JP2009229201A - Ga ION ISOLATION METHOD AND APPARATUS USED IN THE METHOD - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method capable of isolating easily Ga ions at high concentration in a short time from a liquid mixture containing one or more Ga ions selected from Ga isotopes and ions of an element in the fourth period other than Ga, to provide an apparatus used in the method, and to provide a method of producing a Ga label compound and an apparatus for producing the Ga label compound. <P>SOLUTION: The method of isolating Ga ions from a liquid mixture containing the Ga ions and the ions of the element in the fourth period other than Ga includes: contacting the liquid mixture with an anion exchange resin; allowing the Ga ions and the ions of the element in the fourth period other than Ga to be adsorbed in the anion exchange resin; cleaning the adsorbed anion exchange resin with an alcohol; eluting the Ga ions by cleaning with water or a dilute acidic aqueous solution to acquire an aqueous solution containing the Ga ions. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for isolating Ga ions from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements of the fourth period excluding Ga, from Ga isotopes An apparatus for isolating Ga ions from a mixed solution containing one or more selected Ga ions and ions of elements of the fourth period excluding Ga, a Ga labeled compound manufacturing method, and a Ga labeled compound It is related with the apparatus for doing.

  Recently, molecular imaging techniques such as positron emission tomography (hereinafter referred to as “PET”) are increasingly used in the medical field. This PET method is a technique for determining the distribution of radionuclides in each fault by administering a short-lived radionuclide to a living body such as a mammal and measuring annihilation γ-rays generated from positrons emitted from this radionuclide. This PET method is used for diagnosis of a diseased part of a living body.

Examples of the radionuclide for PET include ¹¹ C, ¹⁸ F, ¹⁵ O, ¹³ N, ⁷⁶ Br, and ⁶⁸ Ga. Among them, ⁶⁸ Ga, that is, gallium-68 has a great advantage, and thus attracts attention. The first advantage is that ⁶⁸ Ga is readily available from the ⁶⁸ Ge / ⁶⁸ Ga generator. The ⁶⁸ Ge / ⁶⁸ Ga generator is ⁶⁸ Ge supported on an organic resin or an inorganic material packed in a column. By passing hydrochloric acid having a predetermined concentration through this generator, ⁶⁸ GaCl ₃ produced based on the radiation equilibrium in the generator is eluted. Since such a method is used, ⁶⁸ Ga can be easily obtained without preparing ¹⁸ F and the cyclotron necessary for the nuclide generation. A second advantage is that ⁶⁸ Ga is a metal. ^{Since 68} Ga is a metal, a complex can be easily formed with a chelate-forming compound. Therefore, if a compound capable of forming a chelate is prepared in advance, it is possible to easily prepare a compound containing a short-lived radionuclide at the site using PET by immediately mixing with ⁶⁸ Ga. On the other hand, ¹⁸ F, for example, is available as a solution of fluoride ions, but it is usually necessary to undergo a chemical reaction as a compound containing a hydrogen atom and a short-lived radiation nucleus replacing ¹⁸ F. Against this background, ¹⁸ half-life of F is 2 hours, although longer than 68 minutes ⁶⁸ Ga, that to obtain a compound containing each of the short-lived radionuclide, the more the ⁶⁸ Ga is less time There are advantages.

As described above, ⁶⁸ Ga has a great advantage as a short-lived nuclide for PET, but the ⁶⁸ Ga solution obtained from the ⁶⁸ Ge / ⁶⁸ Ga generator (hereinafter referred to as “milking solution”) has ⁶⁸ Ge, ⁶⁸ Since inorganic substances such as Zn, hydrogen chloride, and substances derived from the column support layer are contained as impurities, it was necessary to remove these inorganic substances before using ⁶⁸ Ga for PET. As a removal method, for example, in order to adsorb ⁶⁸ Ga, ⁶⁸ Ge and the like on the anion exchange resin, the milking solution is adjusted to 4 to 6 M hydrochloric acid, the solution is brought into contact with the anion exchange resin, and ⁶⁸ Ga, ⁶⁸ inorganic substances such as Ge is adsorbed, the anion exchange resin, and washed with a small amount of deionized water is allowed to elute the ⁶⁸ Ga, it was known to obtain the purified ⁶⁸ Ga solution (e.g., Patent Document 1 and Non-Patent Document 1). In addition, by bringing the milking solution into contact with a cation exchange resin, adsorbing inorganic substances such as ⁶⁸ Ga and ⁶⁸ Ge, and washing the cation exchange resin with acetone containing low-concentration hydrochloric acid to elute ⁶⁸ Ga. It was also known to obtain a purified ⁶⁸ Ga solution (see, for example, Patent Document 2 and Non-Patent Document 2).

However, the former method using an anion exchange resin requires a considerable amount of deionized water due to hydrochloric acid adsorbed on the anion exchange resin. In the former method using an anion exchange resin, since the pH of the obtained purified ⁶⁸ Ga solution is low, the pH is adjusted to about 3 to 7 using a base in advance before adding a chelate-forming compound and reacting. There was a need. At the time of this pH adjustment, when the solution becomes basic, gallium forms a chemical species that hardly forms chelation, so that a small amount of the base needs to be added frequently. Moreover, it was inevitable that the amount of the purified ⁶⁸ Ga solution increased due to the neutralization operation. As a result, there is a problem that the concentration of the obtained purified ⁶⁸ Ga solution is lowered, and it becomes easy to form chemical species in which gallium is difficult to form chelation. Further, when neutralized, the salt concentration in the solution increases. The obtained ⁶⁸ Ga solution is reacted with a chelate-forming compound to finally obtain a compound containing a short-lived radionuclide, but in order to prepare the compound in a short time, it is usually used for in vivo administration without purification as much as possible. Prepare to. Then, the solution containing the obtained compound contains a high concentration of salt that has not been removed, and if the solution is administered without dilution, it can be burdened to a level that is lethal to small animals such as mice. There was also.

The latter method using a cation exchange resin contains a large amount of acetone in a purified ⁶⁸ Ga solution. This acetone is toxic to the human body. Acetone has a ketone group in its structure. Then, when the obtained ⁶⁸ Ga solution is reacted with a chelate-forming compound containing an amino group such as a peptide or protein, and finally a compound containing a short-lived radionuclide is obtained, acetone is an amino group in the chelate-forming compound. It can cause a secondary chemical reaction to bind to. In addition, a by-product of acetone itself can be formed under hydrochloric acid acidity. For these reasons, it was essential to completely remove acetone from the purified ⁶⁸ Ga solution. However, the half-life of ⁶⁸ Ga is as short as 68 minutes, and the increase in the number of extra steps significantly reduces the content of ⁶⁸ Ga in compounds containing short-lived radionuclides that are ultimately required for PET. there were.
JP-T-2006-526664 International Publication No. 2006/56395 Pamphlet I. Velikyan et al., Bioconjugate Chem., 2004, Vol. 15, p. 554-560 F. W. E. Strelow et al., Analytical Chemistry, 1971, No. 43, p. 870-876

  Therefore, high-concentration Ga ions are easily isolated in a short time from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements in the fourth period excluding Ga. It aims at providing the method, the apparatus for it, the manufacturing method of Ga labeled compound, and the apparatus for manufacturing Ga labeled compound.

The present invention is a method for isolating the Ga ions from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements in the fourth period excluding Ga,
The mixed solution is brought into contact with an anion exchange resin to adsorb the ions of Ga and the ions of the fourth period to the anion exchange resin,
The adsorbed anion exchange resin is washed with alcohol to elute ions of the elements in the fourth period,
Washing the alcohol-washed anion exchange resin with water or a dilute aqueous acid solution to elute the Ga ions to obtain an aqueous solution containing Ga ions.

