JP2021066736A - Production method of 2-[18f] fluoro-2-deoxy-d-glucose - Google Patents

Abstract

To provide a technique for producing 18 F-FDG stably in high yield, even if using a large scale of [18F] fluoride ion in order to enhance the production amount of 18 F-FDG.SOLUTION: A production method of 18 F-FDG comprises (a) separating [18F] fluoride ion from 18O concentrated water containing [18F] fluoride ion, (b) performing the radioactive fluorination reaction of 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethane sulfonyl-β-D-mannopyranose (TATM) using [18F] fluoride ion separated from the 18O concentrated water, and (c) a deprotection step of performing a hydrolysis reaction to obtain 2-[18F] fluoro-2-deoxy-D-glucose (18 F-FDG), at the time of the start of step (a), 300 GBq or more of [18F] fluoride ion being used, and 40 μg or more of the TATM per 1 GBq of [18F] fluoride ion at the time of the start of step (a) being used.SELECTED DRAWING: None

Description

The present invention relates to a ^{method for producing 2- [18} F] fluoro-2-deoxy-D-glucose.

The radioactive fluorine-labeled organic compound is used in positron emission tomography (hereinafter referred to as “PET”), which is one of medical diagnostic imaging methods. Currently, the major radioactive fluorine-labeled organic compound is produced by an organic chemical reaction between the precursor and the ^{[18 F]} fluoride ions.

Various methods have been reported as methods for producing ^{2- [18} F] fluoro-2-deoxy-D-glucose (hereinafter referred to as " ¹⁸ F-FDG"), which is a typical compound as a radioactive fluorine-labeled organic compound. For example, the method proposed by Hamaha (hereinafter referred to as "Hamaha method") is well known.

In the Hamaha method, first, ^{a solution containing 18} F, potassium carbonate and a phase transfer catalyst is evaporated to dryness to activate ^{18 F.} Next, in the activated solution, the labeled precursor compound 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose (hereinafter, “TATM”) was added. Acetonitrile solution (referred to as ")" is added and heated, and the intermediate 1,3,4,6-tetra-O-acetyl-2-O- [ ¹⁸ F] fluoro-2-deoxyglucose (hereinafter, " ¹⁸ F") is added. -TAFDG ") is obtained. Subsequently, ¹⁸ F-TAFDG is subjected to a deprotection step and a purification step ^{to obtain 18} F-FDG (Non-Patent Documents 1 and 2).

International Publication WO2007 / 063940 International Publication WO2007 / 066667

Hamacher K., Coenen HH, Stocklin G., "Efficient Stereospecific Synthesis of No-carrier-added-2- [18F] fluoro-2-deoxy-D-glucose Using Aminopolyether Supported Nucleophilic Substitutionm." J. Nucl. Med., 1986, 27, 2, p.235-238 K. Hamacher et al., "Computer-aided Synthesis (CAS) of No-carrier-added 2- [18F] Fluoro-2-deoxy-D-glucose: an Efficient Automated System for the Aminopolyether-supported Nucleophilic Fluorination" Applied Radiation and Isotopes, (Great Britain), Pergamon Press, 1990, 41, 1, p.49-55

Applicants have ^{performed a step of adding TATM, which is a labeling precursor, to a mixture containing activated [18} F] fluoride ions under airtight conditions (Patent Document 1), or in a solution in a radioactive fluorine labeling reaction. It has been found that a stable and high radioactive fluorination yield can be achieved by adding a certain amount of water to the mixture (Patent Document 2).

^However, in order to increase the production of 18 ^F-FDG, the use mass ^[18 F] fluoride ^ions, that 18 F-FDG yield may be reduced, revealed by the findings of the present inventors It was.

The present invention has been made in view of the above circumstances, and provides a technique capable of stably producing ^{18 F-FDG in a high yield even when a large amount of [18} F] fluoride ion is used. It is in.

As a result of diligent research for the above purpose, the present inventors ^{produced 18} F-FDG in high yield by adjusting the amount of labeled precursor when a large amount of ^{[18 F] fluoride ion was used.} We have found what we can do and have completed the present invention.

