 8]

In addition, the radiopharmaceutical obtained according to the production method of the present invention may include [ ¹⁸ F] fluorobetaine represented by the following formula (9)

[Chemical Formula 9]

In addition, the radiopharmaceutical to be obtained according to the production method of the present invention can include ^[18 F] F. H. busy ^([18 F] FHBG) represented by Formula 10 below:

[Chemical formula 10]

Further, the radiopharmaceutical obtained according to the production method of the present invention may include [ ¹⁸ F] H x4 ([ ¹⁸ F] HX4) represented by the following formula (11)

(11)

In addition, radiopharmaceuticals are obtained according to the production method of the present invention can include ^[18 F] LB 999 T ^([18 F] LBT999) represented by the formula 12:

[Chemical Formula 12]

In addition, the radiopharmaceutical to be obtained according to the production method of the present invention can include ^[18 F] fluorene Te meth mole ^([18 F] Flutemetamol) represented by Formula 13 below:

[Chemical Formula 13]

In addition, the radiopharmaceutical to be obtained according to the production method of the present invention can include ^[18 F] epeussi 119 S ^([18 F] FC119S) represented by Formula 14 below:

[Chemical Formula 14]

Hereinafter, the present invention will be described in more detail with reference to the following examples. It should be understood, however, that the invention is not construed as being limited to the embodiments set forth herein, but the scope of the invention is not limited thereto. Those skilled in the art will appreciate that various modifications, It will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Example 1 and Example 2. Synthesis of plate with [ ¹⁸ F] fluoropropyl carbomethoxide

1 was applied to a TRACERlab MXFDG cassette (GE Healthcare), and a plate was prepared from [ ¹⁸ F] fluoropropyl carbomethoxide using TRACERlab MX as an automated synthesizer.

4 mg of (3-methanesulfonyloxypropyl) -2? -Carbomethoxy-3 -? - (4-iodophenyl) iodophenyl) tropane or (3-toluenesulfonyloxypropyl) -2? -carbomethoxy-3-? - (4-iodophenyl) tropane 4-iodophenyl) tropane, and 1.0 mL of 1-methoxy-2-methyl-2-propanol as a multifunctional reaction solvent were reacted at 120 ° C. for 10-20 minutes to obtain [ ¹⁸ F] fluoro Propyl carbomethoxysilane was synthesized.

Example 3 and Example 4. Synthesis of plate with [ ¹⁸ F] fluoropropyl carbomethoxide

1 was applied to a TRACERlab MXFDG cassette (GE Healthcare), and a plate was prepared from [ ¹⁸ F] fluoropropyl carbomethoxide using TRACERlab MX as an automated synthesizer.

4 mg of (3-methanesulfonyloxypropyl) -2? -Carbomethoxy-3 -? - (4-iodophenyl) iodophenyl) tropane or (3-toluenesulfonyloxypropyl) -2? -carbomethoxy-3-? - (4-iodophenyl) tropane 4-iodophenyl) tropane) and 1.0 mL of t-amyl alcohol as a protic solvent were added to the reaction mixture and reacted at 120 ° C. for 10-20 minutes to synthesize a plate of [ ¹⁸ F] fluoropropyl carbomethoxide .

Example 5 and Example 6. Synthesis of plate with [ ¹⁸ F] fluoropropyl carbomethoxide

1 was applied to a TRACERlab MXFDG cassette (GE Healthcare), and a plate was prepared from [ ¹⁸ F] fluoropropyl carbomethoxide using TRACERlab MX as an automated synthesizer.

4 mg of (3-methanesulfonyloxypropyl) -2? -Carbomethoxy-3 -? - (4-iodophenyl) iodophenyl) tropane or (3-toluenesulfonyloxypropyl) -2? -carbomethoxy-3-? - (4-iodophenyl) tropane 4-iodophenyl) tropane) was dissolved in 1.1 mL of acetonitrile, and the reaction was carried out at 120 ° C for 10-20 minutes to synthesize a [ ¹⁸ F] fluoropropyl carbomethoxide sheet.

Comparative Example 1-6. Synthesis of [ ¹⁸ F] fluoropropylcarbamethoxysilane plate

Using the same TRACERlab MXFDG Cassette (GE Healthcare) and TRACERlab MX automation synthesizer equipped with the reaction vessel 10a of FIG. 2, [ ¹⁸ F] fluoropropyl carbomethoxide To synthesize a laminated plate.