Further, the present invention is an apparatus for isolating Ga ions from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements in a fourth period excluding Ga. There,
An anion exchange resin column packed with an anion exchange resin;
A unit for supplying alcohol to the ion exchange resin column;
A unit for supplying water or dilute acid aqueous solution to the ion exchange resin column;
A unit for collecting the isolated Ga ions.

The present invention also provides a method for producing a Ga-labeled compound,
Mixing an aqueous solution containing Ga ions with a compound capable of chelating with Ga ions to obtain a Ga-labeled compound,
The aqueous solution containing Ga ions is an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention.

The present invention also provides an apparatus for producing a Ga-labeled compound,
An apparatus for isolating Ga ions of the present invention;
A reactor for reacting the Ga ion with a chelate-forming compound.

  In the present invention, a high-concentration Ga ion can be simply and quickly formed from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements in the fourth period excluding Ga. It is possible to provide a separation method, a device therefor, a method for producing a Ga-labeled compound and a device for producing a Ga-labeled compound.

In the present invention, Ga isotopes include Ga nuclides having the same number of protons 31 and different numbers of neutrons. Specific examples of the isotope of Ga include a stable isotope of Ga and a radioactive isotope. Examples of the stable isotope of Ga include ⁶⁹ Ga and ⁷¹ Ga. Examples of the radioactive isotope of Ga include ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁰ Ga and ⁷² Ga. In the present invention, the isotope of Ga is preferably a radioisotope, more preferably ⁶⁶ Ga and ⁶⁸ Ga.

In the present invention, a mixed liquid containing one or more Ga ions selected from the Ga isotopes and ions of elements in the fourth period excluding Ga was obtained from, for example, a ⁶⁸ Ge / ⁶⁸ Ga generator. Milking solution, ⁶³ Cu (α, n) ⁶⁶ Ga, ⁶⁶ Zn (p, n) ⁶⁶ Ga, ⁶⁸ Zn (p, 3n) ⁶⁶ Ga, ^nat Zn (p, x) ⁶⁶ Ga and ⁶⁶ Zn ( d, n) ⁶⁷ Ga, ⁶⁸ Zn (p, 2n) ⁶⁷ Ga, ^nat Zn (p, x) ⁶⁷ Ga and the like, and target metal solution that has undergone a nuclear reaction.

The ⁶⁸ Ge / ⁶⁸ Ga generator is widely known in the art (see, for example, C. Loc'h et al., J. Nucl. Med. 1980, Vol. 21, p. 171-173). The generator is ⁶⁸ Ge supported on an organic resin or an inorganic metal oxide such as tin oxide, aluminum oxide, or titanium oxide packed in a column.

The milking solution obtained from the ⁶⁸ Ge / ⁶⁸ Ga generator is a solution containing ⁶⁸ GaCl ₃ . In order to obtain a milking solution, a predetermined concentration of hydrochloric acid is passed through the generator, and ⁶⁸ GaCl ₃ released by radiolysis in the generator may be eluted (this operation is called milking). An appropriate concentration of the hydrochloric acid may be selected according to the material packed in the column. Specifically, when ⁶⁸ Ge supported on titanium oxide is packed in a column, for example, 0.05 to 0.2 M hydrochloric acid, preferably 0.09 to 0.11 M hydrochloric acid is passed. When ⁶⁸ Ge supported on tin oxide is packed in a column, for example, 0.5 to 2 M hydrochloric acid, preferably 0.9 to 1.1 M hydrochloric acid is passed.

In addition, the fourth period element in the present invention is a so-called impurity. In the present invention, the element of the fourth period is an element of the fourth period of the periodic table and is not limited as long as it is other than Ga. For example, K, Ca, Sc, Ti, V, Cr, Mn, Fe , Co, Ni, Cu, Zn, Ge, As, Se, Br and the like. Specifically, in the case of a milking solution obtained from the ⁶⁸ Ge / ⁶⁸ Ga generator, examples of the fourth period element include Ge and Zn. In addition to Ti derived from the column support layer of the ⁶⁸ Ge / ⁶⁸ Ga generator, Al as the third period element and Sn as the fifth period element may also be included in the mixed solution. In addition, in the case of the target metal solution after the nuclear reaction, target elements such as Cu and Zn are exemplified. Furthermore, the surrounding elements which can be generated by a side reaction are also mentioned. Moreover, Fe which exists in an environment is also mentioned. The element of the fourth period may be one type or a mixture of two or more types.

In the present invention, the anion exchange resin is not limited, and examples thereof include strongly basic anion exchange resins. Examples of the strongly basic anion exchange resin include those having a counter ion of OH ⁻ , Cl ⁻ , and HCO ₃ ⁻ , and those having a counter ion of HCO ₃ ⁻ and OH ⁻ are preferable.

  In the method for isolating Ga ions of the present invention, the mixed solution is brought into contact with an anion exchange resin, and the ions of the fourth period excluding the Ga ions and the Ga ions are converted into the anion exchange resin. The process of making it adsorb | suck can be performed by allowing the said liquid mixture to pass through the column filled with the said anion exchange resin, for example. When the mixed solution is passed through the column packed with the anion exchange resin, the passing speed (flow rate) of the mixed solution is adjusted to, for example, 1 to 5 cc / min, preferably 2 to 3 cc / min. . Moreover, the process which makes the said liquid mixture contact the said anion exchange resin can be performed at 0-50 degreeC, for example, Preferably it is 15-30 degreeC. The step of bringing the mixed solution into contact with the anion exchange resin can be performed in the presence of an inert gas (such as argon or nitrogen) in the atmosphere, and is preferably performed in the presence of an inert gas. The amount of the anion exchange resin used is not limited as long as it is an amount of the anion exchange resin sufficient to adsorb Ga ions contained in the mixed solution. It should be noted that all or part of the ions of the fourth period element excluding Ga in the mixed solution may be adsorbed on the anion exchange resin. This is because the ion of the element in the fourth period is eluted from the anion exchange resin by the subsequent washing with alcohol.

  The method for isolating Ga ions of the present invention preferably further comprises a step of adjusting the hydrochloric acid concentration of the mixed solution to 2 to 6M, preferably 3 to 5M before contacting with the anion exchange resin. This is because the hydrochloric acid concentration is acidic enough for Ga ions to be adsorbed to the anion exchange resin (for example, “Radiation Overview”, Hiromi Iida, published by Tsusho Sangyo Kenkyusha, 2005, No. 6 Version). Moreover, if it is the said hydrochloric acid density | concentration, the ion of the element of the 4th period except Ga will have a low degree of adsorption | suction to the said anion exchange resin. Therefore, by adjusting the hydrochloric acid concentration in the mixed solution as described above, it is possible to remove part of the ions of the elements in the fourth period excluding Ga.

  In the method for isolating Ga ions according to the present invention, the step of washing the adsorbed anion exchange resin with alcohol includes, for example, passing the alcohol through a column packed with the adsorbed anion exchange resin. Can be performed. When passing the alcohol through the column packed with the anion exchange resin, the passage speed (flow rate) of the alcohol is adjusted to, for example, 1 to 5 cc / min, preferably 2 to 3 cc / min. Moreover, the process of wash | cleaning the said anion exchange resin with the said alcohol can be performed at 0-50 degreeC, for example, Preferably it is 15-30 degreeC. Further, the step of washing the anion exchange resin with the alcohol can be performed in the presence of an inert gas (argon, nitrogen, etc.) in the atmosphere, and is preferably performed in the presence of an inert gas. The amount of the alcohol used is not limited as long as it is a sufficient amount to elute ions of elements in the fourth period excluding Ga adsorbed on the anion exchange resin.