That is, according to the present invention.
^{(A) [18} F] from ¹⁸ O enriched water containing fluoride ions and separating the ^[18 F] fluoride ions,
(B) 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-manno using ^{the [18 F] fluoride ion separated from the 18} O concentrated water. The process of carrying out the radioactive fluorination reaction of pyranose (TATM),
(C) A deprotection step of carrying out a hydrolysis reaction to obtain 2- [ ¹⁸ F] fluoro-2-deoxy-D-glucose ( ¹⁸ F-FDG).
Including
At the start of step (a), 300 GBq or more of [ ¹⁸ F] fluoride ion was used.
Provided is a method for producing ¹⁸ F-FDG, which uses 40 μg or more of the TATM per 1 GBq ^{of [18} F] fluoride ion at the start of step (a).

According to the present invention, in the radioactive fluorination reaction, the ^{amount of TATM used as a labeling precursor for [18} F] fluoride ion 1 GBq is set to a certain amount or more, so that [ ¹⁸ F] fluoride ion is large. Even when the volume is used, ¹⁸ F-FDG can be stably produced with good yield.

Hereinafter, embodiments of the manufacturing method of the present invention will be described, but the present invention is not limited to the embodiments.

The production method of the present invention can be carried out by performing at least the above steps (a) to (c). Hereinafter, each step will be described.

Step (a)
Step (a) ^is a step of separating the ^[18 F] fluoride ions from the ¹⁸ O enriched water containing ^[18 F] fluoride ions. In the present invention, at the start of step (a), 300 GBq or more of [ ¹⁸ F] fluoride ion is used, preferably 500 GBq or more, more preferably 600 to 1000 GBq.

[ ¹⁸ F] Fluoride ion can be obtained by a known method, for example, ^{by performing proton irradiation with 18} O concentrated water as a target. At this time, [ ¹⁸ F] fluoride ions are present in the targeted ¹⁸ O concentrated water.

Step (a) may be carried out by any method as long as it can separate ^{[18 F] fluoride ions from the obtained 18} O concentrated water, but in combination with the separation of ^{[18 F] fluoride ions. It is preferable to include activating [18} F] fluoride ions using potassium carbonate and a correlated transfer catalyst, and examples of such a preferred method include the following steps (a-1) to (a-3). Examples include methods including.

Step (a-1): ^{18 O concentrated water containing [18} F] fluoride ions is brought into contact with the anion exchange resin, and [ ¹⁸ F] fluoride ions are adsorbed on the anion exchange resin.
Step (a-2): An aqueous solution containing potassium carbonate is brought into contact with the anion exchange resin to elute the aqueous solution of ^{[18 F] fluoride ions.}
Step (a-3): The eluted ^{aqueous solution of [18} F] fluoride ion is heated in the presence of a phase transfer catalyst and a water-soluble organic solvent to evaporate the water and the water-soluble organic solvent.

Here, in the present invention, "at the start of step (a)" may be ^{at the end of proton irradiation of 18} O concentrated water, that is, at the start of step (a-1), or an anion. It may be in a state where [ ¹⁸ F] fluoride ions are adsorbed on the exchange resin, that is, at the start of step (a-2), or immediately after elution of ^{[18 F] fluoride ions from the anion exchange resin.} That is, it may be at the start of step (a-3).

Hereinafter, steps (a-1) to (a-3) will be described.

In the step (a-1), ^{18 O concentrated water containing [18} F] fluoride ions is brought into contact with the anion exchange resin ^{to adsorb [18} F] fluoride ions on the anion exchange resin. As the anion exchange resin, a solid-phase extraction cartridge type is preferable, and for example, Accel Plus QMA, a Sep-Pak (registered trademark) product sold by Waters, can be used. Alternatively, AG1X8 (140-1431 Analytical grade, 50-100 mesh) sold by Bio-Rad may be used. Therefore, step (a-1) can be performed, for example, ^{by passing 18} O concentrated water ^{containing [18} F] fluoride ions through a cartridge filled with an anion exchange resin. The anion exchange resin is preferably prepared in the carbonate ion form before use.

