KR100902547B1 - Process for preparing radioisotope 64Cu - Google Patents

Abstract

The present invention provides a method for producing ⁶⁴ Cu by nucleating a nickel target prepared by plating ⁶⁴ Ni on a gold substrate by electrodeposition using an aqueous solution of nickel sulfate by a proton beam in a particle accelerator.

The nickel sulfate is

Reacting ⁶⁴ Ni with nitric acid and heat evaporating to produce nickel nitrate ( ⁶⁴ Ni (NO ₃ ) ₂ );

Reacting the nickel nitrate with sulfuric acid and evaporating it to produce nickel sulfate ( ⁶⁴ Ni (SO ₄ ));

Recrystallization of nickel sulfate for separating nickel sulfate crystals formed by adding a mixed solvent of water and acetone to the nickel sulfate; And

It provides a manufacturing method characterized by being prepared by a method comprising the step of drying the recrystallized nickel sulfate crystals.

Description

Process for preparing radioisotope 64Cu}

The present invention relates to a step of the manufacturing method of radioisotope ⁶⁴ Cu, more specifically, to a gold-coated substrate by means of a ⁶⁴ Ni electrodeposition (electrodeposition) produce a nickel target; Nucleating the nickel target with a proton beam in a particle accelerator to produce ⁶⁴ Cu; And separating and purifying the resultant ⁶⁴ Cu, the method for producing a radioisotope ⁶⁴ Cu, which does not corrode a conventional plating apparatus during plating with nickel sulfate used for preparing a nickel target. The present invention relates to a method for manufacturing to improve plating efficiency and subsequent production efficiency of ⁶⁴ Cu.

⁶⁴ Cu (copper) has been reported to be a very useful radioisotope with the development of diagnostic radiopharmaceuticals due to the increasing clinical use of PET (Positron Emission Tomography) (DW Mccarthy, Nuclear). Medicine & Biology , 24 (1997) 35-43 .; A. Aydin et al., Applied Radiation & Isotopes , 65 (2007) 365-370). In particular, it has been attracting attention as a radiopharmaceutical for PET ([ ⁶⁴ Cu] ATSM), which can show the hypoxic state of malignant tumors and can help radiotherapy effectively (Lweis et al., The Journal of Nuclear Medicine, 43 (2002)). 1557-1569 .; Y. Fujibayashi et al., Nuclear Medicine & Biology , 26 (1999) 117-121.)

⁶⁴ Cu (copper) is complicated because the production process requires plating, enrichment, and chemical separation and purification of concentrated nickel on gold substrates. ⁶⁴ Cu has been developed due to difficult conditions (short half-life and radiation exposure). This difficulty made production in countries other than the developed countries of radiology.

Currently, the method for producing isotope ⁶⁴ Cu

Plating ⁶⁴ Ni on a gold substrate by electrodeposition to produce a nickel target;

Nucleating the nickel target with a proton beam in a particle accelerator to produce ⁶⁴ Cu; And

It is known that it can be prepared by a method comprising the step of separating and purifying the resulting ⁶⁴ Cu (DW Mccarthy, Nuclear) Medicine & Biology , 24 (1997) 35-43).

The plating solution required to plate ⁶⁴ Ni on a gold substrate by electrodeposition to produce the nickel target is a black gray powdery metal that is insoluble in water, so that it is soluble in water by converting nickel into nickel sulfate. It is then prepared to be high. Specifically, as shown in the following chemical formula, nickel is reacted with nitric acid and heated to evaporate to produce nickel nitrate, and then the nickel nitrate is reacted with sulfuric acid and heat evaporated to produce nickel sulfate.

Ammonium sulphate is then neutralized by adding deionized water to the nickel sulphate obtained by the heat evaporation and adding an ammonium salt such as ammonium hydroxide to neutralize the acid by sulfuric acid and nitric acid residues. In addition, in order to prevent a decrease in pH due to dissociation of the ammonium sulfate during subsequent electroplating and to serve as an electrolyte during electroplating, an ammonium salt such as ammonium sulfate is added to prepare a plating solution for plating nickel on a gold substrate ( DW Mccarthy, Nuclear Medicine & Biology , 24 (1997) 35-43).