  In the method for isolating Ga ions of the present invention, examples of the alcohol include linear or branched lower alcohols having 1 to 6 carbon atoms, specifically, methanol, ethanol, n- Propanol, i-propanol, allyl alcohol, n-butanol, i-butanol, sec-butanol, t-butanol, n-pentanol, i-pentanol, sec-pentanol, t-pentanol, 2-methylbutanol, Examples thereof include n-hexanol, 1-methylpentanol, 2-methylpentanol, 3-methylpentanol, 4-methylpentanol, 4-hydroxy-4-methyl-2-pentanone and the like. As said alcohol, C1-C3 linear or branched lower alcohol is preferable, and methanol, ethanol, and i-propanol are more preferable.

  In the method for isolating Ga ions of the present invention, the washed anion exchange resin is washed with water or a dilute acid aqueous solution to elute Ga ions to obtain an aqueous solution containing Ga ions. For example, it can be carried out by passing water or a dilute aqueous acid solution through a column packed with the adsorbed anion exchange resin. When the water or dilute acid aqueous solution is passed through the column packed with the anion exchange resin, the passing speed (flow rate) of the water or dilute acid aqueous solution is, for example, 0.1 to 2 cc / min, preferably Adjust to 0.5-1 cc / min. Moreover, the process of wash | cleaning the said anion exchange resin with the said water or dilute acid aqueous solution can be performed at 0-50 degreeC, for example, Preferably it is 15-30 degreeC. In addition, the step of washing the anion exchange resin with the water or dilute acid aqueous solution can be performed in the atmosphere in the presence of an inert gas (argon, nitrogen, etc.), and is performed in the presence of an inert gas. preferable. The amount of water or dilute acid aqueous solution used is not limited as long as it is sufficient to elute Ga ions adsorbed on the anion exchange resin.

  In the method for isolating Ga ions of the present invention, the water is, for example, deionized water, distilled water, purified water, ultra-purified water, such as MilliQ water (Millipore's ultrapure water production apparatus MilliQ (registered trademark) ) And the like. As the water, MilliQ water is preferable. Examples of the dilute acid aqueous solution include hydrochloric acid, nitric acid and the like, preferably 1M or less hydrochloric acid, more preferably 0.1 to 0.5M hydrochloric acid and the like. This is because Ga radioactive isotopes are more stable in dilute acid solutions and have higher storage stability.

  In the method for isolating Ga ions of the present invention, the anion exchange resin is washed with alcohol before the anion exchange resin is washed with water or a dilute aqueous acid solution to elute the Ga ions. Therefore, the method for isolating Ga ions of the present invention has less hydrochloric acid remaining in the anion exchange resin than the conventional method using an anion exchange resin, so that a smaller amount of water or dilute aqueous acid solution is used. It is possible to elute Ga ions. As a result, according to the method for isolating Ga ions of the present invention, a high concentration solution of Ga ions can be obtained. In the method for isolating Ga ions of the present invention, the pH of the resulting Ga ion solution is not too low. Therefore, according to the method for isolating Ga ions of the present invention, especially in the case of the operation using water, neutralization with a base is unnecessary, and a pH is adjusted by adding a small amount of a buffer solution. The pH can be adjusted to be optimal for use as a raw material for producing a Ga-labeled compound. As a result, according to the method for isolating Ga ions of the present invention, an aqueous solution of Ga ions having a high concentration can be obtained in a short time. Further, according to the method for isolating Ga ions of the present invention, the purified Ga ion solution does not contain an organic solvent harmful to the reaction. Therefore, according to the method for isolating Ga ions of the present invention, the step of removing the organic solvent before producing the Ga-labeled compound is unnecessary. Therefore, according to the method for isolating Ga ions of the present invention, a high concentration aqueous solution of Ga ions can be obtained in a short time.

As described above, the method for producing a Ga-labeled compound of the present invention includes mixing an aqueous solution containing Ga ions with a compound capable of chelating with Ga ions to obtain a Ga-labeled compound, and the Ga ions The aqueous solution containing Ga is an aqueous solution containing Ga ions obtained by the isolation method according to claim 1. In the method for producing the Ga-labeled compound, the Ga ion in the aqueous solution containing the Ga ion includes at least one or more Ga radioisotope ions selected from the group consisting of ⁶⁶ Ga and ⁶⁸ Ga, The Ga-labeled compound is preferably a Ga radioisotope-labeled compound for PET. This is because a Ga radioisotope labeled compound for PET can be easily produced.

  The method for producing a Ga-labeled compound of the present invention may further include a step of adding a small amount of a buffer in advance to an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention. This is because if the pH of the aqueous solution containing Ga ions is adjusted to a pH suitable for the reaction, the chelate-forming compound is stably present in the aqueous solution containing Ga ions, and the reaction is promoted. The buffer is not particularly limited, and examples thereof include acetate buffer, phosphate buffer, PBS buffer, Tris-HCl buffer, EPPS buffer, and PIPES buffer.

  In the method for producing a Ga-labeled compound of the present invention, a mixture of an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention and a compound capable of chelating with Ga ions is the aqueous solution. A compound capable of chelating with Ga ions may be added to the aqueous solution, or a solution of a compound capable of chelating with Ga ions may be added to the aqueous solution. The solvent used for mixing is not limited as long as it does not prevent chelation between Ga ions and compounds capable of chelating with Ga ions. For example, water, acetonitrile, ethanol, dimethyl sulfoxide (DMSO) ) And the like.

  In the method for producing a Ga-labeled compound of the present invention, a mixture of an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention and a compound capable of chelating with Ga ions is, for example, The reaction can be performed at 0 to 100 ° C, preferably 40 to 90 ° C. Moreover, the said mixing process can be performed in air | atmosphere, inert gas (argon, nitrogen, etc.) presence etc., and it is preferable to carry out in inert gas presence.

  In the present invention, the compound capable of chelating with Ga ions is preferably a physiologically acceptable compound. This is because the obtained Ga-labeled compound can be used in PET and the like. In the present invention, the compound capable of chelating with Ga ions is preferably a compound that forms a Ga radioisotope-labeled compound that is stable for the time required for diagnostic investigation using a radiolabeled complex. .

  In the present invention, the compound capable of forming a chelate with Ga ions includes a compound containing an element having a lone electron pair such as oxygen or nitrogen, for example, chelating with Ga ions. Examples of such compounds include polyaza macrocyclic compounds, chain polyazapolycarboxylic acids, or derivatives thereof. Examples of the polyaza macrocyclic compound include porphyrin, pentaaza macrocyclic compound, phthalocyanine, heme, DOTA (1,4,7,10-tetraazacyclododecane-N, N ′, N ″, N ′ ″. -Tetraacetic acid), NOTA (1,4,7-triazacyclononane-N, N ', N' '-triacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N, N' , N ″, N ′ ″-tetraacetic acid) and the like. Examples of the chain polyazapolycarboxylic acid include DTPA (diethylenetriaminepentaacetic acid) and EDTA (ethylenediaminetetraacetic acid).

  In the present invention, the compound capable of chelating with Ga ions may contain various substituents in addition to the sites chelating with Ga ions as described above. Such substituents include amino acid residues, peptides, nucleosides, DNA, RNA, antisense, sugars, proteins, lipoproteins, antibodies, antibody fragments, glycopolypeptides, carbohydrates, organic small molecules with a molecular weight of less than 2000, and the like. Can be mentioned. As these substituents, substituents capable of causing interaction such as hydrogen bond and ionic bond with the target molecule are preferable.