In the step (a-2), the aqueous solution containing potassium carbonate is brought into contact with the anion exchange resin ^{to elute the [18} F] fluoride ion aqueous solution. The step (a-2) can be performed, for example, by passing an aqueous solution containing potassium carbonate through a cartridge filled with an anion exchange resin adsorbing ^{[18 F] fluoride ions.}

An aqueous solution containing potassium carbonate ^{is used as an eluent for [18} F] fluoride ions, where potassium carbonate is 4 to 20 μg per 1 GBq ^{of [18 F] fluoride ions at the start of step (a).} It is preferable to use, and it is more preferable to use 6 to 20 μg.

The amount of water in the eluent is not limited as long as it can dissolve potassium carbonate and minimize the evaporation time in step (a-3), but can be, for example, 0.1 to 1 mL. As will be described later, the following phase transfer catalyst and / or the following water-soluble organic solvent may be mixed in advance with this eluent.

In step (a-3), the eluted [ ¹⁸ F] fluoride ion aqueous solution is heated in the presence of a phase transfer catalyst and a water-soluble organic solvent to evaporate the water and the water-soluble organic solvent.

The phase transfer catalyst is preferably used after being dissolved in a water-soluble organic solvent, and this may be mixed in advance with the eluent of step (a-2), or it may be obtained in step (a-2). It may be mixed with the eluate.

Examples of the phase transfer catalyst include cryptondand and crown ether, but cryptontant is preferable, and 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo- [8,8,8] -hexacosane (trade name). : Cryptand Fix 222) is more preferable.

Since the phase transfer catalyst is used to capture the potassium ion of potassium carbonate, it may be used according to the amount of potassium carbonate used in the step (a-2), but at the start of the step (a). In [ ¹⁸ F], it is preferable to use 30 to 150 μg per 1 GBq of fluoride ion, and it is more preferable to use 45 to 150 μg. The molar ratio of the phase transfer catalyst to potassium carbonate is preferably correlated transfer catalyst / potassium carbonate = 1.5 to 4, more preferably 2 to 3.5.

The water-soluble organic solvent is not particularly limited as long as it is mixed with water used as the eluent in step (a-2), and a solvent having a boiling point close to water and azeotropically boiling with water is preferable, and the boiling point is higher than that of water. The lower one is more preferable. Preferred water-soluble organic solvents include, for example, methanol, tetrahydrofuran, acetone, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol, isopropyl alcohol, butanol, 1,4-dioxane, acetonitrile, and the like. Acetonitrile is particularly preferred.

The amount of the water-soluble organic solvent is not limited as long as it can dissolve the phase transfer catalyst and minimize the evaporation time in step (a-3), but is, for example, 0.5 to 2.5 mL. be able to.

In step (a-3), the eluate obtained in step (a-2) is heated in a container in the presence of a phase transfer catalyst and a water-soluble organic solvent to evaporate water and the water-soluble organic solvent. It can be carried out. The heating temperature is not limited as long as water and the water-soluble organic solvent can evaporate, but is, for example, 70 to 150 ° C.

Step (b)
Step (b) uses 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D- using ^{[18 F] fluoride ions separated from 18} O concentrated water. This is a step of carrying out a radioactive fluorination reaction of mannopyranose (TATM).

In the present invention, TATM is used in an amount of 40 μg or more, preferably 40 to 150 μg, per 1 GBq ^{of [18} F] fluoride ion at the start of step (a). ^{As a result, 18} F-FDG can be produced stably and in good yield.

Potassium carbonate used in step (a-2) acts as a base in the radioactive fluorination reaction and promotes the reaction. Therefore, the molar ratio of potassium carbonate to TATM used in step (b) is preferably potassium carbonate / TATM = 0.3 to 0.6, and more preferably 0.35 to 0.6.

TATM is preferably dissolved in a water-soluble organic solvent ^{and reacted with [18} F] fluoride ions. As the water-soluble organic solvent, those exemplified in the step (a-3) can be used, preferably the same solvent as that used in the step (a-3) is used, and more preferably acetonitrile is used. ..

The amount of the water-soluble organic solvent used is not limited as long as it can dissolve TATM, but can be, for example, 0.5 to 2.5 mL.

The radioactive fluorination reaction is preferably carried out by heating, and the heating temperature is preferably 65 to 125 ° C. The reaction time is appropriately set according to the reaction temperature, but is preferably 10 seconds to 15 minutes, more preferably 30 seconds to 10 minutes, and even more preferably 1.5 to 7 minutes.