However, according to the preparation of such a plating solution, there is a fear of corrosive plating apparatus used for nickel plating by acid residues due to nitric acid and sulfuric acid used in the production of nickel sulfate in the plating solution and ammonium salt added for neutralization of such acid. There is. In addition, the plating solution is not cleared by the sulfuric acid used in the production of nickel sulfate and the ammonium salt used to neutralize the sulfuric acid, and the plating efficiency is not only reduced by the ammonium sulfate in the plating solution. Ammonium sulfate is electrodeposited with ⁶⁴ Ni on a gold substrate. Ammonium sulfate electrodeposited on the gold substrate with ⁶⁴ Ni also reduces the production efficiency of ⁶⁴ Cu later. The problem caused by sulfuric acid and ammonium sulfate in the plating solution is that sulfuric acid and nitric acid used in the production of nickel sulfate are generated by residual nickel sulfate, so efforts have been made to remove the sulfuric acid and nitric acid. Has lost a very expensive ⁶⁴ Ni and has not been commercialized.

Therefore, the present inventors studied a method of removing sulfuric acid and nitric acid mixed during the preparation of nickel sulfate used to prepare ⁶⁴ Cu without losing expensive ⁶⁴ Ni, and recrystallized nickel sulfate using a mixture of specific solvents. The process has been completed to find the invention that nickel sulfate can be selectively crystallized to remove sulfuric acid and nitric acid without loss of nickel.

Accordingly, it is an object of the present invention to provide a method for producing ⁶⁴ Cu, in which nickel sulfate used to prepare a nickel target is prepared so that sulfuric acid and nitric acid are not contained without loss of nickel sulfate.

Still another object of the present invention is to provide a method for producing a nickel target which can improve the production efficiency of ⁶⁴ Cu by plating a gold substrate using nickel sulfate prepared by the above method.

In order to achieve the above object, the present invention

In a method of producing ⁶⁴ Cu by nucleating a nickel target prepared by plating ⁶⁴ Ni on a gold substrate by electrodeposition using an aqueous solution of nickel sulfate by a proton beam in a particle accelerator,

The nickel sulfate is

Reacting ⁶⁴ Ni with nitric acid and heat evaporating to produce nickel nitrate ( ⁶⁴ Ni (NO ₃ ) ₂ );

Reacting the nickel nitrate with sulfuric acid and evaporating it to produce nickel sulfate ( ⁶⁴ Ni (SO ₄ ));

Recrystallization of nickel sulfate for separating nickel sulfate crystals formed by adding a mixed solvent of water and acetone to the nickel sulfate; And

It provides a method for producing ⁶⁴ Cu, characterized in that it is produced by a method comprising the step of drying the recrystallized nickel sulfate crystals.

In addition, the nickel target in the method of producing the ⁶⁴ Cu is

An aqueous solution of nickel sulfate prepared by dissolving the dried nickel sulfate crystals in deionized water was added to an electroplating apparatus equipped with a platinum substrate as a cathode and a gold substrate as a cathode, and supplied with an alternating sin wave current to the aqueous solution of nickel sulfate. Provided is a method for producing ⁶⁴ Cu, which is produced by a method comprising plating ⁶⁴ Ni on a gold substrate.

Hereinafter, the present invention will be described in more detail.

The method for producing the radioisotope ⁶⁴ Cu (copper) provided by the present invention is to solve the problem caused by sulfuric acid and nitric acid mixed in the manufacturing process of nickel sulfate used in the production of ⁶⁴ Cu, to produce nickel sulfate It is then possible to remove sulfuric acid and nitric acid from the nickel sulfate without loss of nickel sulfate by recrystallization using a recrystallization solvent that specifically recrystallizes the nickel sulfate.