  In the present invention, the Ga-labeled compound includes a salt thereof. The salts of Ga-labeled compounds include, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts with inorganic bases such as ammonium salts, and triethylamine, pyridine, picoline, ethanolamine, Organic amine salts such as ethanolamine, dicyclohexylamine, N, N′-dibenzylethyleneamine, and inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and formic acid, acetic acid, trifluoroacetic acid, maleic acid , Organic carboxylates such as tartaric acid, and sulfonic acid addition salts such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and salts with bases such as basic or acidic amino acids such as arginine, aspartic acid and glutamic acid, or Examples include acid addition salts.

  In the present invention, the Ga-labeled compound and the salt thereof may take the form of a solvate, which is also included in the scope of the present invention. Preferred solvates include hydrates and ethanol solvates.

  In the method for producing a Ga-labeled compound of the present invention, after mixing an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention and a compound capable of chelating with Ga ions, further Preferably, a purification step of the Ga-labeled compound is included. This is because a Ga-labeled compound is produced by the mixing, but it is preferable that the purity is higher for administration to a living body. Examples of the purification include solid phase extraction and HPLC purification. Examples of the solid phase extraction include extraction methods using disposable column cartridges such as gel filtration columns, C18 reverse phase columns, silica gel columns, alumina columns, anhydrous sodium sulfate columns, and diatomaceous earth columns. For the solid phase extraction, HPLC purification, etc., lyophilization, solvent removal (distillation, heating, filtration, etc.) and the like may be further performed.

  In the method for producing a Ga-labeled compound of the present invention, after mixing an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention and a compound capable of chelating with Ga ions, further A step of concentrating the solution. This is because the Ga-labeled compound is produced by the mixing, but the higher the concentration of the Ga-labeled compound contained in the solution, the lower the load on the administered organism.

  In the method for producing a Ga-labeled compound of the present invention, after mixing an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention and a compound capable of chelating with Ga ions, further And a step of adding a liquid for formulation such as physiological saline. This is because by adding such a liquid for formulation, the Ga-labeled compound can be used immediately in a dosage form such as injection.

  In the method for producing a Ga-labeled compound of the present invention, after mixing an aqueous solution containing Ga ions obtained by the method for isolating Ga ions of the present invention and a compound capable of chelating with Ga ions, further The step of injecting into a pharmaceutical vial may be included. This is because the Ga-labeled compound can be distributed and stored as an injectable preparation by injecting into such a preparation vial.

  In addition, as described above, the present invention isolates the Ga ions from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements in the fourth period excluding Ga. An anion exchange resin column filled with an anion exchange resin, a unit for supplying alcohol to the ion exchange resin column, and water or dilute aqueous acid solution to the ion exchange resin column A supply unit; and a unit for collecting the isolated Ga ions.

  The mixed liquid containing one or more Ga ions selected from the Ga isotopes and the ions of the elements of the fourth period excluding Ga and the anion exchange resin are as described above.

  An example of an apparatus for isolating the Ga ions of the present invention will be described with reference to the drawings. FIG. 1 shows an example of a basic configuration of an apparatus for isolating Ga ions of the present invention. As shown, the apparatus 1 includes an anion exchange resin column 6, a unit for supplying alcohol to the ion exchange resin column, and a unit for supplying water or a dilute aqueous acid solution to the ion exchange resin column. And a unit for collecting purified Ga ions, and a flow path 10. The flow channel 10 is a flow channel for introducing a mixed solution containing Ga ions and ions of elements in the fourth period excluding Ga. The unit for supplying the alcohol to the ion exchange resin column includes an alcohol tank 4 and a flow path 2 in the figure. The alcohol tank 4 and the anion exchange resin column 6 are connected by a flow path 2. The unit for supplying water or dilute acid aqueous solution to the ion exchange resin column includes a water or dilute acid aqueous solution tank 5 and a flow path 3 in the figure. The water or dilute acid aqueous solution tank 5 and the anion exchange resin column 6 are connected by a flow path 3. The unit for collecting the isolated Ga ions includes a flow path 7 in the figure, and the flow path 7 is led out from the anion exchange resin column 6 toward the outside of the apparatus. The flow path 7 may be connected to a Ga ion recovery tank (not shown) in the apparatus. The apparatus 1 further includes a flow path 8, and the flow path 8 is led out of the apparatus from the anion exchange resin column 6. This flow path 8 may be connected to a waste liquid recovery tank (not shown) in the apparatus.

  Purification of Ga ions using this apparatus is performed, for example, as follows. First, a mixed solution containing Ga ions and ions of elements in the fourth period excluding Ga is introduced into the anion exchange resin column 6 through the flow path 10, and the mixed solution is subjected to anion exchange in the column 6. Contacted with resin. Thereby, the ions of the Ga and the ions of the elements of the fourth period excluding Ga in the mixed solution are adsorbed on the anion exchange resin. Solvents and solutes in the mixed liquid that have not been adsorbed (for example, a part of the ions of the elements in the fourth period excluding Ga) are discharged out of the apparatus through the flow path 8, or a waste liquid recovery tank ( (Not shown). Next, alcohol is supplied to the anion exchange resin column 6 from the alcohol tank 4 through the flow path 2. As a result, the adsorbed anion exchange resin is washed with alcohol, and elements other than Ga ions are washed away. The washed alcohol waste liquid is discharged out of the apparatus through the flow path 8 or is collected in a waste liquid recovery tank (not shown) in the apparatus. Next, water or a dilute acid aqueous solution is supplied to the anion exchange resin column 6 from the water or dilute acid aqueous solution tank 5 through the flow path 3. Thereby, the washed anion exchange resin is washed with water or a dilute aqueous acid solution. By this washing, Ga ions are eluted from the anion exchange resin, and the aqueous solution containing the Ga ions is recovered through a flow path 7 to a Ga ion recovery tank or the like in the apparatus.

Next, FIG. 2 shows an example of another configuration of an apparatus for isolating Ga ions of the present invention. This apparatus is an apparatus that embodies the above-described configuration in which a mixed solution containing Ga ions and ions of elements in the fourth period excluding Ga is obtained from a ⁶⁸ Ge / ⁶⁸ Ga generator. In FIG. 2, the same parts as those in FIG.

As shown in the figure, similar to the apparatus 1, the apparatus 20 includes an anion exchange resin column 6, a unit for supplying alcohol to the ion exchange resin column, and water or dilute acid aqueous solution for the ion exchange. A unit for supplying the resin column, a unit for collecting purified Ga ions, and a flow path 11 are included. Furthermore, the apparatus 20 includes a ⁶⁸ Ge / ⁶⁸ Ga generator 12, the ⁶⁸ Ge / ⁶⁸ Ga generator 12, the passage 11 is introduced. ^{The 68} Ge / ⁶⁸ Ga generator 12 and the anion exchange resin column 6 are connected by a flow path 10, and a pump 13 is disposed in the middle of the flow path 10. A pump 14 is disposed in the middle of the flow path 2 connecting the alcohol tank 4 and the anion exchange resin column 6. A pump 15 is disposed in the middle of the flow path 3 connecting the water or dilute acid aqueous solution tank 5 and the anion exchange resin column 6.