The radioactive fluorination reaction of the step (b) is preferably carried out by adding a water-soluble organic solvent solution of TATM to the residue obtained by evaporating water and the water-soluble organic solvent in the step (a-3). At this time, it is preferable to keep the reaction vessel in an airtight state. Then, after the completion of the radioactive fluorination reaction, it is preferable to evaporate the water-soluble organic solvent in an open state to end the step (b).

Step (c)
Step (c) is a deprotection step of carrying out a hydrolysis reaction to obtain 2- [ ¹⁸ F] fluoro-2-deoxy-D-glucose ( ¹⁸ F-FDG).

The hydrolysis reaction may be an acid hydrolysis reaction or an alkali hydrolysis reaction, but an acid hydrolysis reaction is preferable. The acid hydrolysis reaction can be carried out, for example, by adding an acidic solution to the residue of the radioactive fluorination reaction obtained in step (b). The alkaline hydrolysis reaction can be carried out, for example, by adding an alkaline solution to the residue of the radioactive fluorination reaction obtained in step (b). As the amount of alkali or acid added in the hydrolysis reaction, the reaction temperature, and the reaction time, known ones can be used (“Production and Quality Control of Radioactive Agents for PET-Synthesis and Clinical Use” (No. 1). 4th edition) ”, PET Chemistry Workshop Edition).

The acid hydrolysis reaction is preferably carried out by heating to 100 to 140 ° C. Further, it is preferable to use hydrochloric acid as the acidic solution. In this case, 0.5 to 4 mL of 0.5 to 4 mol / L hydrochloric acid is preferably used, and the reaction time is preferably 30 seconds to 20 minutes, more preferably 6 to 15 minutes.

After the completion of the step (c), if necessary, it may be subjected to a purification step, an additive such as a stabilizer may be added as appropriate, the solution may be passed through a sterilization filter, diluted, and dispensed for formulation.

The purification step can be carried out, for example, by passing a liquid through a series of purification columns (cation exchange resin, ion retardation resin, octadecylsilylated silica gel and alumina).
The above embodiment includes the following technical ideas.
1. 1. ^{(A) [18} F] from ¹⁸ O enriched water containing fluoride ions and separating the ^[18 F] fluoride ions,
(B) 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-manno using ^{the [18 F] fluoride ion separated from the 18} O concentrated water. The process of carrying out the radioactive fluorination reaction of pyranose (TATM),
(C) A deprotection step of carrying out a hydrolysis reaction to obtain 2- [ ¹⁸ F] fluoro-2-deoxy-D-glucose ( ¹⁸ F-FDG).
Including
At the start of step (a), 300 GBq or more of [ ¹⁸ F] fluoride ion was used.
A method for producing ¹⁸ F-FDG, which uses 40 μg or more of the TATM per 1 GBq ^{of [18} F] fluoride ion at the start of step (a).
2. The step (a) ^{comprises activating [18} F] fluoride ions with potassium carbonate and a phase transfer catalyst.
^{The method for producing 18} F-FDG according to 1 above, wherein 4 to 20 μg of the potassium carbonate and 30 to 150 μg of the phase transfer catalyst are used per 1 GBq ^{of [18} F] fluoride ion at the start of the step (a).
3. 3. The step (a)
(A-1) ^{A step of bringing 18 O concentrated water containing [18} F] fluoride ions into contact with an anion exchange resin ^{to adsorb [18} F] fluoride ions on the anion exchange resin.
(A-2) A step of bringing the aqueous solution containing potassium carbonate into contact with the anion exchange resin ^{to elute the aqueous solution of [18 F] fluoride ions.}
(A-3) A step of heating the eluted [ ¹⁸ F] fluoride ion aqueous solution in the presence of the phase transfer catalyst and the water-soluble organic solvent to evaporate the water and the water-soluble organic solvent.
^{The method for producing 18} F-FDG according to 2 above, which comprises.
4. ^{The method for producing 18} F-FDG according to 2 or 3 above, wherein the phase transfer catalyst is cryptond.
5. ^{The method for producing 18} F-FDG according to any one of 2 to 4 above, wherein the water-soluble organic solvent is acetonitrile.
6. ^{The method for producing 18} F-FDG according to any one of 1 to 5 above ^{, wherein 600 to 1000 GBq of [18} F] fluoride ion is used at the start of the step (a).
7. ^{The method for producing 18} F-FDG according to any one of 1 to 6 above, wherein 40 to 150 μg of the TATM is used per 1 GBq ^{of [18} F] fluoride ion at the start of the step (a).
8. ^{The method for producing 18} F-FDG according to any one of 1 to 7 above, wherein the reaction time of the radioactive fluorination reaction in the step (b) is 1.5 to 7 minutes.
9. ^{The method for producing 18} F-FDG according to any one of 1 to 8 above, wherein the radioactive fluorination reaction in the step (b) is to fluorinate the TATM in [ ^{18 F] in acetonitrile.}
10. ^{The method for producing 18} F-FDG according to any one of 1 to 9 above, wherein the hydrolysis reaction in the step (c) is an acid hydrolysis reaction.
11. ^{The method for producing 18} F-FDG according to 10 above, wherein the hydrolysis reaction in the step (c) is carried out in the presence of hydrochloric acid.
12. ^{The method for producing 18} F-FDG according to 11 above, wherein the hydrolysis reaction in the step (c) has a reaction time of 6 to 15 minutes.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these contents.

