WO2006068015A1 - Method of producing potassium [18f] fluoride and quaternary ammonium [18f] fluoride and method of producing radioactive fluorine-labeled organic compound by using the same - Google Patents

Method of producing potassium [18f] fluoride and quaternary ammonium [18f] fluoride and method of producing radioactive fluorine-labeled organic compound by using the same Download PDF

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WO2006068015A1
WO2006068015A1 PCT/JP2005/022947 JP2005022947W WO2006068015A1 WO 2006068015 A1 WO2006068015 A1 WO 2006068015A1 JP 2005022947 W JP2005022947 W JP 2005022947W WO 2006068015 A1 WO2006068015 A1 WO 2006068015A1
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fluoride
potassium
exchange resin
producing
anion exchange
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PCT/JP2005/022947
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French (fr)
Japanese (ja)
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Osamu Ito
Fumie Kurosaki
Masahito Toyama
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Nihon Medi-Physics Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01D—COMPOUNDS OF ALKALI METALS, i.e. LITHIUM, SODIUM, POTASSIUM, RUBIDIUM, CAESIUM, OR FRANCIUM
    • C01D3/00—Halides of sodium, potassium or alkali metals in general
    • C01D3/02—Fluorides
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01D—COMPOUNDS OF ALKALI METALS, i.e. LITHIUM, SODIUM, POTASSIUM, RUBIDIUM, CAESIUM, OR FRANCIUM
    • C01D3/00—Halides of sodium, potassium or alkali metals in general
    • C01D3/14—Purification
    • C01D3/16—Purification by precipitation or adsorption

Definitions

  • [18 F] - 2- Furuoro one 2- Dokishi one D- Gunorekosu hereinafter, [18 F] - abbreviated as FDG
  • FDG in the production of various radioactive fluorine-labeled organic compound, including, substrates minute the method for producing a radioactive fluorine-labeled organic compound, characterized by performing labeling using potassium [18 F] fluoride can suppress the occurrence of side reactions due to the solution and the [18 F] fluoride fourth en Moniumu.
  • Radioactive fluorine-labeled organic compounds are used in positron emission tomography (PET), which is one of medical diagnostic imaging techniques.
  • radioactive fluorine-labeled organic compounds mainly involves their precursors and [ 18 F] fluoride ions.
  • the former method is a method generally used for the synthesis of [ 18 F] -FDG and comprises the following steps. First, a 180- concentrated water containing [ 18 F] fluoride ions (hereinafter referred to as [ 18 F] -containing target water) is added to a column filled with a strongly basic anion exchange resin. To collect F] fluoride ions and collect ls o concentrated water. Next, the [ 18 F] fluoride ions collected on the strong basic anion exchange resin are eluted with an aqueous potassium carbonate solution, and the eluate is collected in a reaction vessel.
  • a 180- concentrated water containing [ 18 F] fluoride ions hereinafter referred to as [ 18 F] -containing target water
  • the [ 18 F] fluoride ions collected on the strong basic anion exchange resin are eluted with an aqueous potassium carbonate solution, and the eluate is collected in a reaction
  • the [ 18 F] fluoride ions collected in the strongly basic anion exchange resin are eluted with an aqueous solution of acetonitrile that dissolves tetraptylammonium bicarbonate.
  • a method for obtaining [ 18 F] _FDG by activating the [ 18 F] fluoride ion by evaporating the eluate and reacting with TATM is also disclosed (see Non-Patent Document 3). ).
  • the on-column method is a method in which a acetonitrile solution in which T ATM as a reaction substrate is dissolved is directly introduced into a column that collects [ 18 F] fluoride ions, and fluorinated labeling is performed.
  • a resin having a salt is packed in a column, and [ 18 F] -containing target water is introduced into this column to collect [ 18 F] fluoride ions.
  • a method for obtaining [ 18 F] FDG by flowing a acetonitrile into the column and then adding a acetonitrile solution in which TATM is dissolved is disclosed (see Patent Document 1).
  • Patent Document 1 JP-A-8-325169
  • Patent Document 2 Japanese Patent Laid-Open No. 11-295494
  • Non-patent ⁇ ffl ⁇ l K. Hamacher et al., Computer- aided synthesis (and AS) of No-carner- added 2_ [18F] Fluoro_2_deoxy_D_glucose: an Efficient Automated System for the A minopolyether-supported Nucleophilic Fluorination Applied Radiation and Isotopes , (Great Britain), Pergamon Press, 1990, 41, 1, p.49-55
  • Non-Patent Document 2 G. Stocklin and VW Pike (ed.), "Radiopharmaceuticals for Positron Emission Tomography, (Netherlands), Kluwer Academic Publishers, 1993, P133 Non-Patent Document 3: PA Culbert et al.,” Automated Synthesis of [ 18F] FDG using Tetrab utylammonium Bicarbonate “Applied Radiation and Isotopes, (Great Britain), Pergam on Press, 1995, 46, 9, p.887-891
  • [18 F] - 1-Amino - 3 Furuoroshikuro butene carboxylic acid (hereinafter, [18 F] - that FACBC) also in the synthesis of, side reactions such as Jen member by civilized reaction of the substrate to produce results This has been clarified by the inventors' investigation.
  • Radioactive fluorine has a very short half-life of 109.8 minutes, and its decay also occurs during the purification process. Therefore, if the purification process takes too much time S, the radiochemical purity of the resulting compound decreases, The yield is also reduced.
  • the present invention has been made in view of the above circumstances, and it is possible to produce a radioactive fluorine-labeled organic compound.
  • the purpose is to suppress the occurrence of side reactions caused by decomposition of the substrate.
  • the present inventors conducted extensive research based on this finding, and as a result, removed cationic impurities from 180- concentrated water containing [ 18 F] fluoride ion using a strongly acidic cation exchange resin.
  • [ 18 F] fluoride ions are adsorbed on a weakly basic anion exchange resin, and the adsorbed [ 18 F] fluoride ions are eluted in the absence of carbonate ions. It was found that the above problems could be overcome by labeling an organic compound with the [ 18 F] fluoride obtained in this way to produce a radioactive fluorine-labeled organic compound, and the present invention was completed.
  • [18 F] step 18 0 concentrated water containing fluoride ions is contacted with a strongly acidic cation exchange resin to remove cationic impurities, and then the 18 ⁇ concentrate It is brought into contact with a weakly basic anion exchange resin [18 F] adsorbing the fluoride ion in the weakly basic anion exchange resin, adsorbed on weakly basic anion exchange resin [18 F] Futsui spoon product
  • a method for producing [ 18 F] potassium fluoride comprising a step of eluting ions using an aqueous solution of potassium salt (excluding potassium carbonate and potassium hydrogen carbonate). More preferably, the potassium salt is a non-nucleophilic potassium salt, preferably a neutral potassium salt.
  • a radioactive fluorine-labeled organic compound comprising a step of labeling an organic compound using [ 18 F] potassium fluoride obtained by the above production method.
  • a manufacturing method is provided.
  • [18 F] 18 ⁇ - concentrated water containing fluoride ions is contacted with a strongly acidic cation exchange resin process for removing cations impurities, then the 18 ⁇ concentrate In contact with a weakly basic anion exchange resin to adsorb [ 18 F] fluoride ions to the weakly basic anion exchange resin, [ 18 F] Fluoride Ion fourth Anmoniumu salt (excluding bicarbonate) step of the solution eluting with a [18 F] Fourth Anmoniumu method of manufacturing a fluoride, which comprises a.
  • the fourth ammonium salt a compound represented by the following general formula (1) is preferably used.
  • R 1, R 2, R and R are each independently a straight-chain or branched C 1-22 carbon atom.
  • Alkyl chain following formula (2):
  • n is an integer between :! and 22
  • n 1 to 5
  • m 0 to 12
  • p is an integer of 1 or 2
  • Z represents a counter ion (excluding bicarbonate ion)
  • the 4th ammonium salt solution is preferably used in the form of an aqueous solution. However, if the solubility of the 4th ammonium salt used in water is low, an amphiphilic solvent such as acetonitrile is dissolved in water appropriately mixed. Can be used.
  • the [ 18 F] fluorinated fourth ammonium obtained by the above method is used.
  • a method for producing a radioactive fluorine-labeled organic compound comprising a step of labeling an organic compound using
  • the ion exchange resin refers to an insoluble synthetic resin having an exchangeable group, and is defined to include a porous type resin, a gel type resin, a polymer type resin, and the like.
  • Neutral potassium salt is a potassium salt that has a pH of 6-8 when dissolved in water at a concentration of about lOOmmolZL, and non-nucleophilic potassium salt is a nucleophilicity whose anion is lower than fluoride ion. It is defined as having a potassium salt.
  • [18 F] fluoride ions [18 F] can be eluted in the fourth Anmoniumu form potassium fluoride or [18 F] fluoride, with these fluoride
  • side reactions such as decomposition of the organic compound as a substrate can be suppressed.
  • the recovered 180- concentrated water since the recovered 180- concentrated water has cations removed, it can be reused in the next production without purification by distillation or the like.
  • [18 F] potassium fluoride and [18 F] fourth Anmoniumu process for producing fluoride according to the present invention, and method for producing a radioactive fluorine-labeled organic compound is described further in detail about using these .
  • the 180- concentrated water used in the present invention is water in which 90% or more of oxygen atoms constituting water molecules are composed of 180 , which is an oxygen isotope.
  • [18 F] 18 ⁇ - concentrated water having containing a fluoride ion ([18 F] containing target water) can be produced according to a conventional method, for example, be obtained by proton irradiation 18 O-concentrated solution as a target it can.
  • manufacturing method according to the present invention is different from the use of potassium carbonate aqueous solution [18 F] conventional method was eluted fluoride ions, in the absence of carbonate ions [18 F] fluoride ion This is a method of performing the collection and elution process.
  • the manufacturing method according to the present invention is roughly divided into two embodiments. Hereinafter, each embodiment will be described step by step.
  • the [ 18 F] -containing target water is brought into contact with the strongly acidic cation exchange resin to remove cation impurities such as heavy metal cations from the [ 18 F] -containing target water.
  • These cationic impurities may form strong salts with [ 18 F] fluoride ions in [ 18 F] -containing target water.
  • the weak basicity described later is used. It is difficult to adsorb and collect [ 18 F] fluoride ions on an anion exchange resin. Therefore, in order to collect the [18 F] fluoride ions by using a weakly basic anion exchange resin, a cation forming the [18 F] fluoride ions and salts, [18 F] fluoride Must be stripped from the fluoride ion.
  • Recovered 18 o-concentrated water is expensive and therefore desirable to be reused. However, if cation impurities are present, they cannot be reused unless they have undergone a process such as distillation. . By removing cation impurities in this step, it is possible to reuse the 18 ⁇ one concentrated water collected after the second step of Nag that performs processing such as distillation.
  • the strong acid cation exchange resin used in the first step may be a commercially available one, but is preferably used after being converted to a hydrogen type.
  • activation is performed, for example, by the following method.
  • the strong acid cation exchange resin is an ion exchange resin having a property of easily releasing an exchange group at a wide pH from an acidic side to an alkaline side and exchanging with a cation in an aqueous solution. Yes, it can be distinguished from weakly acidic cation exchange resins that have the property of reducing the exchange capacity of exchange groups and other cations in acidic solutions.
  • a weakly acidic cation exchange resin contains carboxylic acid or the like as a functional group, whereas a strongly acidic cation exchange resin has a sulfonic acid as a functional group.
  • the strongly acidic cation exchange resin used in the present invention is not particularly limited, but those using a styrene-dibutenebenzene copolymer as a solid phase carrier can be preferably used.
  • the use form of the strongly acidic cation exchange resin is not particularly limited as long as it can be sufficiently contacted with the [ 18 F] -containing target water, but it is preferably used by filling the column tube.
  • the amount of the strongly acidic cation exchange resin is appropriately selected according to the amount of [ 18 F] -containing target water to be treated. For example, 10 mL of [ 18 F] -containing target water is added using a 1 mL capacity column tube. When processing, it is sufficient to fill with 0.5 mL of wet resin.
  • the first obtained in the step [18 F] fluoride containing 18 0- enriched water is contacted with the weakly basic anion exchange resin, said [18 F] Futsui ⁇ containing Contained 18 0—Adsorbs and collects [ 18 F] fluoride ions contained in concentrated water, and 18 O—collects concentrated water.
  • [ 18 F] fluoride ions can be adsorbed onto the weakly basic anion exchange resin, and 18 O—concentrated water is separated from the resin to capture [ 18 F] fluoride ions. Can be gathered.
  • a weakly basic anion exchange resin is a wide base from the acidic side to the alkaline side, and unlike a strongly basic anion exchange resin having ion exchange ability at pH, the degree of dissociation is low on the alkaline side. It is a ion exchange resin that has ion exchange ability only from acidic to near neutral (operating pH: 0 to 9). Strongly basic anion exchange resins have quaternary ammonium as a functional group, while weakly basic anion exchange resins have:! ⁇ Tertiary amine as a functional group.
  • the weakly basic anion exchange resin to be used is not particularly limited, but a styrene-divinylbenzene copolymer, or a copolymer of acrylic acid and / or a derivative thereof and dibutenebenzene is used as a solid support:!
  • a weakly basic anion exchange resin having a functional group of is preferably used. It is more preferable to use a functional group having no counter ion.
  • Examples of the weakly basic anion exchange resin include a resin represented by the following formula (4).
  • P is a styrene-dibutylbenzene copolymer or acrylic copolymer
  • n is an integer from 1 to 10 and Y independently represents a methyl group, an ethyl group, a propyl group, or a butyl group
  • a weakly basic anion exchange resin is not particularly necessary to limit as long as it can sufficiently contact with the [18 F] fluoride containing 18 0- concentrated water, and packed in a column tube It is preferable to use it.
  • the amount of weakly basic anion exchange resin is theoretically determined based on the amount of [ 18 F] fluoride ion contained in the treated [ 18 F] hydrogen fluoride-containing 180- concentrated water and the function contained in the resin. In order to reliably capture [ 18 F] fluoride ions, it is preferable to use more resin if the amount of the group is equal.
  • the [ 18 F] fluoride collected in the second step On the potassium salt (excluding potassium carbonate and potassium hydrogen carbonate) with an aqueous solution as eluent to elute the [18 F] fluoride ions as [18 F] potassium fluoride solution.
  • the potassium salt is not particularly limited as long as it is other than potassium carbonate and potassium hydrogen carbonate, but an anion having a strong affinity for the weakly basic anion exchange resin is equivalent to that of [ 18 F] fluoride ion. It is desirable to use an aqueous salt solution.
  • the potassium salt it is more preferable to use a non-nucleophilic potassium salt, which is desirably a neutral potassium salt. More preferably, various organic acid salts or inorganic oxo acid salts can be used.
  • organic acid salt for example, an alkyl sulfonate, an arene sulfonate, and a perfluoroalkyl carboxylate can be used.
  • Alkyl sulfonates can be used in various forms. Particularly preferred are potassium trifluoromethanesulfonate, potassium methanesulfonate, potassium ethanesulfonate, potassium perfluorobutanesulfonate, and perfluorooctane. Potassium sulfonate can be used, and most preferably potassium trifluoromethanesulfonate or potassium methanesulfonate can be used.
  • the ability to use various arene sulfonic acids particularly preferably potassium benzene sulfonate, potassium 3-nitrobenzenesulfonate, potassium 12-nitrobenzenesulfonate, potassium 4-nitro-1-nitrobenzenesulfonate, Toluene-4-potassium sulfonate and dipotassium benzene-1,2-disulfonate can be used.
  • various perfluoroalkyl carboxylates is particularly preferable, and potassium trifluoroacetate can be used.
  • potassium oxoate having sulfur, phosphorus or boron can be used.