The results of the synthesis yield and cassette breakage of the radiopharmaceuticals of Examples 1 to 6 and Comparative Examples 1 to 6 are shown in Table 1 below.

division The reaction vessel Precursor Reaction solvent Synthesis yield Example 1 Backflow prevention reaction container FP-CIT-OMs Methoxy-2-methyl-2-propanol 31.21% Example 2 FP-CIT-OTs Methoxy-2-methyl-2-propanol 32.94% Example 3 FP-CIT-OMs t-amyl alcohol 20.12% Example 4 FP-CIT-OTs t-amyl alcohol 23.07% Example 5 FP-CIT-OMs Acetonitrile 10.61% Example 6 FP-CIT-OTs Acetonitrile 11.04% Comparative Example 1 existing
The reaction vessel FP-CIT-OMs Methoxy-2-methyl-2-propanol 0% (cassette damage) Comparative Example 2 FP-CIT-OTs Methoxy-2-methyl-2-propanol 0% (cassette damage) Comparative Example 3 FP-CIT-OMs t-amyl alcohol 0% (cassette damage) Comparative Example 4 FP-CIT-OTs t-amyl alcohol 0% (cassette damage) Comparative Example 5 FP-CIT-OMs Acetonitrile 1.41% Comparative Example 6 FP-CIT-OTs Acetonitrile 2.19%

As shown in Table 1, in the case of producing a radiopharmaceutical using the anti-reflux reaction vessel according to the present invention (Examples 1 to 6), the radiopharmaceuticals were stably synthesized with high yield without breaking the cassette, It was confirmed that even using nitrile (Examples 5 and 6), the production was possible with a yield of about 10%. In the case of t-amyl alcohol (Examples 3 and 4), it was confirmed that FP-CIT was produced at a yield of 20-23%. In the case of 1-methoxy-2-methyl- ) Yielded a yield of 31-33%, which was increased by 10%, due to the shortening of the production time.

On the other hand, in the case of producing a radiopharmaceutical by applying the conventional reaction vessel (Comparative Examples 1 to 6), in the case of a cassette of a general material which is not resistant to 1-methoxy-2- Due to the problem that the cassette is broken due to the back flow of the reaction solvent during the reaction, the synthesis of the radiopharmaceuticals fails and even when acetonitrile, which is applicable to the cassette, is used, the reaction reagent does not participate in the whole reaction. %, Respectively. Thus, it can be confirmed that clinical application is impossible.

Example 7. Synthesis of [18F] fluorothymidine

1 was applied to a TRACERlab MXFDG Cassette (GE Healthcare), and [ ¹⁸ F] fluorothymidine was prepared using TRACERlab MX as an automated synthesizer.

5 mg of 5'-O-DMTr-2'-deoxy-3'-O-norosyl-bD-threo-pentofuranosyl) -3-N-BOC- -deoxy-3'-O-nosyl-bD-threo-pentofuranosyl) -3-N-BOC-thymine was dissolved in 1.1 mL of acetonitrile, and the mixture was reacted at 120 ° C. for 10-20 minutes to obtain [ ¹⁸ F] / RTI >

Comparative Example 7. Synthesis of [ ¹⁸ F] fluorothymidine

[ ¹⁸ F] fluorothymidine was synthesized using the same reagents and conditions used in Example 7 using TRACERlab MXFDG Cassette (GE Healthcare) and TRACERlab MX automation synthesizer equipped with the reaction vessel 10a of FIG. 2.

Example 8. Synthesis of [ ¹⁸ F] fluoromonasidazole

1 was applied to a TRACERlab MXFDG Cassette (GE Healthcare), and [ ¹⁸ F] fluoromonadicas was prepared using TRACERlab MX as an automated synthesizer.

1-2 mg of 3- (2-nitroimidazol-1-yl) -2-O-tetrahydropyranyl-1-O-toluenesulfonylpropanediol -O-tetrahydropyranyl-1-O-toluenesulfonyl propanediol) was dissolved in 1.1 mL of acetonitrile, and the reaction was carried out at 100 ° C for 10-20 minutes to synthesize [ ¹⁸ F] fluoromonasdicasol.

Comparative Example 8. Synthesis of [ ¹⁸ F] fluoromonasidazole

Using the same TRACERlab MXFDG Cassette (GE Healthcare) including the reaction vessel 10a of Figure 2 and TRACERlab MX automation synthesizer, [ ¹⁸ F] fluoromonidazole was reacted with the same reagents and conditions used in Example 8 Were synthesized.

Example 9. Synthesis of [18F] fluoroestradiol

1 was applied to TRACERlab MXFDG Cassette (GE Healthcare) and [ ¹⁸ F] fluoroestradiol was prepared using TRACERlab MX as an automated synthesizer.

0.5-1 mg 3- (Methoxymethoxy) -1,3,5 (10) -conatriene-16beta, 17beta diol-16,17-cyclic sulfate (3- (Methoxymethoxy) , 5 (10) -gonatriene-16beta, 17beta diol-16,17-cyclic sulfate) was dissolved in 1.1 mL of acetonitrile and reacted at 100 ° C for 10-20 minutes to synthesize [ ¹⁸ F] fluoroestradiol.