Examples 1-5, Comparative Example 1
[Step (a)]
^{[18 F] Fluoride ion generated by proton irradiation of 18} O irradiated water with TR19 cyclotron (trade name, manufactured by Advanced Cyclotron Systems) is anion exchange resin cartridge (Sep-Pak Accell Plus Light QMA, manufactured by Waters). ), And retained by adsorbing and collecting on an anion exchange resin (step (a-1)). A solution (0.6 mL) in which the amount of potassium carbonate shown in Table 1 was dissolved in water was passed through the cartridge ^{to obtain a [18} F] potassium fluoride eluate (step (a-2)). A solution (1.5 mL) in which the amounts of Cryptofix 222 (trade name) shown in Table 1 were dissolved in acetonitrile was added to [ ¹⁸ F] potassium fluoride eluate and concentrated to dryness (step (a-3)). .. At the start of the step (a-2), about 1 minute and 30 seconds have passed from the start of the step (a-1), and at the start of the step (a-3), the start of the step (a-1). About 2 minutes had passed since that time.

[Step (b)]
A solution (1 mL) in which the amount of TATM shown in Table 1 was dissolved in acetonitrile was added to the residue, and the mixture was heated to 84 to 92 ° C. for reaction, and then concentrated to dryness (step). (B)).

[Step (c)]
A 1 mol / L hydrochloric acid solution (2.0 mL) was added to the residue, and the mixture was reacted under reflux, and then passed through a series of purification columns (cation exchange resin, ion retardation resin, octadecylsilylated silica gel and alumina). Further, the reaction vessel was washed with water for injection (10 mL), passed through a series of purification columns in the same manner, and then roughly filtered through a membrane filter ^{to obtain 18} F-FDG (step (c)).

The synthetic yield of the obtained ¹⁸ F-FDG was determined according to the following formula (1).
¹⁸ F-FDG synthesis yield (%) = B / A × 100 (1)
However, A and B are as follows.
^{A: Adsorption and collection of [18} F] fluoride ions on an anion exchange column (amount of radioactivity at the start of step (a-1)).
B: ^{18 The} amount of radioactivity after completion of purification of F-FDG.
Here, the total amount of radioactivity was calculated based on the start of adsorption and collection ^{of [18} F] fluoride ions on the anion exchange column. Moreover, CRC-712X (trade name, manufactured by CAPINTEC) was used for the measurement of the amount of radioactivity.

The results are shown in Table 1. From the results in Table 1, at the start of step (a), 300 GBq or more of [ ¹⁸ F] fluoride ion was used, and 40 μg of TATM per 1 GBq ^{of [18} F] fluoride ion at the start of step (a). In the cases of Examples 1 to 5 in which 40 μg or more of TATM was used as compared with Comparative Example 1 used below, a higher synthesis yield was obtained, and further, Examples 1 to 1 in which the amounts of potassium carbonate and the phase transfer catalyst used were increased. It can be seen that the variation in the synthesis yield is also small in 2 and 4 to 5.