Purification of Ga ions using this apparatus is performed, for example, as follows. First, a predetermined concentration of hydrochloric acid is introduced into the ⁶⁸ Ge / ⁶⁸ Ga generator 12 through the channel 11. As a result, the ⁶⁸ Ge / ⁶⁸ Ga generator 12 is eluted as a milking solution containing ⁶⁸ Ga and ions of elements of the fourth period (mainly Ge, Zn, etc.) excluding Ga. This solution is pressurized by the pump 13 and introduced into the anion exchange resin column 6 through the flow path 10, and the solution is brought into contact with the anion exchange resin in the column 6. As a result, the ⁶⁸ Ga and ions of the fourth period element excluding Ga in the solution are adsorbed on the anion exchange resin. Solvents and solutes in the mixed liquid that have not been adsorbed (for example, a part of the ions of the elements in the fourth period excluding Ga) are discharged out of the apparatus through the flow path 8, or a waste liquid recovery tank ( (Not shown). Next, pressure is applied by the pump 14, and alcohol is supplied from the alcohol tank 4 to the anion exchange resin column 6 through the flow path 2. Thereby, the adsorbed anion exchange resin is washed with alcohol. The washed alcohol waste liquid is discharged out of the apparatus through the flow path 8 or is collected in a waste liquid recovery tank (not shown) in the apparatus. Next, pressure is applied by the pump 15, and water or dilute acid aqueous solution is supplied from the water or dilute acid aqueous solution tank 5 to the anion exchange resin column 6 through the flow path 3. Thereby, the washed anion exchange resin is washed with water or a dilute aqueous acid solution. By this washing, ⁶⁸ Ga is eluted from the anion exchange resin, and the aqueous solution containing ⁶⁸ Ga is recovered through a flow path 7 in a Ga ion recovery tank or the like in the apparatus.

  Moreover, as described above, the present invention is an apparatus for producing a Ga-labeled compound, wherein one or more Ga ions selected from the Ga isotopes of the present invention and a fourth period excluding Ga are used. An apparatus for isolating Ga ions from a mixed solution containing elemental ions and a reactor for reacting the Ga ions with a chelate-forming compound are included.

  The mixed liquid containing one or more Ga ions selected from the Ga isotopes and the ions of the elements of the fourth period excluding Ga, and the compound capable of chelating with the Ga ions are as described above. It is.

An apparatus for producing a Ga-labeled compound of the present invention is a device in which the apparatus comprises a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements in the fourth period excluding Ga. It is preferable that an apparatus for isolating the Ga ions is further disposed between the unit for producing the mixed liquid and the reactor. This is because according to the apparatus for producing such a Ga-labeled compound, it is possible to carry out from the mixed solution to purification and then reaction at once, which is convenient. In the apparatus for producing such a Ga-labeled compound, the Ga-labeled compound is a Ga radioisotope-labeled compound for PET, and the Ga isotope is selected from the group consisting of ⁶⁶ Ga and ⁶⁸ Ga. More preferably, it is one or more Ga radioactive isotopes. This is because, according to such an apparatus for producing a Ga-labeled compound, a Ga radioisotope-labeled compound for PET can be easily produced. In the case of the latter apparatus, a unit containing a ⁶⁸ Ge / ⁶⁸ Ga generator is preferable as the unit for producing the mixed liquid.

  The example of the apparatus for manufacturing the said Ga labeling compound of this invention is demonstrated based on drawing. FIG. 3 shows an example of a basic configuration of an apparatus for producing the Ga-labeled compound of the present invention. In FIG. 3, the same parts as those in FIG. As shown, the apparatus 30 of the present invention includes an anion exchange resin column 6, a unit for supplying alcohol to the ion exchange resin column, and water or dilute aqueous acid solution for supplying the ion exchange resin column. , A unit for collecting purified Ga ions, a flow path 10, and a reactor 31. The reactor 31 and the anion exchange resin column 6 are connected by a flow path 7. The reactor 31 may include a stirring device, a heating device, a cooling device, etc. (not shown).

  Production of a Ga-labeled compound using this apparatus is performed, for example, as follows. First, a mixed solution containing Ga ions and ions of elements in the fourth period excluding Ga is introduced into the anion exchange resin column 6 through the flow path 10, and the mixed solution is introduced into the anion exchange resin in the column 6. Touched. Thereby, the ions of the Ga and the ions of the elements of the fourth period excluding Ga in the mixed solution are adsorbed on the anion exchange resin. Solvents and solutes in the mixed liquid that have not been adsorbed (for example, a part of the ions of the elements in the fourth period excluding Ga) are discharged out of the apparatus through the flow path 8, or a waste liquid recovery tank ( (Not shown). Next, alcohol is supplied to the anion exchange resin column 6 from the alcohol tank 4 through the flow path 2. Thereby, the adsorbed anion exchange resin is washed with alcohol. The washed alcohol waste liquid is discharged out of the apparatus through the flow path 8 or is collected in a waste liquid recovery tank (not shown) in the apparatus. Next, water or a dilute acid aqueous solution is supplied to the anion exchange resin column 6 from the water or dilute acid aqueous solution tank 5 through the flow path 3. Thereby, the washed anion exchange resin is washed with water or a dilute aqueous acid solution. By this washing, Ga ions are eluted from the anion exchange resin, and the aqueous solution containing the Ga ions is introduced into the in-device reactor 31 through the flow path 7. In particular, in the case of the operation using water, a compound capable of forming a chelate with Ga ions can be introduced into the reactor 31 in advance because the aqueous solution is mildly liquid. In this case, mixing occurs simultaneously with the introduction of the aqueous solution containing Ga ions into the reactor 31, and chelate formation proceeds between the Ga ions and the compound capable of chelating with Ga ions. As a result, a Ga-labeled compound is obtained after a reaction time suitable for each compound capable of forming a chelate.

Next, FIG. 4 shows an example of another configuration of an apparatus for producing the Ga-labeled compound of the present invention. This apparatus is an apparatus embodying the above-described configuration in which a mixed solution containing Ga ions and ions of elements in the fourth period excluding Ga is obtained from a ⁶⁸ Ge / ⁶⁸ Ga generator, and the Ga-labeled compound is purified. In FIG. 4, the same parts as those in FIGS. 2 and 3 are denoted by the same reference numerals.

As shown in the figure, like the device 30, this device 40 also supplies an anion exchange resin column 6, a unit for supplying alcohol to the ion exchange resin column, and water to the ion exchange resin column. A unit for collecting purified Ga ions, and a channel 11. Furthermore, the apparatus 40 includes a ⁶⁸ Ge / ⁶⁸ Ga generator 12, the ⁶⁸ Ge / ⁶⁸ Ga generator 12, the passage 11 is introduced. ^{The 68} Ge / ⁶⁸ Ga generator 12 and the anion exchange resin column 6 are connected by a flow path 10, and a pump 13 is disposed in the middle of the flow path 10. A pump 14 is disposed in the middle of the flow path 2 connecting the alcohol tank 4 and the anion exchange resin column 6. A pump 15 is disposed in the middle of the flow path 3 connecting the water or dilute acid aqueous solution tank 5 and the anion exchange resin column 6. Furthermore, the apparatus 40 includes a reactor 31, and the reactor 31 and the anion exchange resin column 6 are connected by a flow path 7. The device 40 further includes a purification device 43, a concentrator 47, a preparation liquid tank 50, and a vial 53. The purifier 43 and the reactor 31 are connected by a flow path 42, and a pump 41 is disposed in the middle of the flow path 42. The purification apparatus 43 further includes a flow path 44, and the flow path 44 is led out from the purification apparatus 43 toward the outside of the apparatus. The purifier 43 and the concentrator 47 are connected by a flow path 46, and a pump 45 is disposed in the middle of the flow path 46. The concentrator 47 and the vial 53 are connected by a flow path 49, and a pump 48 is disposed in the middle of the flow path 49. The preparation liquid tank 50 and the concentrator 47 are connected by a flow path 51, and a pump 52 is disposed in the middle of the flow path 51.