  • potassium oxalate containing sulfur potassium sulfate, potassium tetrathionate, potassium fluorosulfate, potassium thiosulfate or potassium pyrosulfite can be preferably used, and potassium sulfate can be particularly preferably used.
  • potassium oxalate containing phosphorus potassium dihydrogen phosphate or potassium hexafluorophosphate can be preferably used.
  • potassium oxalate containing boron potassium tetrafluoroborate can be preferably used.
  • neutral potassium salt is dissolved in water at a concentration of about 100 mmol / L.
  • the potassium salt having a pH of 6 to 8 is used, and the non-nucleophilic potassium salt is a potassium salt having a nucleophilicity whose anion is lower than that of fluoride ions.
  • Nucleophilicity is a term that expresses the magnitude of the reaction rate with carbon atoms, and low nucleophilicity means that the reaction rate with carbon atoms is relatively low. In many cases, the stronger the basicity, the higher the nucleophilicity.
  • the amount of the aqueous solution of the eluent used and the potassium salt concentration are adjusted so that the [ 18 F] fluoride ions collected in the weakly basic anion exchange resin can be sufficiently eluted.
  • the amount of aqueous solution is preferably 0.:! To 2 mL. 0.2 to 0 3mL is better than power S. If the amount of the aqueous solution to be used is too large, it is not preferable because it takes too much time for the heating and evaporating and drying process, which is the next step.
  • the potassium salt concentration need not be limited as long as the total amount of potassium is sufficient to elute [ 18 F] fluoride ions from the weakly basic anion exchange resin, but the total amount of potassium is not limited. It is preferable to adjust the molar ratio with respect to the collected [ 18 F] fluoride ions to be 1000 times or more. Here, if the total amount of potassium salt is small, the elution of [ 18 F] fluoride ions becomes insufficient, which is not preferable. For example, when eluting [ 18 F] fluoride ion equivalent to 200 MB q captured in a column packed with 0.2 mL of weakly basic anion exchange resin using potassium trifluoromethanesulfonate, 0. 3 mL of 133 mmol / L potassium trifluoromethanesulfonate aqueous solution was poured into the resin.
  • the [ 18 F] potassium fluoride solution recovered in the third step is placed in a reaction vessel, and after adding a phase transfer catalyst, it is heated to dryness to obtain [ 18 F] fluoride ions. Activate. Thereafter, a reaction substrate is added to perform a nucleophilic substitution reaction to obtain a radioactive fluorine-labeled organic compound. Since the water molecules [18 F] hydrated fluoride ion [18 F] to please the nucleophilicity of fluoride ions low, [18 F] fluoride ions by heating dryness is activated, labeled Reaction is possible.
  • the phase transfer catalyst is not particularly limited, and examples thereof include an aminopolyether. Specifically, Talibufix 222 (trade name, manufactured by Merck & Co., Inc.) can be used. [0030]
  • the reaction substrate is appropriately selected depending on the radioactive fluorine-labeled organic compound to be synthesized. For example
  • the first and second steps are performed in the same manner as in the first embodiment, and [ 18 F] fluoride ions are adsorbed and collected on the weakly basic anion exchange resin.
  • the force to dissolve the [ 18 F] fluoride ions collected in the second step with the eluent is used as the fourth ammonium salt solution.
  • the fourth ammonium salt solution is used as the eluent. Different from one embodiment.
  • R, R 1, R and R are each independently a linear or branched carbon number:!
  • n is an integer between :! and 22
  • n 1 to 5
  • m 0 to 12
  • p is an integer of 1 or 2
  • Z represents a counter ion (excluding bicarbonate ion)
  • the counter ion Z is an anion other than the bicarbonate ion, and is not limited as long as it is a monovalent anion that forms a salt with the fourth ammonium ion. Those that are nuclear are more preferred.
  • the meaning of non-nucleophilic is the same as in the case of non-nucleophilic potassium salt, and refers to a salt having an anion lower than that of fluoride ion.
  • perfluorinated alkane sulfonate ions, alkane sulfonate ions, arene sulfonate ions and the like are preferably used.
  • the fourth ammonium salt represented by the above formula (1) include, for example, tetrabutyl ammonium trifluoromethane sulfonic acid, tetramethyl ammonium trifluoromethane sulfonic acid, and tetraethyl ammonium trifluoromethane.
  • tetrabutylammonium trifluoromethanesulfonic acid or tetraethylammonium p-toluenesulfonic acid is used.
  • the fourth ammonium salt solution is preferably used in the form of an aqueous solution.
  • water in which an amphipathic solvent such as acetonitrile is appropriately mixed is used. It can be dissolved in
  • the amount of the eluent used and the concentration of the fourth ammonium salt are adjusted so that the [ 18 F] fluoride ion collected in the weakly basic anion exchange resin can be sufficiently eluted.
  • the liquid volume is preferably 0.:! ⁇ 2mL. More preferably, it is 3 mL.
  • the fourth ammonium salt concentration need not be limited as long as the total amount of the fourth ammonium salt is sufficient to elute [ 18 F] fluoride ions from the weakly basic anion exchange resin. It is preferable to adjust the total amount S of the fourth ammonium to a molar ratio of 1000 times or more with respect to the collected [ 18 F] fluoride ion. Here, when the total amount of the fourth ammonium salt is small, the elution of [ 18 F] fluoride ion becomes insufficient, which is preferable.
  • the fourth ammonium salt used as the eluent is itself a phase transfer catalyst, it is not necessary to add a phase transfer catalyst. Accordingly, the [ 18 F] 4th ammonium fluoride solution recovered in the third step is heated and evaporated to dryness as it is to activate [ 18 F] fluoride ions, and then reacted with the reaction substrate. Radiolabeled organic compounds can be labeled and synthesized.
  • TAFDG 6-Tetra-O-acetyl-2-fluoro-2-deoxydalose
  • PAG a by-product generated by decomposition of the reaction substrate
  • UV-visible spectrophotometer detection wavelength: 209 nm
  • Test example 1 0. 2 mmol 0. 2 mmol
  • Test Example 3 0. 3 mmol 0. 2 mmol [0041] The results are shown in Tables 3 and 4.
  • the production rate of the target product TAFDG shows a tendency to decrease when potassium carbonate is added to potassium fluoride.In particular, the result of adding 0.05 mmol of potassium carbonate (0.5 equivalent to potassium fluoride) (Test Example) In 3), the reaction time dropped to about 1.4% at 90 minutes (Table 3).
  • the aqueous potassium salt solution shown in Table 5 was passed through the column packed with the weakly basic anion exchange resin, and the aqueous solution was collected in a vial (capacity 3.5 mL).
  • a vial 1.5 mL of a solution of 53.1 z mol of Talyptofix 222 (trade name, manufactured by Merck) in 1 mL of acetonitrile is heated, heated in an oil bath at 110 ° C for 20 minutes, The acetonitrile was evaporated.
  • the procedure of adding 1 mL of acetonitrile and heating at 110 ° C. for 10 minutes was repeated twice, a solution of TATM41.6 ⁇ dissolved in 1 mL of acetonitrile was added, and the mixture was heated at 80 ° C. for 5 minutes.
  • UV-Vis spectrophotometer (Detection wavelength: 209 nm)
  • Test Example 6 Potassium methanesulfonate 133 ⁇ ol / L 0.3 mL
  • Test Example 7 Potassium sulfate 67 mmol / L 0.3 mL
  • Table 6 The results are shown in Table 6.
  • the residual rate of TATM was 3.6% (Test Example 4)
  • TATM The residual rate was 90% or more (Test Examples 5 to 7). From these results, it was confirmed that TATM was decomposed by the presence of potassium carbonate. It was also suggested that the decomposition of T ATM, which is a substrate, can be suppressed by using an aqueous potassium salt solution other than potassium carbonate as the eluent.
  • 0.3 mL of 133 mmol / L tetrabutyl ammonium trifluoromethanesulfonate solution (dissolved in 20% acetonitrile solution) is poured into the column filled with the above weakly basic anion exchange resin, and the solution is poured into a vial ( The volume was recovered to 3.5 mL).
  • 1.5 mL of acetonitrile was heated and heated in an oil bath at 110 ° C for 20 minutes to evaporate water and acetonitrile.
  • the procedure of adding 1 mL of acetonitrile and heating at 110 ° C. for 10 minutes was repeated twice, a solution of 41.6 ⁇ mol of TATM in 1 mL of acetonitrile was added, and the mixture was heated at 80 ° C. for 5 minutes.
  • reaction solution was dispensed with 5 x L, HPLC analysis was performed under the same conditions as in Test Examples 4 to 7, and TATM was quantified by the absolute calibration curve method. Using the calculated quantitative value of TATM, use formula (3) TATM residual rate% was obtained.
  • the residual ratio of TATM was 99.9% or more, and no degradation of the substrate was observed under these conditions.
  • the reaction solution was subjected to TLC analysis under the following conditions, and the radiochemical purity% was determined using the following calculation formula (4). Further, the% dissolution rate of [ 18 F] fluoride ion was determined from the following calculation formula (5).
  • TLC plate Silica Gel 60F254 (trade name, film thickness: 0.25 mm, manufactured by Merck)
  • reaction solution 5 / U was subjected to HPLC analysis under the following conditions, and the PAG production rate% was determined by the following calculation formula (6).
  • UV-Vis spectrophotometer (Detection wavelength: 209 nm)
  • the results are shown in Table 12.
  • the production rate of the PAG produced in Example 4 is about one-tenth of the production rate of the PAG produced in Comparative Example 1.
  • Toluenesulfonic acid [0062] The results are shown in Table 15.
  • the elution rate of TF] fluoride ion showed a value of 97% or more in all Examples. From this result, it was confirmed that the method using a fourth ammonium salt solution as the eluent can achieve the same high [ 18 F] fluorine elution rate as the conventional elution using potassium carbonate.
  • the radiochemical purity of the obtained [ 18 F] _TAFDG also shows a value of 70% or more, indicating that [ 18 F] -TAFDG, which is the synthesis target, can be synthesized by the method according to the present invention. It was done.
  • the present invention is useful for labeling organic compounds with radioactive fluorine, and can be used in fields where contrast agents and other radioactive fluorine-labeled compounds are used in medical image diagnosis.

Abstract

[PROBLEMS] To prevent the formation of impurities caused by the decomposition of a substrate in the process of producing a radioactive fluorine-labeled compound. [MEANS FOR SOLVING PROBLEMS] A method of producing potassium [18F] fluoride or quaternary ammonium [18F] fluoride characterized by comprising the step of contacting 18O-concentrated water containing [18F] fluoride ion with a strongly acidic cation exchange resin and thus removing cationic impurities, the next step of contacting the 18O-concentrated water with a weakly basic anion exchange resin and thus allowing the weakly basic anion exchange resin to adsorb the [18F] fluoride ion, and the step of eluting the [18F] fluoride ion having been adsorbed by the weakly basic anion exchange resin with the use of an aqueous solution of a potassium salt (excluding potassium carbonate and potassium hydrogencarbonate) or a solution of a quaternary ammonium salt (excluding hydrogen carbonate). A method of producing a radioactive fluorine-labeled organic compound which involves the step of labeling an organic compound with the use of the potassium [18F] fluoride or quaternary ammonium [18F] fluoride obtained by the above-described production method.

Description

明 細 書  Specification
[18F]フッ化カリウム及び [18F]フッ化第 4アンモニゥムの製造方法並びに それを用いた放射性フッ素標識有機化合物の製造方法 [18 F] method for producing potassium fluoride and [18 F] the production method of the fourth Anmoniumu fluoride and radioactive fluorine-labeled organic compound using the same
技術分野  Technical field
[0001] 本発明は、 [18F]フッ化カリウム及び [18F]フッ化第 4アンモニゥムの製造方法、並び に、これらの放射性フッ素標識有機化合物の製造における使用に関する。更に詳し くは、 [18F]— 2—フルォロ一 2—デォキシ一 D—グノレコース（以下、 [18F]— FDGと 略す)をはじめとする各種放射性フッ素標識有機化合物の製造において、基質の分 解に起因する副反応の発生を抑え得る [18F]フッ化カリウム及び [18F]フッ化第 4アン モニゥムを用いて標識を行うことを特徴とする放射性フッ素標識有機化合物の製造 方法に関する。 [0001] The present invention, [18 F] potassium fluoride and [18 F] fourth Anmoniumu process for producing fluoride, as well, to the use in the manufacture of these radioactive fluorine-labeled organic compound. Further For details, [18 F] - 2- Furuoro one 2- Dokishi one D- Gunorekosu (hereinafter, [18 F] - abbreviated as FDG) in the production of various radioactive fluorine-labeled organic compound, including, substrates minute the method for producing a radioactive fluorine-labeled organic compound, characterized by performing labeling using potassium [18 F] fluoride can suppress the occurrence of side reactions due to the solution and the [18 F] fluoride fourth en Moniumu.
背景技術  Background art
[0002] 放射性フッ素標識有機化合物は、医療用画像診断技術の一つである陽電子放出 型断層撮影（Positron Emission Tomography, PET)において利用されている。  [0002] Radioactive fluorine-labeled organic compounds are used in positron emission tomography (PET), which is one of medical diagnostic imaging techniques.
[0003] 放射性フッ素標識有機化合物の製造は、主にその前駆体と [18F]フッ化物イオン [0003] The production of radioactive fluorine-labeled organic compounds mainly involves their precursors and [ 18 F] fluoride ions.
8F_)との有機化学反応により行われている。 [18F]フッ化物イオンは、 18〇—濃縮水 をターゲットとしてプロトン照射することにより生成し、 18o—濃縮水に含有された状態 で得ること力 Sできる。生成した [18F]フッ化物イオンを有機化合物の標識に用いるに は、この180—濃縮水から [18F]フッ化物イオンを取り出すことが必要である。また、 18 O—濃縮水は非常に高価であるため、 [18F]フッ化物イオンを取り出した後に回収し て再利用することが望ましい。 8F_) and organic chemical reaction. [18 F] fluoride ion, 18 〇- concentrated water generated by proton irradiation as a target, 18 o-able power S is obtained in a state of being contained in the concentrated water. In order to use the produced [ 18 F] fluoride ion for labeling an organic compound, it is necessary to extract the [ 18 F] fluoride ion from this 180- concentrated water. Also, since 18 O-concentrated water is very expensive, it is desirable to collect and reuse [ 18 F] fluoride ions after they are extracted.
[0004] 放射性フッ素標識有機化合物の合成方法は種々提案されており、例えば、反応容 器内で標識合成を行う方法と、カラム内で標識合成を行うオンカラム法とが知られて いる。以下、 [18F]— FDGの合成を例にとり、それぞれの方法を説明する。 [0004] Various methods of synthesizing radioactive fluorine-labeled organic compounds have been proposed. For example, a method of performing label synthesis in a reaction vessel and an on-column method of performing label synthesis in a column are known. In the following, each method will be described by taking the synthesis of [ 18 F] — FDG as an example.