Examples 6-11
^{Table shows the amount of [18} F] fluoride ion radioactivity at the start of step (a), the amount of TATM, potassium carbonate and phase transfer catalyst used, the reaction time of step (b), and the reaction time of step (c). An experiment was carried out in the same manner as in Example 1 except that the value was changed to the value shown in 2, and the synthesis yield was determined.

The results are shown in Table 2. ^{From the results in Table 2, 18} F-FDG can be obtained in good yield by setting the reaction time of the radioactive fluorination reaction to 1.5 to 7 minutes and the reaction time of the hydrolysis reaction to 6 to 15 minutes. Shown.

The present invention can be used to efficiently mass-produce ^{18 F-FDG used as a radiopharmaceutical.}

Claims (12)

^{(A) [18} F] from ¹⁸ O enriched water containing fluoride ions and separating the ^[18 F] fluoride ions,
(B) 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-manno using ^{the [18 F] fluoride ion separated from the 18} O concentrated water. The process of carrying out the radioactive fluorination reaction of pyranose (TATM),
(C) A deprotection step of carrying out a hydrolysis reaction to obtain 2- [ ¹⁸ F] fluoro-2-deoxy-D-glucose ( ¹⁸ F-FDG).
Including
At the start of step (a), 300 GBq or more of [ ¹⁸ F] fluoride ion was used.
A method for producing ¹⁸ F-FDG, which uses 40 μg or more of the TATM per 1 GBq ^{of [18} F] fluoride ion at the start of step (a). The step (a) ^{comprises activating [18} F] fluoride ions with potassium carbonate and a phase transfer catalyst.
^{The method for producing 18} F-FDG according to claim 1, wherein 4 to 20 μg of the potassium carbonate and 30 to 150 μg of the phase transfer catalyst are used per 1 GBq ^{of [18} F] fluoride ion at the start of the step (a). .. The step (a)
(A-1) ^{A step of bringing 18 O concentrated water containing [18} F] fluoride ions into contact with an anion exchange resin ^{to adsorb [18} F] fluoride ions on the anion exchange resin.
(A-2) A step of bringing the aqueous solution containing potassium carbonate into contact with the anion exchange resin ^{to elute the aqueous solution of [18 F] fluoride ions.}
(A-3) A step of heating the eluted [ ¹⁸ F] fluoride ion aqueous solution in the presence of the phase transfer catalyst and the water-soluble organic solvent to evaporate the water and the water-soluble organic solvent.
^{18. The} method for producing 18 F-FDG according to claim 2. ^{The method for producing 18} F-FDG according to claim 2 or 3, wherein the phase transfer catalyst is cryptond. ^{The method for producing 18} F-FDG according to any one of claims 2 to 4, wherein the water-soluble organic solvent is acetonitrile. ^{The method for producing 18} F-FDG according to any one of claims 1 to 5 ^{, wherein 600 to 1000 GBq of [18} F] fluoride ion is used at the start of the step (a). ^{The method for producing 18} F-FDG according to any one of claims 1 to 6, wherein 40 to 150 μg of the TATM is used per 1 GBq ^{of [18} F] fluoride ion at the start of the step (a). ^{The method for producing 18} F-FDG according to any one of claims 1 to 7, wherein the reaction time of the radioactive fluorination reaction in the step (b) is 1.5 to 7 minutes. ^{The method for producing 18} F-FDG according to any one of claims 1 to 8, wherein the radioactive fluorination reaction in the step (b) ^{carries out [18 F] fluorination of the TATM in acetonitrile.} .. ^{The method for producing 18} F-FDG according to any one of claims 1 to 9, wherein the hydrolysis reaction in the step (c) is an acid hydrolysis reaction. ^{The method for producing 18} F-FDG according to claim 10, wherein the hydrolysis reaction in the step (c) is carried out in the presence of hydrochloric acid. ^{The method for producing 18} F-FDG according to claim 11, wherein the hydrolysis reaction in the step (c) has a reaction time of 6 to 15 minutes.