As described above, the nickel sulfate used to prepare the target nickel may be prepared by a method as shown in the following formula.

That is, ⁶⁴ Ni is reacted with nitric acid to produce nickel nitrate, the nitric acid is evaporated, and then sulfuric acid is added to the residue nickel nitrate to react with nickel sulfate. When this product is evaporated to dryness, the residue nickel sulfate contains the nitric acid and sulfuric acid used above. When preparing a nickel target by using these nickel sulfate the efficiency is falling problem In the manufacture of ⁶⁴ Cu since not only deteriorate the plating efficiency occurs corrosion of the plating vessel, it is the nickel target contains a sulfated ammonium in addition to pure nickel Occurs.

In the present invention, it was found that when the nickel sulfate prepared by the above method is recrystallized in a mixed solution of water and acetone, only nickel sulfate is crystallized purely to remove both sulfuric acid and nitric acid without loss of nickel sulfate.

Therefore, the present invention

In a method of producing ⁶⁴ Cu by nucleating a nickel target prepared by plating ⁶⁴ Ni on a gold substrate by electrodeposition using an aqueous solution of nickel sulfate by a proton beam in a particle accelerator,

The nickel sulfate is

Reacting ⁶⁴ Ni with nitric acid and heat evaporating to produce nickel nitrate ( ⁶⁴ Ni (NO ₃ ) ₂ );

Reacting the nickel nitrate with sulfuric acid and evaporating it to produce nickel sulfate ( ⁶⁴ Ni (SO ₄ ));

Recrystallization of nickel sulfate for separating nickel sulfate crystals formed by adding a mixed solvent of water and acetone to the nickel sulfate; And

It provides a manufacturing method characterized by being prepared by a method comprising the step of drying the recrystallized nickel sulfate crystals.

Reacting ⁶⁴ Ni with nitric acid and evaporating the same in the manufacturing method to produce nickel nitrate ( ⁶⁴ Ni (NO ₃ ) ₂ ); And the method of specifically performing the step of reacting the nickel nitrate with sulfuric acid and heat evaporation to produce nickel sulfate ( ⁶⁴ Ni (SO ₄ )) can be carried out according to the methods known in the art, for example For example DW Mccarthy, Nuclear It may be carried out according to the method disclosed in Medicine & Biology , 24 (1997) 35-43.

The nickel nitrate is reacted with sulfuric acid and heated to evaporate to produce nickel sulfate ( ⁶⁴ Ni (SO ₄ )), followed by a recrystallization step of nickel sulfate to remove sulfuric acid and nitric acid remaining in the residue nickel sulfate. In order to recrystallize nickel sulfate, a mixed solvent of water and acetone is added to the nickel sulfate obtained by the heat evaporation at room temperature. When a mixed solvent is added, nickel sulfate crystallizes and precipitates simultaneously with the dispersion of nickel sulfate. The mixed solvent of water and acetone is preferably 1: 2 to 1: 4 by volume ratio of water: acetone, more preferably 1: 2.5 to 1: 3.5, and most preferably 1 to crystallize nickel sulfate. : 3.

The nickel sulfate crystal thus produced is separated from the mixed solvent by any method. Nickel sulfate crystals can be easily separated from the recrystallized solvent, for example by decantation.

The separated nickel sulfate undergoes a drying process. The drying may be any method, but is preferably completely dried for 12 hours or more by a vacuum pump.

As described above, the method according to the present invention can completely remove sulfuric acid and nitric acid which are inevitably included in the production of nickel sulfate by a recrystallization process, and this process can be performed without loss of nickel sulfate.