前者の方法は、 [18F]—FDGの合成に一般的に用いられている方法であり、以下 の工程により構成されている。まず、 [18F]フッ化物イオンを含有する 180—濃縮水（ 以下、 [18F]含有ターゲット水という）を、強塩基性陰イオン交換樹脂を充填したカラ ムに通して F]フッ化物イオンを捕集し、 lso 濃縮水を回収する。次に、該強塩基 性陰イオン交換樹脂に捕集された [18F]フッ化物イオンを、炭酸カリウム水溶液により 溶離させ、溶出液を反応容器に回収する。その後、該溶出液に相間移動触媒として ァミノポリエーテルを溶解させたァセトニトリル溶液をカ卩えて蒸発乾固させ、 [18F]フッ 化物イオンを活性化させる。この残渣に反応基質の 1 , 3， 4， 6—テトラ _〇_ァセチ ノレ一 2 0—トリフルォロメタンスルホニル一 β _D—マンノピラノース（以下、 ΤΑΤΜ という）を溶解させたァセトニトリル溶液を加えて求核置換反応を行わせ、最後に、 2 M塩酸を用いて脱保護を行い、 [18F] _FDGを得る（非特許文献 1、 2参照）。 The former method is a method generally used for the synthesis of [ 18 F] -FDG and comprises the following steps. First, a 180- concentrated water containing [ 18 F] fluoride ions (hereinafter referred to as [ 18 F] -containing target water) is added to a column filled with a strongly basic anion exchange resin. To collect F] fluoride ions and collect ls o concentrated water. Next, the [ 18 F] fluoride ions collected on the strong basic anion exchange resin are eluted with an aqueous potassium carbonate solution, and the eluate is collected in a reaction vessel. Thereafter, an acetonitrile solution in which aminopolyether is dissolved as a phase transfer catalyst is added to the eluate and evaporated to dryness to activate [ 18 F] fluoride ions. To this residue was added a acetonitrile solution in which the reaction substrate 1, 3, 4, 6-tetra_〇_acetylene 1 20-trifluoromethanesulfonyl 1 β_D-mannopyranose (hereinafter referred to as ΤΑΤΜ) was dissolved. A nucleophilic substitution reaction is performed, and finally, deprotection is performed using 2 M hydrochloric acid to obtain [ 18 F] _FDG (see Non-Patent Documents 1 and 2).
また、上記以外の方法として、強塩基性陰イオン交換樹脂に捕集された [18F]フッ 化物イオンを、テトラプチルアンモニゥム炭酸水素塩を溶解させたァセトニトリル水溶 液を用いて溶出した後、該溶出液を蒸発乾固することにより [18F]フッ化物イオンを活 性化させ、 TATMと反応させることにより、 [18F] _FDGを得る方法も開示されている (非特許文献 3参照)。 As another method, the [ 18 F] fluoride ions collected in the strongly basic anion exchange resin are eluted with an aqueous solution of acetonitrile that dissolves tetraptylammonium bicarbonate. In addition, a method for obtaining [ 18 F] _FDG by activating the [ 18 F] fluoride ion by evaporating the eluate and reacting with TATM is also disclosed (see Non-Patent Document 3). ).
[0005] 一方オンカラム法は、 [18F]フッ化物イオンを捕集したカラムに、反応基質である T ATMを溶解させたァセトニトリル溶液を直接導入し、フッ素化標識を行う方法である 例えば、ホスホニゥム塩を有する樹脂をカラムに充填し、このカラムに [18F]含有タ 一ゲット水を導入することによって [18F]フッ化物イオンを捕集する。このカラムにァセ トニトリルを流して脱水した後、 TATMを溶解させたァセトニトリル溶液を加え、 [18F] FDGを得る方法が開示されている（特許文献 1参照)。 On the other hand, the on-column method is a method in which a acetonitrile solution in which T ATM as a reaction substrate is dissolved is directly introduced into a column that collects [ 18 F] fluoride ions, and fluorinated labeling is performed. A resin having a salt is packed in a column, and [ 18 F] -containing target water is introduced into this column to collect [ 18 F] fluoride ions. A method for obtaining [ 18 F] FDG by flowing a acetonitrile into the column and then adding a acetonitrile solution in which TATM is dissolved is disclosed (see Patent Document 1).
[0006] また、前述した如ぐターゲットに用いる 18〇—濃縮水は、非常に高価であるため回 収して再利用することが望ましい。しかし、上述した方法では、回収した 18o—濃縮水 にターゲット容器等に由来する陽イオンが存在するため、再利用する際には蒸留等 の処理を行って該陽イオンを取り除く必要がある。蒸留等の操作は処理に時間がか 力、る上、 18o—濃縮水の回収量が減少する原因になる。この問題を解決する方法とし て、まず、 [18F]含有ターゲット水を強酸性陽イオン交換樹脂に接触させて陽イオン を取り除き、次いで弱塩基性陰イオン交換樹脂を用いて該ターゲット水から [18F]フッ 化物イオンを捕集し、 180—濃縮水を回収するとともに [18F]フッ化物イオンを得る方 法が開示されている（特許文献 2参照）。この方法により、回収した1 Ό—濃縮水を、 蒸留等の処理を行うことなぐ再利用することが可能となった。 [0006] Further, 18 〇- concentrated water used for如tool targets described above, it is desirable to reuse recovered because it is very expensive. However, in the method described above, cations derived from the target container and the like exist in the recovered 18 o-concentrated water, and therefore, when reusing, it is necessary to remove the cations by performing a treatment such as distillation. Distilling and other operations can be time consuming and can reduce the amount of 18 o-concentrated water recovered. As a method for solving this problem, first, [ 18 F] -containing target water is contacted with a strongly acidic cation exchange resin to remove cations, and then a weakly basic anion exchange resin is used to remove [ 18 F] Fluoride ions are collected, and 18 0—concentrated water is recovered and [ 18 F] fluoride ions are obtained. A law is disclosed (see Patent Document 2). This method makes it possible to reuse the recovered 1 % -concentrated water without performing a treatment such as distillation.
[0007] 特許文献 1 :特開平 8— 325169号公報 [0007] Patent Document 1: JP-A-8-325169
特許文献 2：特開平 11一 295494号公報  Patent Document 2: Japanese Patent Laid-Open No. 11-295494
非特許乂 ffl^l : K. Hamacher et al., Computer- aided synthesis (し AS) of No-carner- added 2_[18F]Fluoro_2_deoxy_D_glucose: an Efficient Automated System for the A minopolyether-supported Nucleophilic Fluorination Applied Radiation and Isotopes, (Great Britain), Pergamon Press, 1990， 41, 1, p.49-55  Non-patent 乂 ffl ^ l: K. Hamacher et al., Computer- aided synthesis (and AS) of No-carner- added 2_ [18F] Fluoro_2_deoxy_D_glucose: an Efficient Automated System for the A minopolyether-supported Nucleophilic Fluorination Applied Radiation and Isotopes , (Great Britain), Pergamon Press, 1990, 41, 1, p.49-55
非特許文献 2 : G. Stocklin and V. W. Pike (ed.), "Radiopharmaceuticals for Positron Emission Tomography , (Netherlands), Kluwer Academic Publishers, 1993, P133 非特許文献 3 : P. A. Culbert et al., "Automated Synthesis of [18F]FDG using Tetrab utylammonium Bicarbonate" Applied Radiation and Isotopes, (Great Britain), Pergam on Press, 1995， 46, 9, p.887-891  Non-Patent Document 2: G. Stocklin and VW Pike (ed.), "Radiopharmaceuticals for Positron Emission Tomography, (Netherlands), Kluwer Academic Publishers, 1993, P133 Non-Patent Document 3: PA Culbert et al.," Automated Synthesis of [ 18F] FDG using Tetrab utylammonium Bicarbonate "Applied Radiation and Isotopes, (Great Britain), Pergam on Press, 1995, 46, 9, p.887-891
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0008] し力、しながら、従来の方法では、 [18F]フッ化物イオンによる標識工程にて、好ましく ない副反応が生じる場合があることが、発明者等の検討の結果明らかとなった。例え ば、 [18F] _FDGの合成において、副反応により反応基質の分解が生じ、 1 , 2， 3， 4, 6—ペンター〇一ァセチルー 2—デォキシ一 D—グルコース（以下、 PAGという） 等の不純物が生成する場合があった。また、 [18F]— 1—ァミノ— 3—フルォロシクロ ブテンカルボン酸（以下、 [18F]— FACBCという）の合成においても、基質の開化反 応によりジェン体が生成するなどの副反応が生じることが、発明者等の検討により明 らかとなつた。 However, as a result of studies by the inventors, it has become clear that in the conventional method, an undesirable side reaction may occur in the labeling step with [ 18 F] fluoride ions. . For example, in the synthesis of [ 18 F] _FDG, decomposition of the reaction substrate occurs due to side reactions, such as 1, 2, 3, 4, 6-penter 0-acetylyl 2-deoxy 1-D-glucose (hereinafter referred to as PAG), etc. In some cases, impurities were generated. Also, [18 F] - 1-Amino - 3 Furuoroshikuro butene carboxylic acid (hereinafter, [18 F] - that FACBC) also in the synthesis of, side reactions such as Jen member by civilized reaction of the substrate to produce results This has been clarified by the inventors' investigation.
このような不純物が生成すると、 目的物の収率が低下し、さらにその後の精製工程 に長時間を要する場合がある。放射性フッ素は半減期が 109. 8分と非常に短ぐま た、その崩壊は精製工程中においても起こるため、精製工程に時間力 Sかかりすぎると 、得られる化合物の放射化学的純度が低下し、その収量も少なくなる。  When such impurities are produced, the yield of the target product is lowered, and further purification steps may take a long time. Radioactive fluorine has a very short half-life of 109.8 minutes, and its decay also occurs during the purification process. Therefore, if the purification process takes too much time S, the radiochemical purity of the resulting compound decreases, The yield is also reduced.
[0009] 本発明は、上記事情に鑑みてなされたもので、放射性フッ素標識有機化合物の製 造において、基質の分解に起因する副反応の発生を抑えることを目的とする。 [0009] The present invention has been made in view of the above circumstances, and it is possible to produce a radioactive fluorine-labeled organic compound. The purpose is to suppress the occurrence of side reactions caused by decomposition of the substrate.
課題を解決するための手段  Means for solving the problem
[0010] 本発明者等は、後述の試験例に示すように、上記のごとき副反応が、炭酸イオンの 存在下において促進されていることを示唆する試験結果を得た。従来法においては [0010] As shown in the following test examples, the present inventors obtained a test result suggesting that the side reaction as described above was promoted in the presence of carbonate ions. In the conventional method
、 [18F]フッ化物イオンに比べて大過剰の炭酸イオンが反応溶液中に存在しており、 この炭酸イオンが副反応の発生に大きく影響することが確認された。 A large excess of carbonate ion was present in the reaction solution compared to [ 18 F] fluoride ion, and it was confirmed that this carbonate ion greatly affects the occurrence of side reactions.
そこで本発明者等はこの知見に基づき鋭意研究を重ねた結果、 [18F]フッ化物ィォ ンを含有する 18〇—濃縮水から強酸性陽イオン交換樹脂を用いて陽イオン不純物を 除去し、次いで弱塩基性陰イオン交換樹脂に [18F]フッ化物イオンを吸着させ、該吸 着した [18F]フッ化物イオンを炭酸イオンの非存在下にて溶出して製造し、このように して得られた [18F]フッ化物を用いて有機化合物を標識して放射性フッ素標識有機 化合物を製造することにより、上記問題を克服し得ることを見出し、本発明を完成した Therefore, the present inventors conducted extensive research based on this finding, and as a result, removed cationic impurities from 180- concentrated water containing [ 18 F] fluoride ion using a strongly acidic cation exchange resin. Next, [ 18 F] fluoride ions are adsorbed on a weakly basic anion exchange resin, and the adsorbed [ 18 F] fluoride ions are eluted in the absence of carbonate ions. It was found that the above problems could be overcome by labeling an organic compound with the [ 18 F] fluoride obtained in this way to produce a radioactive fluorine-labeled organic compound, and the present invention was completed.
[0011] 即ち、本発明は、 [18F]フッ化物イオンを含有する 180—濃縮水を強酸性陽イオン 交換樹脂に接触させて陽イオン不純物を除去する工程、次いで該 18〇 濃縮水を弱 塩基性陰イオン交換樹脂に接触させて [18F]フッ化物イオンを該弱塩基性陰イオン 交換樹脂に吸着させる工程、該弱塩基性陰イオン交換樹脂に吸着した [18F]フツイ匕 物イオンをカリウム塩 (ただし、炭酸カリウム及び炭酸水素カリウムを除く）水溶液を用 レ、て溶出する工程、を含むことを特徴とする [18F]フッ化カリウムの製造方法である。 該カリウム塩は中性カリウム塩であることが好ましぐ非求核性カリウム塩であることが より望ましい。 [0011] That is, the present invention, [18 F] step 18 0 concentrated water containing fluoride ions is contacted with a strongly acidic cation exchange resin to remove cationic impurities, and then the 18 〇 concentrate It is brought into contact with a weakly basic anion exchange resin [18 F] adsorbing the fluoride ion in the weakly basic anion exchange resin, adsorbed on weakly basic anion exchange resin [18 F] Futsui spoon product A method for producing [ 18 F] potassium fluoride, comprising a step of eluting ions using an aqueous solution of potassium salt (excluding potassium carbonate and potassium hydrogen carbonate). More preferably, the potassium salt is a non-nucleophilic potassium salt, preferably a neutral potassium salt.
また、本発明の他の局面によれば、上記製造方法で得られた [18F]フッ化カリウムを 用いて有機化合物を標識する工程を含むことを特徴とする放射性フッ素標識有機化 合物の製造方法が提供される。 According to another aspect of the present invention, there is provided a radioactive fluorine-labeled organic compound comprising a step of labeling an organic compound using [ 18 F] potassium fluoride obtained by the above production method. A manufacturing method is provided.
[0012] また、本発明は、 [18F]フッ化物イオンを含有する 18〇—濃縮水を強酸性陽イオン交 換樹脂に接触させて陽イオン不純物を除去する工程、次いで該 18〇 濃縮水を弱塩 基性陰イオン交換樹脂に接触させて [18F]フッ化物イオンを該弱塩基性陰イオン交 換樹脂に吸着させる工程、該弱塩基性陰イオン交換樹脂に吸着した [18F]フッ化物 イオンを第 4アンモニゥム塩 (ただし、炭酸水素塩を除く）溶液を用いて溶出する工程 、を含むことを特徴とする [18F]フッ化第 4アンモニゥムの製造方法である。ここで、該 第 4アンモニゥム塩は、下記一般式（1)で示される化合物を用いることが好ましい。 [0012] Further, the present invention, [18 F] 18 〇- concentrated water containing fluoride ions is contacted with a strongly acidic cation exchange resin process for removing cations impurities, then the 18 〇 concentrate In contact with a weakly basic anion exchange resin to adsorb [ 18 F] fluoride ions to the weakly basic anion exchange resin, [ 18 F] Fluoride Ion fourth Anmoniumu salt (excluding bicarbonate) step of the solution eluting with a [18 F] Fourth Anmoniumu method of manufacturing a fluoride, which comprises a. Here, as the fourth ammonium salt, a compound represented by the following general formula (1) is preferably used.
[化 4] [Chemical 4]
Ri Ri
R + I— Z - …（"！）  R + I— Z-… ("!)
I  I
〔式中、 R , R , R及び Rは、各々独立に、直鎖若しくは分岐鎖の炭素数 1〜22の [In the formula, R 1, R 2, R and R are each independently a straight-chain or branched C 1-22 carbon atom.
1 2 3 4  1 2 3 4
アルキル鎖、下記式（2)： Alkyl chain, following formula (2):
[化 5]
Figure imgf000007_0001
[Chemical 5]
Figure imgf000007_0001
(式（2)において、 nは:!〜 22の整数)  (In formula (2), n is an integer between :! and 22)
で示される基、 A group represented by
又は下記式（3)： Or the following formula (3):
[化 6] - [ NHCO- iCH )m]p- … )[Chemical 6]-[NHCO- iCH) m ] p- …)
Figure imgf000007_0002
Figure imgf000007_0002
(式（3)において、 nは 1〜5、 mは 0〜12、 pは 1又は 2の整数）  (In formula (3), n is 1 to 5, m is 0 to 12, p is an integer of 1 or 2)
で示される基； A group represented by:
Zは対イオン (ただし、炭酸水素イオンは除く）を表す〕  Z represents a counter ion (excluding bicarbonate ion)
第 4アンモニゥム塩溶液は、水溶液の状態で用いることが望ましいが、用いる第 4ァ ンモニゥム塩の水に対する溶解度が低い場合には、ァセトニトリル等の両親媒性の溶 媒を適宜混合した水に溶解させて用いることができる。  The 4th ammonium salt solution is preferably used in the form of an aqueous solution. However, if the solubility of the 4th ammonium salt used in water is low, an amphiphilic solvent such as acetonitrile is dissolved in water appropriately mixed. Can be used.