Comparative Example 9. Synthesis of [ ¹⁸ F] fluoroestradiol

[ ¹⁸ F] fluoroestradiol was synthesized using the same reagents and conditions as in Example 9 using the conventional TRACERlab MXFDG Cassette (GE Healthcare) and the TRACERlab MX automation synthesizer including the reaction vessel 10a of FIG. 2.

The results of the synthesis yields of the radiopharmaceuticals of Examples 7 to 9 and Comparative Examples 7 to 9 are shown in Table 2 below.

division The reaction vessel Radioactive medicine Synthesis yield Example 7 Backflow prevention
The reaction vessel FLT 25.08% Example 8 FMISO 25.13% Example 9 FES 30.62% Comparative Example 7 existing
The reaction vessel FLT 3.72% Comparative Example 8 FMISO 5.14% Comparative Example 9 FES 1.41%

As shown in Table 2, when a small amount of 0.5-5 mg precursor is used as in Comparative Examples 7 to 9, all the reagents do not participate in the reaction, resulting in a very low synthesis yield of about 1 to 3%. However, in the case of Examples 7 to 9, all the reagents participated in the reaction, and it was confirmed that the production yield of the radiopharmaceuticals increased from 5 times to 30 times that of the Comparative Examples 7 to 9. [

Although several embodiments of the present invention have been shown and described, those skilled in the art will appreciate that various modifications may be made without departing from the principles and spirit of the invention . The scope of the invention will be determined by the appended claims and their equivalents.

10: Anti-reflux reaction vessel
11: Line 1
13: second line

Claims (9)

A method of manufacturing a radiopharmaceutical drug using a cassette including a counterflow prevention reaction container,
Eluting [ ¹⁸ F] fluoride in the reflux preventing reaction vessel;
Drying the eluent in the reflux preventing reaction vessel;
Reacting the dried [ ¹⁸ F] fluoride with the precursor of the radiopharmaceutical in the reaction solvent by supplying a precursor of the radiopharmaceutical and a reaction solvent into the backflow prevention reaction vessel,
Wherein the backflow preventive reaction vessel includes a first line for supplying a reagent used for synthesizing the radiopharmaceutical and a second line for providing a vacuum state, Wherein the reagent is present at a position higher than the surface of the reagent used for synthesis of the supplied radioactive pharmaceutical product. The method according to claim 1,
Wherein the distance between the end point of the first line and the surface of the reagent is at most 5 cm. ≪ Desc / Clms Page number 19 > 3. The method of claim 2,
Wherein the cassette including the backflow prevention reaction vessel is a cassette in the form of a manifold. 2. The method of manufacturing a radiopharmaceutical according to claim 1, wherein the backflow prevention reaction vessel is a cassette. 3. The method of claim 2,
Wherein the reaction solvent is any one of an aprotic solvent, a protic solvent and a polyfunctional solvent. 5. The method of claim 4,
Wherein the non-protonic solvent is any one selected from the group consisting of acetonitrile, dimethylformamide, and dimethysulfoxide. 5. The method of claim 4,
Wherein the protonic solvent is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, primary alcohol comprising n-octanol, isopropanol, Amyl alcohol, secondary alcohol containing 3-pentanol, t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol, 2- (trifluoromethyl) -2- propanol, Pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl- 2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-ethylcyclopentanol, 1-methylcyclopentanol, 1-methylcyclopentanol, -Propyl cyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, and a tertiary alcohol including 1-methylcycloheptanol. Radioactive medicines using cassettes The method of manufacture. 5. The method of claim 4,
Wherein the polyfunctional solvent is a compound represented by the following formula (1): < EMI ID =

[Chemical Formula 1]
(1)
R ₁ and R ₂ are each independently hydrogen, a C ₁ -C ₁₀ alkyl group or a functional group same as X,
Ln is a C ₁ ~ C ₁₀ alkyl group or a polyethylene glycol (OCH ₂ CH ₂₎ in a n n = 1 ~ 10,
X is a polar group, and is selected from an alkoxy group (OR ₃ ), a nitrile group (CN), and a halide. 8. The method of claim 7,
The R ₃ is a C ₁ ~ C ₁₀ alkyl group,
Wherein the halide is any one selected from the group consisting of chloride (Cl), bromide (Br), and iodide (I). 9. The method of claim 8,
The polyfunctional solvent is selected from the group consisting of 1-methoxy-2-methyl-2-propanol, 1-ethoxy-2-methyl- Methyl-2-propanol, 1-t-butoxy-2-methyl-2-propanol, Bromo-2-methyl-2-propanol, 1-iodo-2-methyl-2-propanol, and the like.

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