As described above, the nickel sulfate from which sulfuric acid and nitric acid has been removed is different from the conventional nickel sulfate containing sulfuric acid and nitric acid, and therefore, since the sulfuric acid and nitric acid are removed when preparing a plating solution for preparing a nickel target, There is no need to add ammonium salt compounds such as ammonium hydroxide. In addition, there is no need to add an electrolyte separately. Therefore, it is possible to prevent a decrease in the plating efficiency of nickel and a decrease in the ⁶⁴ Cu production efficiency, which is a problem in the conventional method caused by using such an additive.

Therefore, the nickel sulfate prepared according to the production method of the present invention can prepare a plating solution by dissolving nickel sulfate in deionized water without any additives. Nickel sulfate can be dissolved in deionized water at 0.2-0.5 M, in which case the pH is 3-4. In order to produce a nickel target, the plating solution is added to an electroplating apparatus equipped with platinum as an anode and a gold substrate as a cathode, and subjected to electroplating. In order for the nickel target to produce ⁶⁴ Cu later, the nickel target must be nucleated by a proton beam in the particle accelerator, and nickel is plated on the gold substrate in a uniform and thin thickness to mount the nickel target inside the particle accelerator. It is necessary to be. In order to perform nickel plating on the gold substrate in a uniform state in the electroplating apparatus using a plating solution prepared by dissolving nickel sulfate prepared according to the present invention in deionized water, an alternating current waveform of alternating current is supplied to the plating solution. It is desirable to. Electroplating can be performed until the average thickness of nickel formed on the gold substrate is in the range of 10 to 20 mu m. The magnitude of the current can be 0.5-0.9 mA and the plating time can be performed for 18-24 hours.

In the plating process, since no additives such as ammonium salt compounds are used in addition to nickel sulfate, no additive material other than nickel sulfate is present in the plating solution. Therefore, in the plating process for generating a nickel target according to the present invention, since the ammonium sulfate compound is not present in the plating solution, the plating efficiency is increased and corrosion of the plating vessel due to acid does not occur. In addition, a material such as ammonium sulfate is not incorporated into the nickel plating formed on the gold substrate so that only nickel can be plated purely on the gold substrate. In addition, impurities such as ammonium sulfate on the gold substrate are not plated with nickel, thereby increasing production efficiency even when ⁶⁴ Cu is subsequently produced.

After the target nickel is produced by the above method, the nickel target is nucleated by a proton beam in a particle accelerator by a conventional method to produce ⁶⁴ Cu. Thereafter, ⁶⁴ Cu may be obtained by performing a step of separating and purifying the produced ⁶⁴ Cu. Such nuclear reaction and separation and purification methods can be carried out by methods known in the art, and can be prepared, for example, by the methods described in DW Mccarthy, Nuclear Medicine & Biology , 24 (1997) 35-43). .

As described above, according to the present invention, sulfuric acid and nitric acid can be removed from nickel sulfate without loss of nickel sulfate by recrystallizing nickel sulfate for producing a ⁶⁴ Ni target, so that corrosion of the electroplating apparatus, which has been a problem in the past, does not occur. In addition, the nickel plating efficiency on the gold substrate may be improved since it is not necessary to add a separate additive such as ammonium salt in preparing the plating solution for preparing the nickel target. In addition, since the impurity such as ammonium sulfate is not plated with nickel on the gold substrate, the nickel plating is made pure, and thereafter, the production efficiency is increased when ⁶⁴ Cu is produced by nuclear reaction.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are merely illustrative and are in no way intended to limit the invention.

Example  One

A. Nickel sulfate  Manufacture and recrystallization

1 g, 16 mmol of concentrated nickel (ISOFLEX, USA) was dissolved in 6.0 M nitric acid and then stirred for 10 minutes and evaporated to dryness while maintaining a temperature of 180-200 ° C. The residue was treated with concentrated sulfuric acid and diluted with deionized water. Then, the mixture was stirred and evaporated to dryness in the same manner as before.