また、本発明の他の局面によれば、上記方法で得られた [18F]フッ化第 4アンモニゥ ムを用いて有機化合物を標識する工程を含むことを特徴とする放射性フッ素標識有 機化合物の製造方法が提供される。 According to another aspect of the present invention, the [ 18 F] fluorinated fourth ammonium obtained by the above method is used. There is provided a method for producing a radioactive fluorine-labeled organic compound comprising a step of labeling an organic compound using
[0014] 尚、本発明においてイオン交換樹脂とは、交換能のある基を有する不溶性の合成 樹脂をいい、多孔質型、ゲル型、ポリマー型などの樹脂を含むものと定義する。また、 中性カリウム塩とは水に約 lOOmmolZLの濃度で溶解した場合の pHが 6〜8となる カリウム塩、非求核性カリウム塩とは陰イオンがフッ化物イオンよりも低い求核性を有 するカリウム塩と定義する。  In the present invention, the ion exchange resin refers to an insoluble synthetic resin having an exchangeable group, and is defined to include a porous type resin, a gel type resin, a polymer type resin, and the like. Neutral potassium salt is a potassium salt that has a pH of 6-8 when dissolved in water at a concentration of about lOOmmolZL, and non-nucleophilic potassium salt is a nucleophilicity whose anion is lower than fluoride ion. It is defined as having a potassium salt.
発明の効果  The invention's effect
[0015] 本発明によれば、 [18F]フッ化物イオンを [18F]フッ化カリウム又は [18F]フッ化第 4 アンモニゥムの形態で溶出することができ、これらのフッ化物を用いて有機化合物を 標識した場合、基質たる有機化合物の分解等の副反応を抑えることができる。更に、 回収した 18〇—濃縮水は陽イオンが除去されているので、蒸留等により精製すること なく次の製造に再利用できる。 According to [0015] the present invention, [18 F] fluoride ions [18 F] can be eluted in the fourth Anmoniumu form potassium fluoride or [18 F] fluoride, with these fluoride When an organic compound is labeled, side reactions such as decomposition of the organic compound as a substrate can be suppressed. Furthermore, since the recovered 180- concentrated water has cations removed, it can be reused in the next production without purification by distillation or the like.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0016] 以下、本発明に係る [18F]フッ化カリウム及び [18F]フッ化第 4アンモニゥムの製造 方法、並びに、これらを用いた放射性フッ素標識有機化合物の製造方法について更 に詳しく説明する。 [0016] Hereinafter, [18 F] potassium fluoride and [18 F] fourth Anmoniumu process for producing fluoride according to the present invention, and method for producing a radioactive fluorine-labeled organic compound is described further in detail about using these .
本発明において使用される 180—濃縮水は、水分子を構成する酸素原子の 90% 以上が、酸素の同位体である 180で構成された水である。 [18F]フッ化物イオンを含 有する 18〇—濃縮水（[18F]含有ターゲット水）は、常法に従って製造でき、例えば、 18 O—濃縮水をターゲットとしてプロトン照射することにより得ることができる。 The 180- concentrated water used in the present invention is water in which 90% or more of oxygen atoms constituting water molecules are composed of 180 , which is an oxygen isotope. [18 F] 18 〇- concentrated water having containing a fluoride ion ([18 F] containing target water) can be produced according to a conventional method, for example, be obtained by proton irradiation 18 O-concentrated solution as a target it can.
[0017] 本発明に係る製造方法は、炭酸カリウム水溶液を使用して [18F]フッ化物イオンを 溶出していた従来法とは異なり、炭酸イオンの非存在下で [18F]フッ化物イオンの捕 集及び溶出工程を行う方法である。 [0017] manufacturing method according to the present invention is different from the use of potassium carbonate aqueous solution [18 F] conventional method was eluted fluoride ions, in the absence of carbonate ions [18 F] fluoride ion This is a method of performing the collection and elution process.
[18F]フッ化物イオンを陰イオン交換樹脂を用レ、て吸着捕集するためには、官能基 とその対イオンとの親和力が、 [18F]フッ化物イオンとの親和力と同等以下である陰ィ オン交換樹脂を用いるか、又は、官能基が対イオンを有していない陰イオン交換樹 脂を用いることが望ましい。そこで本発明では、このような条件を満たす樹脂として、 弱塩基性陰イオン交換樹脂を用いる事とした。 In order to adsorb and collect [ 18 F] fluoride ions using an anion exchange resin, the affinity between the functional group and its counter ion must be less than or equal to that of [ 18 F] fluoride ions. It is desirable to use an anion exchange resin or an anion exchange resin whose functional group does not have a counter ion. Therefore, in the present invention, as a resin that satisfies such conditions, We decided to use a weakly basic anion exchange resin.
本発明に係る製造方法には、大きく分けて二つの実施形態がある。以下、それぞ れの実施形態につき、工程ごとに説明する。  The manufacturing method according to the present invention is roughly divided into two embodiments. Hereinafter, each embodiment will be described step by step.
[0018] (第 1実施形態）  [0018] (First embodiment)
まず、溶離液としてカリウム塩 (ただし、炭酸カリウム及び炭酸水素カリウムを除く）水 溶液を用いる製造方法について説明する。  First, a production method using an aqueous solution of potassium salt (excluding potassium carbonate and potassium hydrogen carbonate) as an eluent will be described.
第一の工程では、 [18F]含有ターゲット水を強酸性陽イオン交換樹脂に接触させる ことにより、 [18F]含有ターゲット水から重金属陽イオン等の陽イオン不純物を取り除く 。 18〇—濃縮水は、プロトン照射を行う際にステンレスや銀などの金属製のターゲット ボックスに納められているため、このターゲットボックスから溶出する陽イオンを不純物 として含有する。 In the first step, the [ 18 F] -containing target water is brought into contact with the strongly acidic cation exchange resin to remove cation impurities such as heavy metal cations from the [ 18 F] -containing target water. 18 〇—Concentrated water is contained in a target box made of metal such as stainless steel or silver when proton irradiation is performed, and therefore contains cations eluted from this target box as impurities.
これらの陽イオン不純物は [18F]含有ターゲット水中で [18F]フッ化物イオンと強固 な塩を形成している場合があり、そのような塩を形成している場合、後述する弱塩基 性陰イオン交換樹脂に [18F]フッ化物イオンを吸着させて捕集することは困難である 。従って、弱塩基性陰イオン交換樹脂を用いて [18F]フッ化物イオンを捕集するため には、 [18F]フッ化物イオンと塩を形成している陽イオンを、 [18F]フッ化物イオンから 引き剥がす必要がある。そこで、当該第一の工程で [18F]フッ化物イオン力 陽ィォ ン不純物を引き剥がすことにより、第二の工程にて [18F]フッ化物イオンを弱塩基性 陰イオン交換樹脂に吸着させることが容易になる。 These cationic impurities may form strong salts with [ 18 F] fluoride ions in [ 18 F] -containing target water. When such salts are formed, the weak basicity described later is used. It is difficult to adsorb and collect [ 18 F] fluoride ions on an anion exchange resin. Therefore, in order to collect the [18 F] fluoride ions by using a weakly basic anion exchange resin, a cation forming the [18 F] fluoride ions and salts, [18 F] fluoride Must be stripped from the fluoride ion. Therefore, the by peeling the [18 F] fluoride ion force cation I O emissions impurity in the first step, adsorbed on the second weakly basic anion exchange resin [18 F] fluoride ion in the step It becomes easy to make.
また、回収した 18o—濃縮水は高価であるので再利用することが望ましいが、陽ィォ ン不純物が存在している場合は、蒸留等の工程を経た後でないと再利用することが できない。本工程にて陽イオン不純物を除去することにより、蒸留等の処理を行うこと なぐ第二の工程後に回収した 18〇一濃縮水を再利用することが可能となる。 Recovered 18 o-concentrated water is expensive and therefore desirable to be reused. However, if cation impurities are present, they cannot be reused unless they have undergone a process such as distillation. . By removing cation impurities in this step, it is possible to reuse the 18 〇 one concentrated water collected after the second step of Nag that performs processing such as distillation.
[0019] 第一の工程で用レ、る強酸性陽イオン交換樹脂は、市販のものを使用できるが、水 素型に変換して使用するのが好ましい。本発明で使用する際には、例えば以下の方 法により活性化を行う。 [0019] The strong acid cation exchange resin used in the first step may be a commercially available one, but is preferably used after being converted to a hydrogen type. When used in the present invention, activation is performed, for example, by the following method.
まず、強酸性陽イオン交換樹脂約 1 OOmLを適当なガラス製のカラム管に充填する 。次に、約 500mLの lmol/L塩酸水溶液をカラム管に通過させ、樹脂のイオン型を 水素型に変換する。その後、溶離液の液性が中性になるまで脱イオン水でカラム中 の樹脂を洗浄する。このように活性化された強酸性陽イオン交換樹脂に [18F]含有タ 一ゲット水を接触させると、陽イオン不純物と樹脂の水素イオンが交換されて、 [18F] フツイ匕水素含有 18o—濃縮水となる。 First, about 1 OOmL of strongly acidic cation exchange resin is packed into a suitable glass column tube. Next, about 500 mL of lmol / L hydrochloric acid aqueous solution is passed through the column tube, and the ionic form of the resin is changed. Convert to hydrogen form. Then wash the resin in the column with deionized water until the eluent is neutral. When [ 18 F] -containing target water is brought into contact with the strongly acidic cation exchange resin thus activated, the cation impurities and the hydrogen ions of the resin are exchanged, and [ 18 F] fluorine-hydrogen containing 18 o—Concentrated water.
[0020] なお、強酸性陽イオン交換樹脂とは、酸性側からアルカリ性側までの広レ、 pHにて 容易に交換基を放出して水溶液中の陽イオンと交換する性質を持つイオン交換樹脂 であり、酸性溶液中では交換基と他の陽イオンとの交換能が低下する性質を持つ弱 酸性陽イオン交換樹脂と区別される。弱酸性陽イオン交換樹脂が、官能基としてカル ボン酸等を含むのに対し、強酸性陽イオン交換樹脂はスルホン酸を官能基として有 している。本発明で使用する強酸性陽イオン交換樹脂としては特に限定されないが、 スチレン一ジビュルベンゼン共重合体を固相担体としたものを好ましく用いることがで きる。 [0020] It should be noted that the strong acid cation exchange resin is an ion exchange resin having a property of easily releasing an exchange group at a wide pH from an acidic side to an alkaline side and exchanging with a cation in an aqueous solution. Yes, it can be distinguished from weakly acidic cation exchange resins that have the property of reducing the exchange capacity of exchange groups and other cations in acidic solutions. A weakly acidic cation exchange resin contains carboxylic acid or the like as a functional group, whereas a strongly acidic cation exchange resin has a sulfonic acid as a functional group. The strongly acidic cation exchange resin used in the present invention is not particularly limited, but those using a styrene-dibutenebenzene copolymer as a solid phase carrier can be preferably used.
強酸性陽イオン交換樹脂の使用形態は、 [18F]含有ターゲット水と十分に接触可能 である限り特に限定する必要は無レ、が、カラム管に充填して用いることが好ましい。 強酸性陽イオン交換樹脂の量としては、処理する [18F]含有ターゲット水の量に応じ て適宜選択される力 例えば容量 lmLのカラム管を用いて 10mLの [18F]含有ター ゲット水を処理する場合は、 0. 5mLの湿潤樹脂を充填すれば十分である。 The use form of the strongly acidic cation exchange resin is not particularly limited as long as it can be sufficiently contacted with the [ 18 F] -containing target water, but it is preferably used by filling the column tube. The amount of the strongly acidic cation exchange resin is appropriately selected according to the amount of [ 18 F] -containing target water to be treated. For example, 10 mL of [ 18 F] -containing target water is added using a 1 mL capacity column tube. When processing, it is sufficient to fill with 0.5 mL of wet resin.
[0021] 第二の工程では、第一の工程で得られた [18F]フッ化水素含有 180—濃縮水を弱 塩基性陰イオン交換樹脂に接触させ、該 [18F]フツイ匕水素含有 180—濃縮水に含ま れる [18F]フッ化物イオンを吸着捕集するとともに 18〇—濃縮水を回収する。この工程 により、弱塩基性陰イオン交換樹脂上に [18F]フッ化物イオンを吸着させることができ 、 18〇—濃縮水を該樹脂から分離することにより、 [18F]フッ化物イオンを捕集すること ができる。 [0021] In the second step, the first obtained in the step [18 F] fluoride containing 18 0- enriched water is contacted with the weakly basic anion exchange resin, said [18 F] Futsui匕水containing Contained 18 0—Adsorbs and collects [ 18 F] fluoride ions contained in concentrated water, and 18 O—collects concentrated water. By this process, [ 18 F] fluoride ions can be adsorbed onto the weakly basic anion exchange resin, and 18 O—concentrated water is separated from the resin to capture [ 18 F] fluoride ions. Can be gathered.
[0022] 弱塩基性陰イオン交換樹脂とは、酸性側からアルカリ性側までの広レ、 pHにてィォ ン交換能を有する強塩基性陰イオン交換樹脂と異なり、アルカリ性側では解離度が 低ぐ主に酸性から中性付近まで (操作 pH : 0〜9)でのみイオン交換能を有するィォ ン交換樹脂である。強塩基性陰イオン交換樹脂が、 4級アンモニゥムを官能基とする のに対し、弱塩基性陰イオン交換樹脂は、：!〜 3級アミンを官能基として有している。 使用する弱塩基性陰イオン交換樹脂としては特に限定されないが、スチレンージビ ニルベンゼン共重合体、又はアクリル酸及び/又はその誘導体とジビュルベンゼン の共重合体を固相担体とし、：!〜 3級アミンを官能基とした弱塩基性陰イオン交換樹 脂が好ましく用いられる。また、官能基に対イオンを有しないものを用いるのがより好 ましい。 [0022] A weakly basic anion exchange resin is a wide base from the acidic side to the alkaline side, and unlike a strongly basic anion exchange resin having ion exchange ability at pH, the degree of dissociation is low on the alkaline side. It is a ion exchange resin that has ion exchange ability only from acidic to near neutral (operating pH: 0 to 9). Strongly basic anion exchange resins have quaternary ammonium as a functional group, while weakly basic anion exchange resins have:! ~ Tertiary amine as a functional group. The weakly basic anion exchange resin to be used is not particularly limited, but a styrene-divinylbenzene copolymer, or a copolymer of acrylic acid and / or a derivative thereof and dibutenebenzene is used as a solid support:! A weakly basic anion exchange resin having a functional group of is preferably used. It is more preferable to use a functional group having no counter ion.
弱塩基性陰イオン交換樹脂としては、例えば、下記式 (4)で表される樹脂が挙げら れる。  Examples of the weakly basic anion exchange resin include a resin represented by the following formula (4).