Purification of Ga ions using this apparatus is performed, for example, as follows. First, a predetermined concentration of hydrochloric acid is introduced into the ⁶⁸ Ge / ⁶⁸ Ga generator 12 through the channel 11. Thus, the ⁶⁸ Ge / ⁶⁸ Ga generator 12 is eluted as a milking solution containing ⁶⁸ Ga ions and ions of elements in the fourth period excluding Ga (mainly Ge, Zn, etc.). This solution is pressurized by the pump 13 and introduced into the anion exchange resin column 6 through the flow path 10, and the solution is brought into contact with the anion exchange resin in the column 6. As a result, the ⁶⁸ Ga ions in the solution and the ions of the fourth period element excluding Ga are adsorbed on the anion exchange resin. Solvents and solutes in the mixed liquid that have not been adsorbed (for example, a part of the ions of the elements in the fourth period excluding Ga) are discharged out of the apparatus through the flow path 8, or a waste liquid recovery tank ( (Not shown). Next, pressure is applied by the pump 14, and alcohol is supplied from the alcohol tank 4 to the anion exchange resin column 6 through the flow path 2. Thereby, the adsorbed anion exchange resin is washed with alcohol. The washed alcohol waste liquid is discharged out of the apparatus through the flow path 8 or is collected in a waste liquid recovery tank (not shown) in the apparatus. Next, pressure is applied by the pump 15, and water or dilute acid aqueous solution is supplied from the water or dilute acid aqueous solution tank 5 to the anion exchange resin column 6 through the flow path 3. Thereby, the washed anion exchange resin is washed with water or a dilute aqueous acid solution. By this washing, ⁶⁸ Ga ions are eluted from the anion exchange resin, and the aqueous solution containing the ⁶⁸ Ga ions is introduced into the in-device reactor 31 through the flow path 7. When a compound capable of forming a chelate with Ga ions is introduced into the reactor 31 in advance, mixing occurs at the same time as an aqueous solution containing ⁶⁸ Ga ions is introduced into the reactor 31, and the Ga ions and chelate are mixed. Chelate formation proceeds between the compound that can be formed and the ⁶⁸ Ga ion, and a ⁶⁸ Ga-labeled compound is obtained. After the reaction, the reaction mixture in the reactor 31 is pressurized by the pump 41 and supplied to the purification device 43 via the flow path 42. Thereby, the reaction mixture is purified by the purification device 43. The solution containing the ⁶⁸ Ga-labeled compound that has been purified and led out from the purification apparatus 43 is pressurized by the pump 45 and supplied to the concentrator 47 through the flow path 46. The solution containing the ⁶⁸ Ga-labeled compound concentrated in the concentrator 47 is then pressurized by the pump 48 and supplied to the vial 53 via the flow path 49. At this time, if necessary, the liquid is pressurized by the pump 52 and the liquid for preparation is introduced into the concentrator 47 from the liquid tank for preparation 50 through the flow path 51. The ⁶⁸ Ga-labeled compound concentrated in the concentrator 47 is washed out by the liquid for formulation, and the liquid solution for formulation of ⁶⁸ Ga-labeled compound is washed in the vial 53. As a result, a preparation liquid solution of ⁶⁸ Ga-labeled compound is prepared in the vial 53.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the examples.

A device for purifying ⁶⁸ Ga ions having the configuration shown in FIG. 5 was produced by using the ⁶⁸ Ge / ⁶⁸ Ga generator 12, the pump 13, the anion exchange resin column 6, and the pump 14 as follows. . In FIG. 5, the same parts as those in FIG. ^{As the 68} Ge / ⁶⁸ Ga generator 12,
IPL (Isotope Products Laboratories) manufactured by the product name "Gallium-68 Ionic Positron Generator (IGG099 ), 370MBq " (which was adsorbed Germanium-68 in the oxidation Suzukaramu, the daughter nuclide ⁶⁸ Ga using a milking operation by 1M hydrochloric acid A generator whose elution is guaranteed was used. As the anion exchange resin in the anion exchange resin column 6, the product name “Chromafix 30-PS-HCO ₃ ” manufactured by MACHEREY-NAGEL (polystyrene gel / anion exchange filler, HCO ₃ ⁻ type, 45 mg) , FDG synthesis ^- using commercially available) for the ⁽¹⁸ F purification).

As shown in the figure, like the apparatus 20, the apparatus 60 also supplies an anion exchange resin column 6, a unit for supplying alcohol to the ion exchange resin column, and water to the ion exchange resin column. A unit for collecting purified ⁶⁸ Ga ions, a channel 11, and a ⁶⁸ Ge / ⁶⁸ Ga generator 12. Further, the device 60 includes a concentrated hydrochloric acid tank 64, a flow path 65, a pump 66, a mixer 67, a pump 68, and a flow path 69. The concentrated hydrochloric acid tank 64 and the mixer 67 are connected by a flow path 65, and a pump 66 is disposed in the middle of the flow path 65. Further, the mixer 67 and the anion exchange resin 6 are connected by a flow path 69, and a pump 68 is disposed in the middle of the flow path 69. Further, the ⁶⁸ Ge / ⁶⁸ Ga generator 12 and the mixer 67 are connected by a flow path 10, and a pump 13 is disposed in the middle of the flow path 10. In the apparatus 60, as a unit for supplying alcohol to the ion exchange resin column and a unit for supplying water to the ion exchange resin column, an alcohol tank 4, a water tank 5, a flow path 61, A three-way cock 62 and a pump 63 are included. The alcohol tank 4 and the water tank 5 are connected to the anion exchange resin column 6 by a Y-shaped channel 61, and a three-way cock 62 is disposed at a branch point of the channel 61. Further, a pump 63 is disposed in the middle of the flow path 61.

In this apparatus 60, first, 1 M hydrochloric acid (10.5 ml) was supplied to the ⁶⁸ Ge / ⁶⁸ Ga generator 12 through the flow path 11. As a result, a milking solution (10.5 mL) containing ⁶⁸ Ga ions from the ⁶⁸ Ge / ⁶⁸ Ga generator 12 and ions of elements in the fourth period excluding Ga (mainly Ge, Zn, etc.) passes through the channel 10. It was led to the mixer 67. Next, concentrated hydrochloric acid (4 mL) is supplied from the concentrated hydrochloric acid tank 64 to the mixer 67 through the flow path 65 by the pump 66, so that the milking solution in the mixer 67 becomes 4M HCl. Adjusted. This adjusted milking solution (14.5 mL) was pressurized by a pump 68 through a flow path 69 and supplied to the anion exchange resin column 6. Next, the anion exchange resin column 6 was pressurized by the pump 63 from the alcohol tank 4 through the flow path 61 and supplied with ethanol (3 mL). Thereby, the anion exchange resin was washed with alcohol. Next, MilliQ water (0.8 mL) was supplied to the anion exchange resin column 6 from the water tank 5 through the flow path 61 and pressurized by the pump 63. As a result, an aqueous solution containing ⁶⁸ Ga ions (a little less than 0.8 mL) was obtained from the anion exchange resin through the flow path 7. Radiation dose remaining rate (average) (%) in anion exchange resin after washing with cleaning solution, ⁶⁸ Ga ion elution rate (average) (%) in the resulting aqueous solution, anion after elution with water Radiation dose remaining rate (average) in exchange resin (%), ⁶⁸ Ge radiation dose remaining amount (average) (Bq) and remaining rate (average) (%) in the aqueous solution containing ⁶⁸ Ga ions obtained, Table 1 shows the pH of the obtained aqueous solution containing ⁶⁸ Ga ions. All the operations in Example 1 were performed under a nitrogen atmosphere.