The light green nickel sulfate thus obtained was added with a mixed solvent of water and acetone (1: 3 V / V) and dispersed. Crystals of nickel sulfate immediately precipitated, and the nickel sulfate solution was slowly flowed over the filter (Whatman, UK) under reduced pressure. The nickel sulfate filtered on the filter is washed with 10-20 ml of pure acetone using a Pasteur pipette to remove the residual traces of sulfuric acid and nitric acid and then evaporated naturally in a sterile hood. The nickel sulfate crystals thus obtained were dried with stirring for at least 12 hours while maintaining a high vacuum (1 × 10 ⁻⁴ mmHg) with a vacuum pump to obtain nickel sulfate crystals from which sulfuric acid and nitric acid were removed.

The amount of nickel sulfate obtained by drying purely was 2.8-2.9 g to obtain a yellowish green fine powdery solid (Merck Index 11th, 6545). Therefore, when the yield of nickel sulfate was based on the theoretical value of 16 mmol (2.98 g), the average of 2.86 ± 0.03 mg (96%) of nickel sulfate was stably obtained when the experiment was repeated 20 times. At this time, the yield measurement used a precision scale (METTLER TOLEDO, USA) that can be measured to four decimal places. The purity and molecular weight of nickel sulfate were measured by the infrared spectroscopy (FT-IR, Bruker, Germany) and the observation of S = O binding, which is the main functional group. The natural frequencies of the bonds (1100, 1380, 1480, 1650 cm ⁻¹ ) were coincident, and the mass spectrometer (JEOL, Japan) confirmed the molecular weight of m / z: 159.8 (99%). From these results, it can be seen that both sulfuric acid and nitric acid were removed with little loss of nickel sulfate in nickel sulfate.

B. Preparation of Target Nickel

To 150 mg of the nickel sulfate prepared above, 7 mL of deionized water was added without any additives to prepare a plating solution having a pH of 3-4. The plating solution was added to a cell of an electroplating apparatus in which the anode was made of platinum and the cathode was mounted with a gold substrate having a thickness of 0.1 mm. The nickel target was prepared by electroplating by adding an average current amount of 0.73 mA for 20 hours in the form of an alternating sin waveform as shown in FIG. 1 to the plating solution contained in the cell. In order to measure the thickness and uniformity of the nickel-plated gold substrate surface, it was taken by observing with a scanning electron microscope (Scanning Electron Microscope, SEM, JEOL, Japan). A SEM photograph of the surface of the nickel plated gold substrate is shown in FIG. 2. 2A is a photograph taken at 500 magnification, and FIG. 2B is a photograph taken at 1000 magnification. As a result, it was confirmed that nickel was uniformly plated with a thickness of 10-20 μm on the gold substrate.

C. by nuclear reaction ⁶⁴ Cu Manufacture

The prepared nickel target was mounted in a particle accelerator (Scantronics, USA) and fixed inside a nuclear reactor (manufactured by Korea Atomic Energy Research Institute) causing a nuclear reaction. The nuclear reactor was designed and used to have an angle of 13 degrees from the beam direction as disclosed in Korean Patent Publication No. 2000-0019824 (name of the invention: multi-targeting apparatus for beam irradiation for radioisotope production). The nickel target was fixed inside the nuclear reactor, and then attached to it, Ta foil (0.025 mm) and duralumin (0.8 mm), which were proton beam reducers, to reduce the emission energy of the particle accelerator to 15 MeV for irradiation. Upon receiving the proton beam of the particle accelerator, nickel on the surface of the gold substrate caused a nuclear reaction (p, n), where a small amount of ⁶⁴ Cu was generated.

D. Purification Stage

Liquid chromatography was performed using a resin (AG1-X8 100-200 mesh, Bio-Rad, USA) to selectively separate the ⁶⁴ Cu produced on the nickel target by the nuclear reaction.