[化 7]  [Chemical 7]
、 ,
P— (CH2)n ~ N
Figure imgf000011_0001
… 4 ) P— (CH 2 ) n ~ N
Figure imgf000011_0001
… Four )
Y  Y
(式中、 Pはスチレン—ジビュルベンゼン共重合体又はアクリル共重合体、 nは 1〜： 10 までの整数、 Yはそれぞれ独立にメチル基、ェチル基、プロピル基又はブチル基を 表す） (In the formula, P is a styrene-dibutylbenzene copolymer or acrylic copolymer, n is an integer from 1 to 10 and Y independently represents a methyl group, an ethyl group, a propyl group, or a butyl group)
[0023] 弱塩基性陰イオン交換樹脂の使用形態は、 [18F]フッ化水素含有 180—濃縮水と 十分に接触可能である限り特に限定する必要は無いが、カラム管に充填して用いる ことが好ましい。弱塩基性陰イオン交換樹脂の量は、理論的には処理する [18F]フッ 化水素含有 180—濃縮水に含まれる [18F]フッ化物イオンの量と、樹脂に含まれる官 能基の量が等量であれば良レ、が、確実に [18F]フッ化物イオンを捕捉するためには、 より多くの樹脂を用いることが好ましい。具体的には、例えば 185GBq ( [18F]フツイ匕 物イオンとして約 3nmol相当）の [18F]フッ化水素含有 180—濃縮水を処理する場合 であって、用いる樹脂が官能基濃度 0. 8meq/mLの樹脂である場合は、 0. 2mL の湿潤樹脂を充填すれば十分である。 Using the form of [0023] a weakly basic anion exchange resin is not particularly necessary to limit as long as it can sufficiently contact with the [18 F] fluoride containing 18 0- concentrated water, and packed in a column tube It is preferable to use it. The amount of weakly basic anion exchange resin is theoretically determined based on the amount of [ 18 F] fluoride ion contained in the treated [ 18 F] hydrogen fluoride-containing 180- concentrated water and the function contained in the resin. In order to reliably capture [ 18 F] fluoride ions, it is preferable to use more resin if the amount of the group is equal. Specifically, for example 185GBq a case of processing a [18 F] fluoride containing 18 0- concentrated water ([18 F] Futsui spoon was about 3nmol equivalent as ions) resin used functional group concentration 0 If the resin is 8 meq / mL, it is sufficient to fill it with 0.2 mL of wet resin.
[0024] 第二の工程にて回収した 18〇—濃縮水は、第一の工程にて陽イオン不純物が除去 されているので、特に蒸留等の処理を施すことなぐ [18F]フッ化物イオンの製造に再 利用することができる。 [0024] Since 18 cation-concentrated water recovered in the second step is free of cationic impurities in the first step, it is not subjected to any treatment such as distillation [ 18 F] fluoride ion It can be reused for manufacturing.
[0025] 本発明における第三の工程では、前記第二の工程で捕集された [18F]フッ化物ィ オンをカリウム塩 (ただし、炭酸カリウム及び炭酸水素カリウムを除く）水溶液を溶離液 として用い、 [18F]フッ化カリウム溶液として [18F]フッ化物イオンを溶出する。該カリウ ム塩としては炭酸カリウム及び炭酸水素カリウム以外であれば特に限定されないが、 弱塩基性陰イオン交換樹脂に対して [18F]フッ化物イオンと同等力 り親和性の強い 陰イオンを対イオンとする塩の水溶液を用いることが望ましい。 [0025] In the third step of the present invention, the [ 18 F] fluoride collected in the second step On the potassium salt (excluding potassium carbonate and potassium hydrogen carbonate) with an aqueous solution as eluent to elute the [18 F] fluoride ions as [18 F] potassium fluoride solution. The potassium salt is not particularly limited as long as it is other than potassium carbonate and potassium hydrogen carbonate, but an anion having a strong affinity for the weakly basic anion exchange resin is equivalent to that of [ 18 F] fluoride ion. It is desirable to use an aqueous salt solution.
前記カリウム塩としては、中性カリウム塩を用いることが望ましぐ非求核性カリウム 塩を用いることがより好ましい。さらに好ましくは、種々の有機酸塩または無機ォキソ 酸塩を用いることができる。  As the potassium salt, it is more preferable to use a non-nucleophilic potassium salt, which is desirably a neutral potassium salt. More preferably, various organic acid salts or inorganic oxo acid salts can be used.
有機酸塩としては、例えば、アルキルスルホン酸塩、アレーンスルホン酸塩、パーフ ルォロアルキルカルボン酸塩を用いることができる。アルキルスルホン酸塩は、種々 のものを用いることができる力 特に好ましくは、トリフルォロメタンスルホン酸カリウム 、メタンスルホン酸カリウム、エタンスルホン酸カリウム、パーフルォロブタンスルホン酸 カリウム、パーフルォロオクタンスルホン酸カリウムを用いることができ、最も好ましくは 、トリフルォロメタンスルホン酸カリウム又はメタンスルホン酸カリウムを用いることがで きる。アレーンスルホン酸は種々のものを用いることができる力 特に好ましくは、ベン ゼンスルホン酸カリウム、 3—二トロベンゼンスルホン酸カリウム、 4一二トロベンゼンス ノレホン酸カリウム、 4—ニトロ一 3—ニトロベンゼンスルホン酸カリウム、トルエン一 4— スルホン酸カリウム、ベンゼン一 1 , 2—ジスルホン酸ジカリウムを用いることができる。 パーフルォロアルキルカルボン酸塩は種々のものを用いることができる力 特に好ま しくは、トリフルォロ酢酸カリウムを用いることができる。  As the organic acid salt, for example, an alkyl sulfonate, an arene sulfonate, and a perfluoroalkyl carboxylate can be used. Alkyl sulfonates can be used in various forms. Particularly preferred are potassium trifluoromethanesulfonate, potassium methanesulfonate, potassium ethanesulfonate, potassium perfluorobutanesulfonate, and perfluorooctane. Potassium sulfonate can be used, and most preferably potassium trifluoromethanesulfonate or potassium methanesulfonate can be used. The ability to use various arene sulfonic acids, particularly preferably potassium benzene sulfonate, potassium 3-nitrobenzenesulfonate, potassium 12-nitrobenzenesulfonate, potassium 4-nitro-1-nitrobenzenesulfonate, Toluene-4-potassium sulfonate and dipotassium benzene-1,2-disulfonate can be used. The ability to use various perfluoroalkyl carboxylates is particularly preferable, and potassium trifluoroacetate can be used.
無機ォキソ酸塩としては、種々のものを用いることができ、特に硫黄、リン又はホウ 素を有するォキソ酸カリウムを用いることができる。硫黄を含むォキソ酸カリウムとして は、硫酸カリウム、四チオン酸カリウム、フルォロ硫酸カリウム、チォ硫酸カリウム又は ピロ亜硫酸カリウムを好ましく用いることができ、特に好ましくは硫酸カリウムを用いる こと力 Sできる。リンを含むォキソ酸カリウムとしては、リン酸二水素カリウム又はへキサフ ルォロリン酸カリウムを好ましく用いることができる。ホウ素を含むォキソ酸カリウムとし ては、テトラフルォロホウ酸カリウムを好ましく用いることができる。  Various inorganic oxoacid salts can be used, and in particular, potassium oxoate having sulfur, phosphorus or boron can be used. As potassium oxalate containing sulfur, potassium sulfate, potassium tetrathionate, potassium fluorosulfate, potassium thiosulfate or potassium pyrosulfite can be preferably used, and potassium sulfate can be particularly preferably used. As potassium oxalate containing phosphorus, potassium dihydrogen phosphate or potassium hexafluorophosphate can be preferably used. As potassium oxalate containing boron, potassium tetrafluoroborate can be preferably used.
なお、本明細書において、中性カリウム塩とは水に約 100mmol/Lの濃度で溶解 した場合の pHが 6〜8となるようなカリウム塩をレ、い、非求核性カリウム塩とは、陰ィォ ンがフッ化物イオンよりも低い求核性を有するカリウム塩をいう。求核性とは、炭素原 子との反応速度の大きさを表す用語であり、求核性が低いとは、相対的に炭素原子 との反応速度が小さいことを表す。多くの場合、塩基性が強くなるほど求核性が高く なるィ頃向がある。 In this specification, neutral potassium salt is dissolved in water at a concentration of about 100 mmol / L. In this case, the potassium salt having a pH of 6 to 8 is used, and the non-nucleophilic potassium salt is a potassium salt having a nucleophilicity whose anion is lower than that of fluoride ions. Nucleophilicity is a term that expresses the magnitude of the reaction rate with carbon atoms, and low nucleophilicity means that the reaction rate with carbon atoms is relatively low. In many cases, the stronger the basicity, the higher the nucleophilicity.
[0027] 用いる溶離液の水溶液量及びカリウム塩濃度は、前記弱塩基性陰イオン交換樹脂 に捕集された [18F]フッ化物イオンを十分に溶出し得るように調整される。例えば、 0. 2mLの弱塩基性陰イオン交換樹脂から [18F]フッ化物イオンを溶出させるためには、 水溶液量としては 0.：!〜 2mLであることが好ましぐ 0. 2〜0. 3mLであること力 Sより 好ましレ、。用いる水溶液の量が多すぎると、次工程である加熱蒸発乾固処理に時間 力かかりすぎるため好ましくない。カリウム塩濃度は、カリウムの総量が、前記弱塩基 性陰イオン交換樹脂から [18F]フッ化物イオンを溶出するために十分な量である限り 限定する必要はないが、カリウムの総量が、捕集された [18F]フッ化物イオンに対して モル比にして 1000倍量以上となるように調整することが好ましい。ここで、カリウム塩 の総量が少ないと、 [18F]フッ化物イオンの溶出が不十分となるため好ましくない。例 えば、 0. 2mLの弱塩基性陰イオン交換樹脂を充填したカラムに捕捉された 200MB q相当の [18F]フッ化物イオンをトリフルォロメタンスルホン酸カリウム水溶液を用いて 溶出する場合には、 0. 3mLの 133mmol/Lトリフルォロメタンスルホン酸カリウム水 溶液を該樹脂に流せばょレ、。 [0027] The amount of the aqueous solution of the eluent used and the potassium salt concentration are adjusted so that the [ 18 F] fluoride ions collected in the weakly basic anion exchange resin can be sufficiently eluted. For example, in order to elute [ 18 F] fluoride ions from 0.2 mL of weakly basic anion exchange resin, the amount of aqueous solution is preferably 0.:! To 2 mL. 0.2 to 0 3mL is better than power S. If the amount of the aqueous solution to be used is too large, it is not preferable because it takes too much time for the heating and evaporating and drying process, which is the next step. The potassium salt concentration need not be limited as long as the total amount of potassium is sufficient to elute [ 18 F] fluoride ions from the weakly basic anion exchange resin, but the total amount of potassium is not limited. It is preferable to adjust the molar ratio with respect to the collected [ 18 F] fluoride ions to be 1000 times or more. Here, if the total amount of potassium salt is small, the elution of [ 18 F] fluoride ions becomes insufficient, which is not preferable. For example, when eluting [ 18 F] fluoride ion equivalent to 200 MB q captured in a column packed with 0.2 mL of weakly basic anion exchange resin using potassium trifluoromethanesulfonate, 0. 3 mL of 133 mmol / L potassium trifluoromethanesulfonate aqueous solution was poured into the resin.
[0028] 前記第三の工程により回収された [18F]フッ化カリウム溶液は、反応容器に収めら れ、相間移動触媒を加えた後に加熱蒸発乾固して [18F]フッ化物イオンを活性化さ せる。その後、反応基質を加えて求核置換反応を行い、放射性フッ素標識有機化合 物を得る。水分子は [18F]フッ化物イオンに水和し [18F]フッ化物イオンの求核性を低 下させるので、加熱蒸発乾固することで [18F]フッ化物イオンが活性化し、標識反応 が可能となる。 [0028] The [ 18 F] potassium fluoride solution recovered in the third step is placed in a reaction vessel, and after adding a phase transfer catalyst, it is heated to dryness to obtain [ 18 F] fluoride ions. Activate. Thereafter, a reaction substrate is added to perform a nucleophilic substitution reaction to obtain a radioactive fluorine-labeled organic compound. Since the water molecules [18 F] hydrated fluoride ion [18 F] to please the nucleophilicity of fluoride ions low, [18 F] fluoride ions by heating dryness is activated, labeled Reaction is possible.
[0029] 前記相間移動触媒としては特に限定されないが、例えば、ァミノポリエーテル等が 挙げられ、具体的にはタリブトフィックス 222 (商品名、メルク社製)等を用いることがで きる。 [0030] 反応基質は合成する放射性フッ素標識有機化合物により適宜選択される。例えば [0029] The phase transfer catalyst is not particularly limited, and examples thereof include an aminopolyether. Specifically, Talibufix 222 (trade name, manufactured by Merck & Co., Inc.) can be used. [0030] The reaction substrate is appropriately selected depending on the radioactive fluorine-labeled organic compound to be synthesized. For example
[18F]— FDGを合成する場合は TATMを、 [18F]— FACBCを合成する場合は、 an ti—1—tert—ブトキシカルバメートー3—トリフロメタンスルホ二ルーシクロブタン一 1 —メチルエステル（Boc_TfACBC_OMe)を使用することができる。 When synthesizing [ 18 F] — FDG, TATM, and when synthesizing [ 18 F] — FACBC, an ti—1—tert-butoxycarbamate-3-trifluoromethanesulfocyclobutane-1-methyl ester ( Boc_TfACBC_OMe) can be used.
[0031] (第 2実施形態）  [0031] (Second Embodiment)
次に溶離液として第 4アンモニゥム塩 (ただし、炭酸水素塩を除く）溶液を用いる場 合の製造方法について説明する。  Next, the production method when a 4th ammonium salt solution (excluding bicarbonate) is used as the eluent is explained.
第一及び第二の工程は第 1実施形態と同様に行い、弱塩基性陰イオン交換樹脂 に [18F]フッ化物イオンを吸着捕集する。 The first and second steps are performed in the same manner as in the first embodiment, and [ 18 F] fluoride ions are adsorbed and collected on the weakly basic anion exchange resin.
[0032] 第三の工程では、第二の工程で捕集された [18F]フッ化物イオンを溶離液により溶 出する力 ここで、溶離液として第 4アンモニゥム塩溶液を用いる点で、第 1実施形態 と異なっている。 [0032] In the third step, the force to dissolve the [ 18 F] fluoride ions collected in the second step with the eluent. Here, the fourth ammonium salt solution is used as the eluent. Different from one embodiment.
第 4アンモニゥム塩としては、下記式（1)で示される化合物を用いることができる。  As the fourth ammonium salt, a compound represented by the following formula (1) can be used.
[化 8]  [Chemical 8]
Ri Ri
R2— R4 Z …（"！）
Figure imgf000014_0001
R 2 — R 4 Z… ("!)
Figure imgf000014_0001
〔式中、 R， R , R及び Rは、各々独立に、直鎖又は分岐鎖の炭素数:!〜 22のアル  [Wherein R, R 1, R and R are each independently a linear or branched carbon number:!
1 2 3 4  1 2 3 4
キル鎖、下記式（2)：  Kill chain, following formula (2):
[化 9]
Figure imgf000014_0002
[Chemical 9]
Figure imgf000014_0002
(式（2)において、 nは:!〜 22の整数)  (In formula (2), n is an integer between :! and 22)
で示される基、  A group represented by
又は下記式（3)：  Or the following formula (3):
[化 10] (CH2)n- [ NHCO- (CH )m ] P- … ) [Chemical 10] (CH 2 ) n- [NHCO- (CH) m] P- …)
(式（3)において、 nは 1〜5、 mは 0〜12、 pは 1又は 2の整数） (In formula (3), n is 1 to 5, m is 0 to 12, p is an integer of 1 or 2)
で示される基；  A group represented by:
Zは対イオン (ただし、炭酸水素イオンは除く）を表す〕  Z represents a counter ion (excluding bicarbonate ion)
ここで、式（1)中、 R , R , R又は Rがアルキル鎖である場合、炭素数はそれぞれ  Here, in the formula (1), when R 1, R 2, R or R is an alkyl chain, the number of carbon atoms is
1 2 3 4  1 2 3 4
：!〜 22のものを用いることができる力 \好ましくは:!〜 8、更には 1〜4のものを用いるこ とが好ましい。  : The force which can use the thing of! ~ 22 \: Preferably:! ~ 8, Furthermore, it is preferable to use the thing of 1-4.