The same procedure as in Example 1 was performed except that the amount of MilliQ water was 0.4 mL. In Example 2, the residual dose rate (average) (%) of the radiation dose in the anion exchange resin after cleaning with the cleaning solution, the ion elution rate (average) ( ⁶⁸ %) of ⁶⁸ Ga into the obtained aqueous solution, Radiation dose remaining rate (average) (%) in the anion exchange resin after elution, ⁶⁸ Ge radiation dose remaining (average) (Bq) and remaining rate (average) in the obtained aqueous solution containing ⁶⁸ Ga ions ) (%) And the pH of the obtained aqueous solution containing ⁶⁸ Ga ions are shown in Table 1, respectively.

The same procedure as in Example 1 was performed except that the amount of MilliQ water was 0.2 mL. In Example 3, the residual dose rate (average) (%) of the radiation dose in the anion exchange resin after cleaning with the cleaning solution, the ion elution rate (average) ( ⁶⁸ %) of ⁶⁸ Ga into the obtained aqueous solution, Radiation dose remaining rate (average) (%) in the anion exchange resin after elution, ⁶⁸ Ge radiation dose remaining (average) (Bq) and remaining rate (average) in the obtained aqueous solution containing ⁶⁸ Ga ions ) (%) And the pH of the obtained aqueous solution containing ⁶⁸ Ga ions are shown in Table 1, respectively.

It carried out like Example 3 except having used methanol instead of ethanol. In Example 4, the residual dose rate (average) (%) of the radiation dose in the anion exchange resin after cleaning with the cleaning solution, the ion elution rate (average) ( ⁶⁸ ) of ⁶⁸ Ga into the obtained aqueous solution, Radiation dose remaining rate (average) (%) in the anion exchange resin after elution, ⁶⁸ Ge radiation dose remaining (average) (Bq) and remaining rate (average) in the obtained aqueous solution containing ⁶⁸ Ga ions ) (%) And the pH of the obtained aqueous solution containing ⁶⁸ Ga ions are shown in Table 1, respectively.

It carried out like Example 3 except having used i-propanol instead of ethanol. In Example 5, the residual dose rate (average) (%) of the radiation dose in the anion exchange resin after cleaning with the cleaning solution, the ion elution rate (average) ( ⁶⁸ ) of ⁶⁸ Ga into the obtained aqueous solution, Radiation dose remaining rate (average) (%) in the anion exchange resin after elution, ⁶⁸ Ge radiation dose remaining (average) (Bq) and remaining rate (average) in the obtained aqueous solution containing ⁶⁸ Ga ions ) (%) And the pH of the obtained aqueous solution containing ⁶⁸ Ga ions are shown in Table 1, respectively.

(Comparative Example 1)
The same procedure as in Example 1 was performed except that 4N hydrochloric acid was used instead of ethanol. In Comparative Example 1, the residual dose rate (average) (%) of the radiation dose in the anion exchange resin after cleaning with the cleaning solution, the ion elution rate (average) ( ⁶⁸ %) of ⁶⁸ Ga into the obtained aqueous solution, Radiation dose remaining rate (average) (%) in the anion exchange resin after elution, ⁶⁸ Ge radiation dose remaining (average) (Bq) and remaining rate (average) in the obtained aqueous solution containing ⁶⁸ Ga ions ) (%) And the pH of the obtained aqueous solution containing ⁶⁸ Ga ions are shown in Table 1, respectively. This Comparative Example 1 is described in I. Velikyan et al., Bioconjugate Chem., 2004, Vol. 15, p. This corresponds to the conditions described in 554-560 (Non-Patent Document 1). In addition, since 0.8 Ga of MilliQ water used as an eluate did not obtain ⁶⁸ Ga at all, 0.8 mL of MilliQ water was used.

(Comparative Example 2)
This was carried out in the same manner as in Example 1 except that ethanol was not washed. In Comparative Example 2, the remaining dose rate (average) (%) of the radiation dose in the anion exchange resin after cleaning with the cleaning solution, the ion elution rate (average) ( ⁶⁸ %) of ⁶⁸ Ga into the obtained aqueous solution, Radiation dose remaining rate (average) (%) in the anion exchange resin after elution, ⁶⁸ Ge radiation dose remaining (average) (Bq) and remaining rate (average) in the obtained aqueous solution containing ⁶⁸ Ga ions ) (%) And the pH of the obtained aqueous solution containing ⁶⁸ Ga ions are shown in Table 1, respectively. This comparative example 2 corresponds to the conditions described in JP-T-2006-526664 (Patent Document 1). In addition, since 0.8 Ga of MilliQ water used as an eluate did not obtain ⁶⁸ Ga at all, 0.8 mL of MilliQ water was used.

(Comparative Example 3)
It carried out like Example 3 except having used acetonitrile instead of ethanol. In Comparative Example 3, the residual amount rate (average) (%) of the radiation dose in the anion exchange resin after washing with the washing solution, the ion elution rate (average) ( ⁶⁸ %) of ⁶⁸ Ga into the obtained aqueous solution, Radiation dose remaining rate (average) (%) in the anion exchange resin after elution, ⁶⁸ Ge radiation dose remaining (average) (Bq) and remaining rate (average) in the obtained aqueous solution containing ⁶⁸ Ga ions ) (%) And the pH of the obtained aqueous solution containing ⁶⁸ Ga ions are shown in Table 1, respectively.

The ⁶⁸ Ga radiation dose for calculating the residual dose rate (average) (%) in the anion exchange resin after washing with the washing solution was measured using a dose calibrator for Atomlab300 PET manufactured by BIODEX. The radiation dose (attenuation correction value) of the anion exchange resin after cleaning is compared with the radiation dose (average) of the anion exchange resin when the ions of the elements in the fourth period excluding Ga ions and ⁶⁸ Ga are adsorbed. The average value was calculated in%. That is, it calculated using the following formula.
[Equation 1]
(Remaining radiation dose rate in anion exchange resin after washing with washing liquid (average) (%)) = [(Average value of radiation dose (attenuation correction value) in anion exchange resin after washing) / (First ⁶⁸ Radiation dose of the anion exchange resin when ions of Ga and ions of the fourth period excluding Ga are adsorbed)] × 100

The ⁶⁸ Ga radiation dose for calculating the dissolution rate (average) (%) of the obtained ⁶⁸ Ga ion-containing aqueous solution was measured using a dose calibrator for Atomlab300 PET manufactured by BIODEX. The radiation dose (average) (%) of the anion exchange resin when the ⁶⁸ Ga ions and the ions of the fourth period element excluding Ga are adsorbed is 100%, and the resulting aqueous solution containing ⁶⁸ Ga ions is obtained. The average value of the radiation dose (attenuation correction value) was calculated in%. That is, it calculated using the following formula.
[Equation 2]
(Dissolution rate in an aqueous solution containing ions of the resulting ⁶⁸ Ga (average) (%)) = [(radiation dose of an aqueous solution containing ions of the resulting ⁶⁸ Ga average of (attenuation correction value)) / (wash Average value of radiation dose in later anion exchange resin)] × 100