The nuclear reacted nickel target was placed in 10 mL of 6M HCl solution and heated to 80 ° C. for 10 min. The solution of the dissolved nickel target is left at room temperature for 10 minutes and then slowly passed through the column. ⁶⁴ Cu (copper) remains in the column and nickel can be recovered through the column. Further 10 mL of tertiary distilled water was slowly added to the column to recover ⁶⁴ Cu (copper). The yield of ⁶⁴ Cu (copper) obtained through this purification process was an average of about 740 MBq / h (when irradiated with a current amount of 30 µA).

E. ⁶⁴ Cu (Copper) quality check

In order to confirm the quality of the purified ⁶⁴ Cu (copper), a signal from ⁶⁴ Cu was confirmed by a MCA (Mutichannel Analyzer, HPGe detector) equipped with an HPGe detector. The results are shown in FIG. As shown in FIG. 3, gamma rays of about 511, 1022, and 1364 KeV were detected and proved to be ⁶⁴ Cu (copper).

In addition, in order to confirm the utilization of the purified ⁶⁴ Cu PET diagnostic radioisotope, the photo was taken with a positron tomography camera (PET, Giemens, Germany) in a phantom for PET measurement. Clinically commercialized ¹⁸ F was used for comparison. The photographing result is shown in FIG. As shown in FIG. 4, ⁶⁴ Cu had almost the same sensitivity or accuracy as ¹⁸ F commercialized in clinical practice, indicating that ⁶⁴ Cu can be used as a radioisotope for PET diagnosis.

1 is a graph showing waveforms, amount of current, and time applied to a plating solution containing nickel sulfate during electroplating using nickel sulfate prepared according to an embodiment of the present invention.

Figure 2a is a SEM photograph taken at 500 magnification of nickel plated on a gold substrate by electroplating using nickel sulfate prepared according to an embodiment of the present invention.

2b is a SEM (Scanning Electron Microscope, SEM, JEOL, Japan) photograph taken at 1000 magnification of nickel plated on a gold substrate by electroplating using nickel sulfate prepared according to one embodiment of the present invention. .

Figure 3 is a graph showing the results of analyzing the purified ⁶⁴ Cu (copper) prepared according to an embodiment of the present invention with a MCA (Mutichannel Analyzer, HPGe detector) equipped with an HPGe detector.

FIG. 4 is a photograph taken with a positron emission tomography (PET), each containing ^{64 C} purified in accordance with one embodiment of the present invention in a PET measurement phantom with ¹⁸ F for comparison.

Claims (5)

In a method of producing ⁶⁴ Cu by nucleating a nickel target prepared by plating ⁶⁴ Ni on a gold substrate by electrodeposition using an aqueous solution of nickel sulfate by a proton beam in a particle accelerator, The nickel sulfate is Reacting ⁶⁴ Ni with nitric acid and heat evaporating to produce nickel nitrate ( ⁶⁴ Ni (NO ₃ ) ₂ ); Reacting the nickel nitrate with sulfuric acid and evaporating it to produce nickel sulfate ( ⁶⁴ Ni (SO ₄ )); Recrystallization of nickel sulfate for separating nickel sulfate crystals formed by adding a mixed solvent of water and acetone to the nickel sulfate; And A method for producing ⁶⁴ Cu, characterized in that it is produced by a method comprising the step of drying the recrystallized nickel sulfate crystal. The method of claim 1, wherein the recrystallization is performed by adding a mixed solvent of water and acetone to nickel sulfate at room temperature. The method of claim 1, wherein the mixed solvent of water and acetone has a water: acetone ratio of 1: 2.5 to 1: 3.5. The method of claim 1, wherein the nickel target is An aqueous solution of nickel sulfate prepared by dissolving the dried nickel sulfate crystals in deionized water was added to an electroplating apparatus equipped with a platinum substrate as a cathode and a gold substrate as a cathode, and supplied with an alternating sin wave current to the aqueous solution of nickel sulfate. A method prepared by a method comprising plating ⁶⁴ Ni onto a gold substrate. The method of claim 4, wherein the current is an intensity of 0.5-0.9 mA.

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