[0033] 上記式中、対イオン Zは炭酸水素イオン以外の陰イオンであって、第 4アンモニゥム イオンと共に塩を形成する一価の陰イオンである限り限定されないが、形成された塩 が非求核性であるものがより好ましい。非求核性の意味は、非求核性カリウム塩の場 合と同様であり、陰イオンがフッ化物イオンよりも低い求核性を有する塩をいう。例え ば、過フッ素化アルカンスルホン酸イオン、アルカンスルホン酸イオン、アレーンスノレ ホン酸イオン等が好ましく用いられる。  [0033] In the above formula, the counter ion Z is an anion other than the bicarbonate ion, and is not limited as long as it is a monovalent anion that forms a salt with the fourth ammonium ion. Those that are nuclear are more preferred. The meaning of non-nucleophilic is the same as in the case of non-nucleophilic potassium salt, and refers to a salt having an anion lower than that of fluoride ion. For example, perfluorinated alkane sulfonate ions, alkane sulfonate ions, arene sulfonate ions and the like are preferably used.
[0034] 上記式（1)で表される第 4アンモニゥム塩の具体例としては、例えば、テトラブチル アンモニゥムトリフルォロメタンスルホン酸、テトラメチルアンモニゥムトリフルォロメタン スルホン酸、テトラエチルアンモニゥムトリフルォロメタンスルホン酸、テトラプロピルァ ンモニゥムトリフルォロメタンスルホン酸、テトラペンチルアンモニゥムトリフルォロメタ ンスルホン酸、テトラへキシルアンモニゥムトリフルォロメタンスルホン酸、テトラエチル アンモニゥム p—トルエンスルホン酸等が挙げられ、好ましくはテトラブチルアンモニゥ ムトリフルォロメタンスルホン酸、テトラエチルアンモニゥム p—トルエンスルホン酸を使 用する。  Specific examples of the fourth ammonium salt represented by the above formula (1) include, for example, tetrabutyl ammonium trifluoromethane sulfonic acid, tetramethyl ammonium trifluoromethane sulfonic acid, and tetraethyl ammonium trifluoromethane. Fluoromethanesulfonic acid, tetrapropyl ammonium trifluoromethanesulfonic acid, tetrapentyl ammonium trifluoromethanesulfonic acid, tetrahexyl ammonium trifluoromethanesulfonic acid, tetraethyl ammonium p-toluenesulfonic acid, etc. Preferably, tetrabutylammonium trifluoromethanesulfonic acid or tetraethylammonium p-toluenesulfonic acid is used.
[0035] 第 4アンモニゥム塩溶液は、水溶液の状態で用いることが望ましいが、用いる第 4ァ ンモニゥム塩の水に対する溶解度が低い場合には、ァセトニトリル等の両親媒性の溶 媒を適宜混合した水に溶解させて用いることができる。  [0035] The fourth ammonium salt solution is preferably used in the form of an aqueous solution. However, when the solubility of the fourth ammonium salt used in water is low, water in which an amphipathic solvent such as acetonitrile is appropriately mixed is used. It can be dissolved in
[0036] 用いる溶離液の液量及び第 4アンモニゥム塩濃度は、前記弱塩基性陰イオン交換 樹脂に捕集された [18F]フッ化物イオンを十分に溶出し得るように調整される。例え ば、 0. 2mLの弱塩基性陰イオン交換樹脂から [1SF]フッ化物イオンを溶出させるた めには、液量としては 0. ：!〜 2mLであることが好ましぐ 0. 2〜0. 3mLであることが より好ましい。このとき、用いる第 4アンモニゥム塩溶液の量が多すぎると、次工程であ る加熱蒸発乾固処理に時間力 Sかかりすぎるため好ましくなレ、。第 4アンモニゥム塩濃 度は、第 4アンモニゥムの総量が、前記弱塩基性陰イオン交換樹脂から [18F]フツイ匕 物イオンを溶出するために十分な量である限り限定する必要はないが、第 4アンモニ ゥムの総量力 S、捕集された [18F]フッ化物イオンに対してモル比にして 1000倍量以 上となるように調整することが好ましい。ここで、第 4アンモニゥム塩の総量が少ないと 、 [18F]フッ化物イオンの溶出が不十分となるため好ましくなレ、。例えば、 0. 2mLの 弱塩基性陰イオン交換樹脂を充填したカラムに捕捉された 200MBq相当の [18F]フ ッ化物イオンをテトラェチルアンモニゥム p—トルエンスルホン酸溶液を用いて溶出す る場合には、 0. 3mLの 133mmol/Lテトラエチルアンモニゥムト p—トルエンスルホ ン酸溶液を該樹脂に流せばょレ、。 [0036] The amount of the eluent used and the concentration of the fourth ammonium salt are adjusted so that the [ 18 F] fluoride ion collected in the weakly basic anion exchange resin can be sufficiently eluted. example For example, in order to elute [ 1S F] fluoride ion from 0.2 mL of weakly basic anion exchange resin, the liquid volume is preferably 0.:!~2mL. More preferably, it is 3 mL. At this time, if the amount of the fourth ammonium salt solution to be used is too large, it takes a time S for the heating and evaporating and drying process, which is the next step, which is preferable. The fourth ammonium salt concentration need not be limited as long as the total amount of the fourth ammonium salt is sufficient to elute [ 18 F] fluoride ions from the weakly basic anion exchange resin. It is preferable to adjust the total amount S of the fourth ammonium to a molar ratio of 1000 times or more with respect to the collected [ 18 F] fluoride ion. Here, when the total amount of the fourth ammonium salt is small, the elution of [ 18 F] fluoride ion becomes insufficient, which is preferable. For example, you eluting with weakly basic 200MBq corresponding captured an anion exchange resin column filled [18 F] off Tsu hydride ion tetra E chill ammonium Niu arm p- toluenesulfonic acid solution 0. 2 mL In this case, 0.3 mL of 133 mmol / L tetraethylammonium p-toluenesulfonic acid solution can be poured onto the resin.
[0037] 溶離液として用いる第 4アンモニゥム塩は、それ自体が相間移動触媒であるため、 さらに相間移動触媒を加える必要は無い。従って、前記第三の工程で回収された [18 F]フッ化第 4アンモニゥム溶液をそのまま加熱蒸発乾固して [18F]フッ化物イオンを 活性化させた後、反応基質と反応させることによって、放射性フッ素標識有機化合物 を標識合成することができる。 [0037] Since the fourth ammonium salt used as the eluent is itself a phase transfer catalyst, it is not necessary to add a phase transfer catalyst. Accordingly, the [ 18 F] 4th ammonium fluoride solution recovered in the third step is heated and evaporated to dryness as it is to activate [ 18 F] fluoride ions, and then reacted with the reaction substrate. Radiolabeled organic compounds can be labeled and synthesized.
[0038] 以下、本発明の試験例、実施例及び比較例を示し、本発明を具体的に説明するが 、本発明は下記実施例等になんら制限されるものではない。  Hereinafter, the present invention will be specifically described with reference to test examples, examples and comparative examples of the present invention. However, the present invention is not limited to the following examples.
(試験例 1〜3)炭酸イオンが基質の分解反応発生に与える影響 (非放射性フッ素を 用いた FDG合成実験による検討）  (Test Examples 1 to 3) Effects of carbonate ions on substrate decomposition reaction (examination by FDG synthesis experiment using non-radioactive fluorine)
炭酸イオンの副反応発生に与える影響を調べるために、非放射性フッ素を用いて、 下記の実験を行った。  In order to investigate the effect of carbonate ions on the occurrence of side reactions, the following experiment was conducted using non-radioactive fluorine.
反応容器 (3 mL容）にフッ化カリウムおよび炭酸カリウムを表 1に示す量秤量した。 ついで、 TATMおよびタリプトフィックス 222 (商品名、メルク社製）を表 2に示す量秤 量し、ァセトニトリル 2 mLに溶解させて前記反応容器に添加した。これを、還流しなが ら 80°Cに加温して反応させた。反応直後、ならびに反応 10、 30、 60および 90分後の それぞれの時間点にて、マイクロシリンジを用いて反応溶液 5 / Lを直接採取し、以 下の条件にて HPLC分析を行い、絶対検量線法にて、本合成反応における目的化 合物である 1, 3, 4, 6—テトラー O—ァセチルー 2—フルオロー 2—デォキシダルコ ース（FDG中間体。以下、 TAFDGという）、及び反応基質 TATMの分解によって生 成する副生成物である PAGの量を定量した。 TAFDGおよび PAGの生成率％をそ れぞれ下記計算式（1)又は（2)により求めた。 In a reaction vessel (3 mL volume), potassium fluoride and potassium carbonate were weighed as shown in Table 1. Subsequently, TATM and Taliptofix 222 (trade name, manufactured by Merck & Co., Inc.) were weighed as shown in Table 2, dissolved in 2 mL of acetonitrile, and added to the reaction vessel. This was reacted by heating to 80 ° C. while refluxing. Immediately after the reaction and after 10, 30, 60 and 90 minutes of the reaction At each time point, directly collect 5 / L of the reaction solution using a microsyringe, perform HPLC analysis under the following conditions, and use the absolute calibration curve method to obtain the target compound in this synthesis reaction. 1, 3, 4, 6-Tetra-O-acetyl-2-fluoro-2-deoxydalose (FDG intermediate; hereinafter referred to as TAFDG) and the amount of PAG, a by-product generated by decomposition of the reaction substrate TATM Quantified. The% TAFDG and PAG production rates were determined by the following formula (1) or (2), respectively.
[数 1]  [Number 1]
7¾f Gの生成量//; no/ 7¾f G production /// no /
： MfDGの生成率％ 100% ( 1 )  : MfDG production rate% 100% (1)
7 ΓΜの仕込み ¾umo/  7 Preparation of ΓΜ ¾umo /
PAGの生成率％ = ^の,生'成—量 x 100% ( 2 ) Production rate of PAG% = ^, raw production-amount x 100 % (2)
7 ΓΛίの仕込み量// mo,  7 ΓΛί's charge // mo,
(HPLC分析条件） (HPLC analysis conditions)
カラム: Asahipak (登録商標） ODP_50 (商品名、昭和電工株式会社製、 4.6 mm X l ΰϋ mm;  Column: Asahipak (registered trademark) ODP_50 (trade name, manufactured by Showa Denko KK, 4.6 mm X l ΰϋ mm;
移動相：水/ァセトニトリル = 80/20  Mobile phase: water / acetonitrile = 80/20
流 速： 1.5 mL/min  Flow rate: 1.5 mL / min
検 出：紫外可視吸光光度計 (検出波長: 209 nm)  Detection: UV-visible spectrophotometer (detection wavelength: 209 nm)
[0039] [表 1] [0039] [Table 1]
Figure imgf000017_0001
Figure imgf000017_0001
[0040] [表 2] クリプトフィックス 222 TATM [0040] [Table 2] Cryptofix 222 TATM
試験例 1 0. 2 mmol 0. 2 mmol  Test example 1 0. 2 mmol 0. 2 mmol
試験例 2 0. 22 mmol 0. 2 mmol  Test Example 2 0.22 mmol 0.2 mmol
試験例 3 0. 3 mmol 0. 2 mmol [0041] 結果を表 3及び 4に示す。 目的物である TAFDGの生成率は、炭酸カリウムをフッ 化カリウムに添加することにより減少する傾向を示し、特に、炭酸カリウムを 0.05 mmol (フッ化カリウムに対して 0.5当量)添加した結果 (試験例 3)においては、反応時間 90 分にぉレ、て、約 1.4%まで減少した (表 3)。 Test Example 3 0. 3 mmol 0. 2 mmol [0041] The results are shown in Tables 3 and 4. The production rate of the target product TAFDG shows a tendency to decrease when potassium carbonate is added to potassium fluoride.In particular, the result of adding 0.05 mmol of potassium carbonate (0.5 equivalent to potassium fluoride) (Test Example) In 3), the reaction time dropped to about 1.4% at 90 minutes (Table 3).
一方、副生成物である PAGの生成率は、炭酸カリウムの添カ卩量の増加に伴って増 加する傾向を示していた（表 4)。  On the other hand, the production rate of PAG, a by-product, tended to increase as the amount of potassium carbonate added increased (Table 4).
この結果より、炭酸カリウムの存在により、基質の分解を伴う副反応が発生し、副生 成物である PAGが生成することが確認された。さらに、このような副反応は、炭酸カリ ゥム量の増加により促進される傾向があることが確認された。以上の結果は、炭酸ィ オンの存在により、基質の分解を伴う副反応が促進されることを示唆する結果である  From this result, it was confirmed that by the presence of potassium carbonate, a side reaction accompanied by decomposition of the substrate occurred and PAG as a by-product was produced. Furthermore, it was confirmed that such a side reaction tends to be promoted by an increase in the amount of potassium carbonate. These results suggest that the presence of carbonate ions promotes side reactions involving substrate degradation.
[0042] [表 3] [0042] [Table 3]
Figure imgf000018_0001
Figure imgf000018_0001
[0043] [表 4] [0043] [Table 4]
Figure imgf000018_0002
Figure imgf000018_0002
[0044] (試験例 4〜7)各種カリウム塩水溶液存在下における基質の分解反応発生比較 [0044] (Test Examples 4 to 7) Comparison of occurrence of decomposition reaction of substrates in the presence of various potassium salt aqueous solutions
各種力リウム塩の副反応発生に与える影響を調べるために、各種カリウム塩水溶液 の存在下で、 TATMの加熱処理をフッ素化反応時と同様の条件にて行い、 TATM の残存率を調べる実験を行った。 強酸性陽イオン交換樹脂 AG50W-X8 (商品名、ノくィォ'ラッドラボラトリーズ株式会 社製） 0.5 mLを充填したカラムに水 5 mLを流し、該カラムから溶出した水を、弱塩基 性陰イオン交換樹脂 AG4-X4 (商品名、バイオ'ラッドラボラトリーズ株式会社製) 0.2 mLを充填したカラムに流した。次いで、上記弱塩基性陰イオン交換樹脂を充填した カラムに表 5記載のカリウム塩水溶液を流し、該水溶液をバイアル (容量 3.5 mL)に回 収した。このバイアルに、タリプトフィックス 222 (商品名、メルク社製） 53.1 z molをァ セトニトリル 1 mLに溶解した液 1.5 mLをカロえ、オイルバス中で 110°Cに 20分加温し、 水及びァセトニトリルを蒸散させた。次いで、ァセトニトリル 1 mLを加えて 110°Cで 10分 間加温する操作を 2回繰り返し、 TATM41.6 μ πιοΐをァセトニトリル 1 mLに溶解した 液を加え、 80°Cで 5分間加熱した。 In order to investigate the effect of various power lithium salts on the occurrence of side reactions, an experiment was conducted to examine the residual ratio of TATM by performing heat treatment of TATM in the presence of various aqueous potassium salt solutions under the same conditions as in the fluorination reaction. went. Strongly acidic cation exchange resin AG50W-X8 (trade name, manufactured by Nokuo Rad Laboratories Co., Ltd.) Run 5 mL of water on a column packed with 0.5 mL, and wash the water eluted from the column with weakly basic anion. Ion exchange resin AG4-X4 (trade name, manufactured by Bio's Rad Laboratories Co., Ltd.) was applied to a column packed with 0.2 mL. Next, the aqueous potassium salt solution shown in Table 5 was passed through the column packed with the weakly basic anion exchange resin, and the aqueous solution was collected in a vial (capacity 3.5 mL). In this vial, 1.5 mL of a solution of 53.1 z mol of Talyptofix 222 (trade name, manufactured by Merck) in 1 mL of acetonitrile is heated, heated in an oil bath at 110 ° C for 20 minutes, The acetonitrile was evaporated. Next, the procedure of adding 1 mL of acetonitrile and heating at 110 ° C. for 10 minutes was repeated twice, a solution of TATM41.6 μπιοΐ dissolved in 1 mL of acetonitrile was added, and the mixture was heated at 80 ° C. for 5 minutes.