When calculating the residual dose rate (average) (%) of the anion exchange resin after washing with water, the radiation dose remaining on the anion exchange resin after elution with water is the dose for BIODEX, Atomlab300 PET Measurement was performed using a calibrator. ⁶⁸ Radiation dose (average) (%) of the anion exchange resin when the ions of the fourth cycle excluding Ga and the ions of the fourth period excluding Ga are adsorbed is defined as 100%, and the radiation dose in the anion exchange resin after washing ( The average value of the remaining amount of the attenuation correction value was calculated in%. That is, it calculated using the following formula.
[Equation 3]
(Remaining radiation dose rate in anion exchange resin after washing with water (average) (%)) = [(Average value of radiation dose (attenuation correction value) remaining in anion exchange resin after elution with water) / (Average value of radiation dose in anion exchange resin after washing)] × 100

Further, as the amount of ⁶⁸ Ge mixed (average) (Bq) and the mixing rate (average) (%) in the obtained aqueous solution, the obtained aqueous solution is considered to be completely disappeared as ⁶⁸ Ga radiation over 20 half-life ( 2 to 3 days), and the radiation dose (Bq) was measured by using a GEM-20 germanium semiconductor detector manufactured by SEIKO EG & G as ⁶⁸ Ge radiation dose as 511 keV gamma rays of daughter nuclide ⁶⁸ Ga. Similarly, the ⁶⁸ Ge radiation dose (Bq) of the milking solution stored as it was was measured, and the residual dose rate (average) (%) was calculated based on the radiation dose with respect to the average value of the obtained radiation doses. That is, it calculated using the following formula.
[Equation 4]
( ⁶⁸ Ge radiation dose remaining rate (average) (%)) = [(average value of ⁶⁸ Ge radiation dose mixed in the obtained aqueous solution) / (average value of ⁶⁸ Ge radiation dose in milking solution)] × 100

As shown in Table 1, from the results of Examples 1 to 5, according to the method for isolating Ga ions of the present invention, in the anion exchange resin after ⁶⁸ Ga ion elution with respect to the amount of the eluate, It was confirmed that the residual radiation rate was low and that the ⁶⁸ Ga ion elution rate in the obtained aqueous solution containing ⁶⁸ Ga ions was high. Further, it was confirmed that the ⁶⁸ Ge mixing amount was reduced to about 1/20 at maximum with respect to Comparative Example 1 and about 1/100 at maximum with respect to Comparative Example 2. Furthermore, it was also confirmed that the pH of the aqueous solution containing ⁶⁸ Ga ions obtained for both was about 1 large, and the amount of acid was reduced to about 1/40 at maximum considering the liquid volume. As a result, according to the method for isolating Ga ions of the present invention and the apparatus for isolating Ga ions of the present invention, it is not necessary to neutralize the obtained solution of Ga ions. It was confirmed that it was unnecessary to remove the organic solvent, and the process could be omitted. Therefore, it was possible to easily obtain a high-concentration and high-purity Ga ion solution in a short time.

The present invention is, for example, in the medical field the use of PET, which is useful in that process is omitted and stable quality in the production ⁶⁸ Ga-labeled compounds by medical personnel.

In the present invention, the mixing amount of ⁶⁸ Ge, which is a long half-life nuclide contained in the milking solution, is reduced to a detection error level, so that in the future, the handling limitation of ⁶⁸ Ga will be a so-called PET nuclide ( ¹¹ C, It is very useful in that it can be expected to be relaxed to the same degree as ¹³ N, ¹⁵ O, ¹⁸ F).

FIG. 1 is a diagram showing a configuration of an example of an apparatus for isolating Ga ions of the present invention. FIG. 2 is a diagram showing the configuration of another example of an apparatus for isolating Ga ions of the present invention. FIG. 3 is a diagram showing a configuration of an example of an apparatus for producing the Ga-labeled compound of the present invention. FIG. 4 is a diagram showing the configuration of another example of an apparatus for producing the Ga-labeled compound of the present invention. FIG. 5 is a diagram showing a configuration of still another example of an apparatus for isolating Ga ions of the present invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Apparatus for isolating Ga ion 2 Flow path 3 Flow path 4 Alcohol tank 5 Water or dilute aqueous acid tank 6 Anion exchange resin column 7 Flow path 8 Flow path 10 Flow path 11 Flow path 12 ⁶⁸ Ge / ⁶⁸ Ga generator 13-15 Pump 20 Equipment for isolating Ga ions 30 Equipment for producing Ga-labeled compounds 31 Reactor 40 Equipment for producing Ga-labeled compounds 41 Pump 42 Channel 43 Purifier 44 Flow Channel 45 Pump 46 Channel 47 Concentrator 48 Pump 49 Channel 50 Formulation liquid tank 51 Channel 52 Pump 53 Vial 60 ⁶⁸ Device for isolating Ga 61 Channel 62 Three-way cock 63 Pump 64 Concentrated hydrochloric acid tank 65 Flow Path 66 pump 67 mixer 68 pump 69 flow path

Claims (10)

A method of isolating Ga ions from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements of a fourth period excluding Ga,
The mixed solution is brought into contact with an anion exchange resin to adsorb the ions of Ga and the ions of the fourth period to the anion exchange resin,
The adsorbed anion exchange resin is washed with alcohol to elute ions of the elements in the fourth period,
A method comprising washing the alcohol-washed anion exchange resin with water or a dilute aqueous acid solution to elute the Ga ions to obtain an aqueous solution containing Ga ions.   The method according to claim 1, further comprising a step of adjusting the acid concentration of the mixed solution to 2 to 6 M before contacting with an anion exchange resin. The method according to claim 1 or 2, wherein the mixed solution is a milking solution obtained from a ⁶⁸ Ge / ⁶⁸ Ga generator. An apparatus for isolating Ga ions from a mixed solution containing one or more Ga ions selected from Ga isotopes and ions of elements of a fourth period excluding Ga,
An anion exchange resin column packed with an anion exchange resin;
A unit for supplying alcohol to the ion exchange resin column;
A unit for supplying water or dilute acid aqueous solution to the ion exchange resin column;
A unit for collecting the isolated Ga ions. A method for producing a Ga-labeled compound, comprising:
Mixing an aqueous solution containing Ga ions with a compound capable of chelating with Ga ions to obtain a Ga-labeled compound,
The method in which the aqueous solution containing Ga ions is an aqueous solution containing Ga ions obtained by the isolation method according to claim 1. A method for producing a Ga-labeled compound according to claim 5,
Ga ions in the aqueous solution containing Ga ions at least include one or more Ga radioisotope ions selected from the group consisting of ⁶⁶ Ga and ⁶⁸ Ga;
The method wherein the Ga-labeled compound is a Ga radioisotope-labeled compound for positron emission tomography. An apparatus for producing a Ga-labeled compound,
An apparatus for isolating Ga ions according to claim 4;
And a reactor for reacting the Ga ion with a chelate-forming compound. An apparatus for producing the Ga-labeled compound according to claim 7,
The apparatus further includes a unit for producing a mixed solution including one or more Ga ions selected from Ga isotopes and ions of elements of the fourth period excluding Ga,
An apparatus in which an apparatus for isolating Ga ions is disposed between a unit for producing the mixed solution and the reactor. An apparatus for producing the Ga-labeled compound according to claim 8,
The Ga-labeled compound is a Ga radioisotope-labeled compound for positron emission tomography, and the Ga isotope is one or more Ga radioisotopes selected from the group consisting of ⁶⁶ Ga and ⁶⁸ Ga. An apparatus for producing a Ga-labeled compound according to claim 9,
An apparatus in which the unit for producing the mixed liquid is a unit including a ⁶⁸ Ge / ⁶⁸ Ga generator.

Images