反応溶液 5 x Lにっき、下記の条件にて HPLC分析を行レ、、絶対検量線法にて T ATMの定量を行った。求めた TATMの定量値より、下記計算式（3)を用いて TAT Mの残存率％を求めた。  In 5 x L of the reaction solution, HPLC analysis was performed under the following conditions, and T ATM was quantified by the absolute calibration curve method. Based on the obtained quantitative value of TATM, the residual rate% of TAT M was obtained using the following formula (3).
[数 3] [Equation 3]
— 7¾™の残量 ; no _ — Remaining 7¾ ™; no _
7¾TMの残存率％ 100% ( 3 )  Residual rate of 7¾TM% 100% (3)
L 7¾fの仕込み量/ zmof  L 7¾f charge / zmof
(HPLC分析条件） (HPLC analysis conditions)
カラム： Inertsil (登録商標） ODS_3 (商品名、ジーエルサ 株式会社製、 4.6 mm X 250 mm)  Column: Inertsil (registered trademark) ODS_3 (trade name, manufactured by GELSA, 4.6 mm x 250 mm)
移動相：水/ァセトニトリル/イソプロパノール = 55Z30Zl5  Mobile phase: water / acetonitrile / isopropanol = 55Z30Zl5
流 1 mL/min  Flow 1 mL / min
検 出：紫外可視吸光光度計 (検出波長： 209 nm)  Detection: UV-Vis spectrophotometer (Detection wavelength: 209 nm)
[表 5] カリウム塩 濃度 液量 [Table 5] Potassium salt concentration Liquid volume
試験例 4 炭酸カリウム o i mmol/L 0. 3 mL  Test Example 4 Potassium carbonate o i mmol / L 0.3 mL
トリフルォロメタンスルホ  Trifluoromethanesulfo
試験例 5 133 匪 ol/L 0. 3 mL  Test Example 5 133 匪 ol / L 0.3 mL
ン酸カリウム  Potassium acid
試験例 6 メタンスルホン酸カリウム 133 匪 ol/L 0. 3 mL 試験例 7 硫酸カリウム 67 mmol/L 0. 3 mL [0046] 結果を表 6に示す。炭酸カリウムの存在下で加熱処理を行った実験では、 TATM の残存率は 3.6%であったのに対し (試験例 4)、その他のカリウム塩の存在下で加熱 処理を行った実験では、 TATMの残存率は 90%以上であった（試験例 5〜7)。これ らの結果より、炭酸カリウムの存在により TATMの分解が生じることが確認された。ま た、溶離液に炭酸カリウム以外のカリウム塩水溶液を用いることにより、基質である T ATMの分解が抑えられることが示唆された。 Test Example 6 Potassium methanesulfonate 133 匪 ol / L 0.3 mL Test Example 7 Potassium sulfate 67 mmol / L 0.3 mL The results are shown in Table 6. In the experiment where heat treatment was performed in the presence of potassium carbonate, the residual rate of TATM was 3.6% (Test Example 4), whereas in the experiment where heat treatment was performed in the presence of other potassium salts, TATM The residual rate was 90% or more (Test Examples 5 to 7). From these results, it was confirmed that TATM was decomposed by the presence of potassium carbonate. It was also suggested that the decomposition of T ATM, which is a substrate, can be suppressed by using an aqueous potassium salt solution other than potassium carbonate as the eluent.
[0047] [表 6]  [0047] [Table 6]
Figure imgf000020_0001
Figure imgf000020_0001
[0048] (試験例 8)テトラプチルアンモニゥムトリフルォロメタンスルホン酸塩溶液存在下にお ける基質の分解反応 [0048] (Test Example 8) Substrate decomposition reaction in the presence of tetraptyl ammonium trifluoromethanesulfonate solution
第 4アンモニゥム塩の副反応発生に与える影響を調べるために、テトラプチルアン モニゥムトリフルォロメタンスルホン酸塩溶液の存在下において TATMの加熱処理を フッ素化反応時と同様の条件にて行レ、、 TATMの残存率を調べる実験を行った。 強酸性陽イオン交換樹脂 AG50W- X8 (商品名、ノィォ 'ラッドラボラトリーズ株式会 社製） 0.5 mLを充填したカラムに水 5 mLを流し、該カラムより溶出した水を、弱塩基性 陰イオン交換樹脂 AG4-X4 (商品名、ノくィォ'ラッドラボラトリーズ株式会社製) 0.2 mL を充填したカラムに流した。次いで、上記弱塩基性陰イオン交換樹脂を充填したカラ ムに 133 mmol/Lテトラプチルアンモニゥムトリフルォロメタンスルホン酸塩溶液（20% ァセトニトリル溶液に溶解） 0.3 mLを流し、該溶液をバイアル (容量 3.5 mL)に回収し た。このバイアルに、ァセトニトリノレ 1.5 mLをカロえ、オイルバス中で 110°Cに 20分加温 し、水及びァセトニトリルを蒸散させた。次いで、ァセトニトリル 1 mLを加えて 110°Cで 1 0分間加温する操作を 2回繰り返し、 TATM41.6 μ molをァセトニトリル 1 mLに溶解し た液を加え、 80°Cで 5分間加熱した。  In order to investigate the effect of the 4th ammonium salt on the side reaction, heat treatment of TATM was conducted under the same conditions as in the fluorination reaction in the presence of tetraptyl ammonium trifluoromethanesulfonate solution. An experiment was conducted to examine the residual rate of TATM. Strongly acidic cation exchange resin AG50W-X8 (trade name, manufactured by Neo Rad Laboratories Co., Ltd.) Run 5 mL of water on a column packed with 0.5 mL and use the weakly basic anion exchange resin to elute the water eluted from the column. AG4-X4 (trade name, manufactured by Nokuo Rad Laboratories Co., Ltd.) was applied to a column packed with 0.2 mL. Then, 0.3 mL of 133 mmol / L tetrabutyl ammonium trifluoromethanesulfonate solution (dissolved in 20% acetonitrile solution) is poured into the column filled with the above weakly basic anion exchange resin, and the solution is poured into a vial ( The volume was recovered to 3.5 mL). In this vial, 1.5 mL of acetonitrile was heated and heated in an oil bath at 110 ° C for 20 minutes to evaporate water and acetonitrile. Next, the procedure of adding 1 mL of acetonitrile and heating at 110 ° C. for 10 minutes was repeated twice, a solution of 41.6 μmol of TATM in 1 mL of acetonitrile was added, and the mixture was heated at 80 ° C. for 5 minutes.
反応溶液 5 x Lにっき、試験例 4〜7と同様の条件にて HPLC分析を行レ、、絶対検 量線法にて TATMの定量を行った。求めた TATMの定量値より、計算式（3)を用い て TATMの残存率％を求めた。 The reaction solution was dispensed with 5 x L, HPLC analysis was performed under the same conditions as in Test Examples 4 to 7, and TATM was quantified by the absolute calibration curve method. Using the calculated quantitative value of TATM, use formula (3) TATM residual rate% was obtained.
結果として得られた TATMの残存率は、 99.9%以上であり、本条件による基質の分 解は認められなかった。  As a result, the residual ratio of TATM was 99.9% or more, and no degradation of the substrate was observed under these conditions.
(実施例 1 3)各種カリウム塩を用レ、た [18F]—TAFDGの合成 Example 13 3 Synthesis of [ 18 F] -TAFDG using various potassium salts
18〇—濃縮水（0— 18濃度 99.9%以上）にプロトン照射を行うことにより生成した [18 F]フッ化物イオン含有 18〇—濃縮水 0.2 mL (全放射能量は、表 7を参照）を、強酸性 陽イオン交換樹脂 AG50W-X8 (商品名、バイオ'ラッドラボラトリーズ株式会社製) 0.5 mLを充填したカラムに流し、次いで、弱塩基性陰イオン交換樹脂 AG4_X4 (商品名、 バイオ'ラッドラボラトリーズ株式会社製) 0.2 mLを充填したカラムに流した。次に、上 記弱塩基性陰イオン交換樹脂に表 8記載のカリウム塩水溶液 0.3 mLを流して該弱塩 基性陰イオン交換樹脂に吸着した [18F]フッ化物イオンを溶出させ、溶出液をバイァ ルに回収した。 18 〇—Concentrated water (0—18 concentration 99.9% or more) produced by proton irradiation [ 18 F] fluoride ion-containing 18 〇—Concentrated water 0.2 mL (see Table 7 for total radioactivity) , Strong acidic cation exchange resin AG50W-X8 (trade name, manufactured by Bio's Rad Laboratories Co., Ltd.) Run on a column packed with 0.5 mL, and then weakly basic anion exchange resin AG4_X4 (trade name, Bio's Rad Laboratories Co. It was applied to a column packed with 0.2 mL. Next, 0.3 mL of the potassium salt aqueous solution shown in Table 8 was passed through the weakly basic anion exchange resin to elute the [ 18 F] fluoride ions adsorbed on the weakly basic anion exchange resin. Was collected in a vial.
その後、該溶出液に、タリプトフィックス 222 (商品名、メルク社製） 35.4 /i molをァセ トニトリル 1 mLに溶解した液 1.5 mLをカロえ、 110°Cで 10分加温し、水及びァセトニトリ ルを蒸散させた。次いで、ァセトニトリル 1 mLを加えて 110°Cで 5分間加温する操作を 2回繰り返し、蒸発乾固させた。この残渣に、 TATM41.6 /i molをァセトニトリル 1 mL に溶解した液を加え、 80°Cで 5分間加熱し [18F]—TAFDGを得た。 Thereafter, 1.5 mL of a solution obtained by dissolving 35.4 / i mol of Talyptofix 222 (trade name, manufactured by Merck) in 1 mL of acetonitrile is added to the eluate, heated at 110 ° C for 10 minutes, And the acetonitrile was evaporated. Next, the operation of adding 1 mL of acetonitrile and heating at 110 ° C. for 5 minutes was repeated twice to evaporate to dryness. To this residue, a solution of TATM41.6 / i mol dissolved in 1 mL of acetonitrile was added and heated at 80 ° C. for 5 minutes to obtain [ 18 F] -TAFDG.
この反応溶液につき、下記の条件にて TLC分析を行レ、、下記計算式 (4)を用いて 放射化学的純度％を求めた。また、下記計算式 (5)より、 [18F]フッ化物イオンの溶 出率％を求めた。 The reaction solution was subjected to TLC analysis under the following conditions, and the radiochemical purity% was determined using the following calculation formula (4). Further, the% dissolution rate of [ 18 F] fluoride ion was determined from the following calculation formula (5).
[数 4] 放射化学的純度 ( % ) - [1„ 麟 [Equation 4] Radiochemical purity (%)- [1 „麟
の全放H射能量 lOO ( 4 ) ICプレー卜上  Total release H amount of radiation lOO (4) IC play
[数 5] [Equation 5]
[ フッ議麵率 (¾) = [Foot rate (¾) =
陰イオン交換 S樹脂i^に捕[集8 ッ化物イオンの - loo ( 5 > された [18F】フッ化物ィわの放射能量 , Anion exchange resin S i ^ in capturing [of the current 8 Tsu hydride ion - loo (5> has been [18F] radioactivity amount of fluoride Iwa,
(TLC条件) 展開相：クロ口ホルム/酢酸ェチル =4/1 (TLC condition) Deployment phase: Black mouth form / Ethyl acetate = 4/1
TLCプレート： Silica Gel 60F254 (商品名、膜厚： 0.25 mm、メルク社製)  TLC plate: Silica Gel 60F254 (trade name, film thickness: 0.25 mm, manufactured by Merck)
展開長： 10 cm  Deployment length: 10 cm
[0050] [表 7] [0050] [Table 7]
Figure imgf000022_0001
Figure imgf000022_0001
[0051] [表 8] [0051] [Table 8]
Figure imgf000022_0002
Figure imgf000022_0002
[0052] 結果を表 9に示す。 TF]フッ化物イオンの溶出率は、何れの実施例においても、 9 8%以上の値を示していた。この結果より、本発明に係る方法によっても、炭酸力リウ ムを用いた従来法による溶出と同様の高い [18F]フッ化物イオンの溶出率が達成し得 ることが確認された。また、何れの実施例においても、得られた [18F] _TAFDGは 40 %以上の放射化学的純度を示しており、本発明に係る方法によって合成目的物であ る [18F]—TAFDGが合成し得ることが示された。 [0052] The results are shown in Table 9. The elution rate of TF] fluoride ion showed a value of 98% or more in all Examples. From these results, it was confirmed that the high elution rate of [ 18 F] fluoride ions can be achieved by the method according to the present invention as well as the elution by the conventional method using carbonic power. In any of the examples, the obtained [ 18 F] _TAFDG has a radiochemical purity of 40% or more, and [ 18 F] -TAFDG, which is a synthesis target by the method according to the present invention, is obtained. It was shown that it could be synthesized.
[0053] [表 9] 本発明に係る方法による [ 1 8 F ] フッ化物イオン溶出率及び放射化学的純度
Figure imgf000022_0003
[0053] [Table 9] [ 1 8 F] fluoride ion elution rate and radiochemical purity by the method of the present invention
Figure imgf000022_0003
(実施例 4及び比較例 1)各種カリウム塩を用いた [1SF]—TAFDGの合成による PA G生成比較 (Example 4 and Comparative Example 1) Comparison of PAG production by synthesis of [ 1S F] -TAFDG using various potassium salts
[18F]フッ化物イオン含有 180—濃縮水を 0.1 mL (全放射能量は、表 10を参照）用 レ、、溶離液として表 11に示す溶液 0.3 mLを用いた以外は、実施例：!〜 3と同様の操 作を行い、 [18F]—TAFDGの合成を行った。 [ 18 F] fluoride ion-containing 18 0—for 0.1 mL of concentrated water (see Table 10 for total radioactivity) Except for using a solution 0.3 mL shown in Table 11 as Le ,, eluent Example: The same operation and ~ 3, was synthesized [18 F] -TAFDG.
得られた反応溶液 5 / Uこっき、下記の条件にて HPLC分析を行レ、、 PAGの生成 率％を下記計算式 (6)により求めた。  The obtained reaction solution 5 / U was subjected to HPLC analysis under the following conditions, and the PAG production rate% was determined by the following calculation formula (6).
[数 6] Gの生成率％= ( 6 )  [Equation 6] G production rate% = (6)
7¾ΓΛίの仕込み ¾w/no/  7¾ΓΛί ¾w / no /
(HPLC分析条件） (HPLC analysis conditions)
カラム： Inertsil (登録商標） ODS-3 (商品名、ジーエルサイエンス株式会社製、 4.6 mm X 250 mm)  Column: Inertsil (registered trademark) ODS-3 (trade name, manufactured by GL Sciences Inc., 4.6 mm X 250 mm)
移動相：水/ァセトニトリル/イソプロパノール  Mobile phase: water / acetonitrile / isopropanol
流 速- : 1 mL/ min  Flow rate-: 1 mL / min
検 出：紫外可視吸光光度計 (検出波長： 209 nm)  Detection: UV-Vis spectrophotometer (Detection wavelength: 209 nm)
[表 10]  [Table 10]
Figure imgf000023_0001
Figure imgf000023_0001
[0056] [表 11」 [0056] [Table 11]
Figure imgf000023_0002
Figure imgf000023_0002
[0057] 結果を表 12に示す。実施例 4で生成した PAGの生成率は、比較例 1にて生成した PAGの生成率の約 10分の 1であり、 [18F]フッ素の溶出にトリフルォロメタンスルホン 酸カリウム水溶液を用いることにより、基質の分解が抑えられることが標識実験におい ても確認された。 [0057] The results are shown in Table 12. The production rate of the PAG produced in Example 4 is about one-tenth of the production rate of the PAG produced in Comparative Example 1. Use a potassium trifluoromethanesulfonate aqueous solution for elution of [ 18 F] fluorine. As a result, it was confirmed in the labeling experiment that the degradation of the substrate was suppressed.
[0058] [表 12] P A Gの生成率 （％) [0058] [Table 12] PAG generation rate (%)
実施例 4 2. 5  Example 4 2.5
比較例 1 25. 9  Comparative Example 1 25. 9
[0059] (実施例 5及び 6)各種第 4アンモニゥム塩溶液を用いた TF]—TAFDGの合成 [0059] (Examples 5 and 6) Synthesis of TF] -TAFDG using various fourth ammonium salt solutions
18〇—濃縮水（0— 18濃度 99.9%以上）にプロトン照射を行うことにより生成した [18 F]フッ化物イオン含有 18〇—濃縮水 0.2 mL (全放射能量は、表 13参照）を、強酸性 陽イオン交換樹脂 AG50W-X8 (商品名、バイオ'ラッドラボラトリーズ株式会社製) 0.5 mLを充填したカラムに流し、次いで、弱塩基性陰イオン交換樹脂 AG4_X4 (商品名、 バイオ'ラッドラボラトリーズ株式会社製) 0.2 mLを充填したカラムに流した。次に、上 記弱塩基性陰イオン交換樹脂に表 14記載の第 4アンモニゥム塩溶液 0.3 mLを流し て該弱塩基性陰イオン交換樹脂に吸着した [18F]フッ化物イオンを溶出させ、溶出液 をバイアルに回収した。 18 〇—Concentrated water (0—18 concentration 99.9% or more) produced by proton irradiation [ 18 F] fluoride ion-containing 18 〇—Concentrated water 0.2 mL (see Table 13 for total radioactivity) Strong acid cation exchange resin AG50W-X8 (trade name, manufactured by Bio's Rad Laboratories Co., Ltd.) Pour into a column packed with 0.5 mL, then weakly basic anion exchange resin AG4_X4 (trade name, Bio's Rad Laboratories Co., Ltd. The product was applied to a column packed with 0.2 mL. Next, 0.3 mL of the fourth ammonium salt solution shown in Table 14 was passed through the weakly basic anion exchange resin to elute the [ 18 F] fluoride ions adsorbed on the weakly basic anion exchange resin. The liquid was collected in a vial.
その後、該溶出液を 110°Cで 10分力卩温し、水及びァセトニトリルを蒸散させた。次い で、ァセトニトリル 1 mLを加えて 110°Cで 5分間加温する操作を 2回繰り返し、蒸発乾 固させた。この残渣に、 TATM41.6 /i molをァセトニトリル 1 mLに溶解した液を加え、 80°Cで 5分間加熱した。  Thereafter, the eluate was heated at 110 ° C. for 10 minutes to evaporate water and acetonitrile. Next, the operation of adding 1 mL of acetonitrile and heating at 110 ° C. for 5 minutes was repeated twice to evaporate to dryness. A solution of TATM41.6 / i mol dissolved in 1 mL of acetonitrile was added to this residue and heated at 80 ° C. for 5 minutes.
この反応溶液につき、実施例 1〜3と同様の条件にて TLC分析を行レ、、計算式 (4) を用いて放射化学的純度％を求めた。また、計算式（5)より、 [18F]フッ化物イオンの 溶出率％を求めた。 This reaction solution was subjected to TLC analysis under the same conditions as in Examples 1 to 3, and the radiochemical purity% was determined using the calculation formula (4). In addition, the elution rate% of [ 18 F] fluoride ion was obtained from the calculation formula (5).
[0060] [表 13]  [0060] [Table 13]
Figure imgf000024_0001
Figure imgf000024_0001
[0061] [表 14] 第 4アンモニゥム塩 溶媒 濃度 テトラプチルアンモニゥムトリ [0061] [Table 14] 4th ammonium salt Solvent concentration Tetraptyl ammonium
実施例 5 20¾ ァセトニトリル  Example 5 20¾ Acetonitrile
フルォロメ夕ンスルホン酸 133 imol/L テトラェチルアンモニゥム p - 実施例 6 水 133 匪 ol/L  Fluorome sulfonic acid 133 imol / L tetraethyl ammonium p-Example 6 Water 133 匪 ol / L
トルエンスルホン酸 [0062] 結果を表 15に示す。 TF]フッ化物イオンの溶出率は、何れの実施例においても 9 7%以上の値を示していた。この結果より、溶出液に第 4アンモニゥム塩溶液を用いる 方法によっても、炭酸カリウムを用いた従来法による溶出と同様の高い [18F]フッ素溶 出率を達成し得ることが確認された。また、得られた [18F] _TAFDGの放射化学的 純度も 70%以上の値を示しており、本発明に係る方法によって合成目的物である [18F ]—TAFDGが合成し得ることが示された。 Toluenesulfonic acid [0062] The results are shown in Table 15. The elution rate of TF] fluoride ion showed a value of 97% or more in all Examples. From this result, it was confirmed that the method using a fourth ammonium salt solution as the eluent can achieve the same high [ 18 F] fluorine elution rate as the conventional elution using potassium carbonate. In addition, the radiochemical purity of the obtained [ 18 F] _TAFDG also shows a value of 70% or more, indicating that [ 18 F] -TAFDG, which is the synthesis target, can be synthesized by the method according to the present invention. It was done.
[0063] [表 15] 本発明に係る方法による [ 1 8 F ] フッ化物イオン溶出率及び放射化学的純度
Figure imgf000025_0001
産業上の利用可能性 [0063] [Table 15] Elution rate and radiochemical purity of [ 1 8 F] fluoride ion by the method according to the present invention
Figure imgf000025_0001
Industrial applicability
本発明は、有機化合物を放射性フッ素標識するために有用であり、医療用画像診 断における造影剤及びその他の放射性フッ素標識化合物が用いられる分野で利用 すること力 Sできる。  INDUSTRIAL APPLICABILITY The present invention is useful for labeling organic compounds with radioactive fluorine, and can be used in fields where contrast agents and other radioactive fluorine-labeled compounds are used in medical image diagnosis.

Claims

請求の範囲 The scope of the claims
[1] [18F]フッ化物イオンを含有する 180—濃縮水を強酸性陽イオン交換樹脂に接触さ せて陽イオン不純物を除去する工程、 [1] A step of removing cationic impurities by contacting 180- concentrated water containing a [ 18 F] fluoride ion with a strongly acidic cation exchange resin;
次レ、で該 180 -濃縮水を弱塩基性陰イオン交換樹脂に接触させて [18F]フッ化物ィ オンを該弱塩基性陰イオン交換樹脂に吸着させる工程、 A step of contacting the 18 0 -concentrated water with a weakly basic anion exchange resin to adsorb [ 18 F] fluoride ion to the weakly basic anion exchange resin;
該弱塩基性陰イオン交換樹脂に吸着した [18F]フッ化物イオンをカリウム塩 (ただし 、炭酸カリウム及び炭酸水素カリウムを除く）水溶液を用いて溶出する工程、 を含むことを特徴とする [18F]フッ化カリウムの製造方法。 A step of eluting [ 18 F] fluoride ions adsorbed on the weakly basic anion exchange resin with an aqueous solution of potassium salt (except potassium carbonate and potassium hydrogencarbonate) [ 18 F] A method for producing potassium fluoride.
[2] 前記カリウム塩が中性カリウム塩であることを特徴とする請求項 1に記載の [18F]フッ 化カリウムの製造方法。 [2] [18 F] method for producing potassium fluoride according to claim 1 wherein the potassium salt, which is a neutral potassium salt.
[3] 前記カリウム塩が非求核性カリウム塩であることを特徴とする請求項 1又は 2に記載 の [18F]フッ化カリウムの製造方法。 [3] [18 F] method for producing potassium fluoride according to claim 1 or 2, wherein the potassium salt is a non-nucleophilic potassium salt.
[4] 前記カリウム塩力 トリフルォロメタンスルホン酸カリウム、硫酸カリウム及びメタンス ルホン酸カリウムからなる群より選択される 1種であることを特徴とする請求項 3に記載 の [18F]フッ化カリウムの製造方法。 [4] Potassium the potassium salt force triflate Ruo b methanesulfonic acid, [18 F] potassium fluoride according to claim 3, characterized in that the one selected from the group consisting of potassium potassium sulfate and methanesulfonic sulfonic acid Manufacturing method.
[5] 前記弱塩基性陰イオン交換樹脂が、官能基に対イオンを有しなレ、ものであることを 特徴とする請求項 1乃至 4のいずれ力、 1項に記載の [18F]フッ化カリウムの製造方法。 [5] The weakly basic anion exchange resin, any force of claims 1 to 4, characterized les such have a counter ion in the functional group, it is intended, according to item 1 [18 F] A method for producing potassium fluoride.
[6] 前記強酸性陽イオン交換樹脂及び前記弱塩基性陰イオン交換樹脂を、カラム管に 充填した状態で使用することを特徴とする請求項 1乃至 5のいずれ力 4項に記載の[6] The force according to any one of claims 1 to 5, wherein the strong acid cation exchange resin and the weakly basic anion exchange resin are used in a state of being packed in a column tube.
8F]フッ化カリウムの製造方法。 8 F] Method for producing potassium fluoride.
[7] 請求項 1乃至 6の何れ力、 1項に記載の方法で得られた [18F]フッ化カリウムを用いて 有機化合物を標識する工程を含むことを特徴とする放射性フッ素標識有機化合物の 製造方法。 [7] A radioactive fluorine-labeled organic compound comprising a step of labeling an organic compound with [ 18 F] potassium fluoride obtained by any one of claims 1 to 6 and the method according to claim 1 The manufacturing method.
[8] [18F]フッ化物イオンを含有する 180—濃縮水を強酸性陽イオン交換樹脂に接触さ せて陽イオン不純物を除去する工程、 [8] A step of removing cationic impurities by contacting 18 0-concentrated water containing a [ 18 F] fluoride ion with a strongly acidic cation exchange resin;
次レ、で該 180—濃縮水を弱塩基性陰イオン交換樹脂に接触させて [18F]フッ化物ィ オンを該弱塩基性陰イオン交換樹脂に吸着させる工程、 In the next step, contacting the 180- concentrated water with a weakly basic anion exchange resin to adsorb [ 18 F] fluoride ions to the weakly basic anion exchange resin;
該弱塩基性陰イオン交換樹脂に吸着した [18F]フッ化物イオンを第 4アンモニゥム 塩 (ただし、炭酸水素塩を除く）溶液を用いて溶出する工程、 [ 18 F] fluoride ions adsorbed on the weakly basic anion exchange resin Eluting with a salt solution (excluding bicarbonate),
を含むことを特徴とする [18F]フッ化第 4アンモニゥムの製造方法。 A process for producing [ 18 F] 4th ammonium fluoride characterized by comprising:
前記第 4アンモニゥム塩が、下記一般式（1)で示されることを特徴とする請求項 8に 記載の [18F]フッ化第 4アンモニゥムの製造方法。 The method for producing [ 18 F] fluorinated fourth ammonium according to claim 8, wherein the fourth ammonium salt is represented by the following general formula (1).
[化 1]  [Chemical 1]
Ri Ri
R + I— Z - …（"！）  R + I— Z-… ("!)
I  I
〔式中、 R , R , R及び Rは、各々独立に、直鎖若しくは分岐鎖の炭素数 1〜22の [In the formula, R 1, R 2, R and R are each independently a straight-chain or branched C 1-22 carbon atom.
1 2 3 4  1 2 3 4
アルキル鎖、下記式（2)：  Alkyl chain, following formula (2):
[化 2]
Figure imgf000027_0001
[Chemical 2]
Figure imgf000027_0001
(式（2)において、 nは:!〜 22の整数)  (In formula (2), n is an integer between :! and 22)
で示される基、  A group represented by
又は下記式（3)：  Or the following formula (3):
[化 3] - [ NHCO- iCH )m]p- … )[Chemical 3]-[NHCO- iCH) m ] p- …)
Figure imgf000027_0002
Figure imgf000027_0002
(式（3)において、 nは 1〜5、 mは 0〜12、 pは 1又は 2の整数）  (In formula (3), n is 1 to 5, m is 0 to 12, p is an integer of 1 or 2)
で示される基；  A group represented by:
Zは対イオン (ただし、炭酸水素イオンは除く）を表す〕  Z represents a counter ion (excluding bicarbonate ion)
[10] 前記 Zが、非求核性陰イオンであることを特徴とする請求項 9に記載の [18F]フッ化 第 4アンモニゥムの製造方法。 [10] The Z is, [18 F] Fourth Anmoniumu method for producing a fluoride of claim 9 which is a non-nucleophilic anion.
[11] 前記 Zが、過フッ素化アルカンスルホン酸イオン、アルカンスルホン酸イオン及びァ レーンスルホン酸イオンからなる群より選択される 1種であることを特徴とする請求項 1 0に記載の [18F]フッ化第 4アンモニゥムの製造方法。 [11] Z is a perfluorinated alkane sulfonate ion, alkane sulfonate ion and The method for producing [ 18 F] quaternary ammonium fluoride according to claim 10, wherein the method is one selected from the group consisting of lane sulfonate ions.
[12] 前記第 4アンモニゥム塩がテトラプチルアンモニゥムトリフルォロメタンスルホン酸又 はテトラェチルアンモニゥム p—トルエンスルホン酸であることを特徴とする請求項 11 に記載の [18F]フッ化第 4アンモニゥムの製造方法。 [12] the fourth Anmoniumu salt according to claim 11, wherein the tetra-Petit Ruan monitor © beam triflate Ruo b methanesulfonic acid or a tetra-E chill ammonium Niu arm p- toluenesulfonic acid [18 F] fluoride The manufacturing method of the 4th ammonia.
[13] 前記弱塩基性陰イオン交換樹脂が、官能基に対イオンを有しなレ、ものであることを 特徴とする請求項 8乃至 12のいずれ力、 1項に記載の [18F]フッ化第 4アンモニゥムの 製造方法。 [13] The weakly basic anion exchange resin, any force of claims 8 to 12, wherein Les such have a counter ion in the functional group, it is intended, according to item 1 [18 F] A method for producing 4th ammonium fluoride.
[14] 前記強酸性陽イオン交換樹脂及び前記弱塩基性陰イオン交換樹脂を、カラム管に 充填した状態で使用することを特徴とする請求項 8乃至 13のいずれ力 4項に記載の [ [14] The force according to any one of [8] to [13], wherein the strong acid cation exchange resin and the weakly basic anion exchange resin are used in a state of being packed in a column tube.
18F]フッ化第 4アンモニゥムの製造方法。 18 F] Method for producing fluorinated fourth ammonium.
[15] 請求項 8乃至 14の何れ力、 1項に記載の方法で得られた [18F]フッ化第 4アンモニゥ ムを用いて有機化合物を標識する工程を含むことを特徴とする放射性フッ素標識有 機化合物の製造方法。 [15] any force of claims 8 to 14, the radioactive fluorine, which comprises the step of labeling the organic compound with [18 F] Fourth Anmoniu arm fluoride obtained by the method described in item 1 A method for producing a labeled organic compound.
PCT/JP2005/022947 2004-12-22 2005-12-14 Method of producing potassium [18f] fluoride and quaternary ammonium [18f] fluoride and method of producing radioactive fluorine-labeled organic compound by using the same WO2006068015A1 (en)

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