A method for separating 166 Dy- 166 Ho generator and 166 Ho

Abstract

The present invention discloses a method based on 166 Dy‑ 166 Ho generator separation 166 Ho's method, which first prepares 166 Dy / 166 Ho acid solution, then prepare the complex 166 Dy / 166 Ho‑DOTP, and finally by 166 Dy / 166 Ho-DOTP was loaded onto an anion exchange column and separated into radionuclides with a purity of more than 99% through acid activation, pure water pre-rinsing, standing, and pure water rinsing. 166 Ho. This method implements 166 The process of Ho separation is simple; pure water is used for elution. 166 Ho has no carrier, does not contain complexing molecules, and does not require further purification. 166 The radionuclide purity of Ho is greater than 99%; the DOTP used is a common chemical reagent, and its cost is significantly lower than that of DOTATOC.

Description

Technical Field

[0001] The invention belongs to the technical field of radionuclide separation, and particularly relates to a method for separating 166 Ho based on a 166 Dy-[[]] 166 Ho generator. Background Technique

[0002] 166 Ho mainly emits two β - particles (E βmax = 1854 keV (50%) and E βmax = 1774 keV (48.7%), with an average energy E βav = 666 keV), 166 and Ho can be used for disease treatment. At the same time, 166 Ho also emits 166 γ-rays with a main energy of 80.6 keV, enabling 166 Ho to have the function of integrating disease diagnosis and treatment. Therefore,

[0003] 166 Ho is produced by reactor irradiation. There are mainly two preparation methods: one is the direct preparation method, that is, using natural 165 Ho (abundance 100%) for reactor irradiation 165 to obtain 166 Ho through 165 Ho(n,γ). This method is relatively simple, and the irradiation products do not need to be separated. However, due to the low 166 Ho reaction cross-section (61.2 barn), the products contain a large amount of carriers, and it is difficult to obtain high-specific-activity 166m Ho. Moreover, there are a large number of 1 / 2 Ho (t 164 = 1200 a) by-products with long half-lives, which is not conducive to its clinical application in nuclear medicine; the other is the indirect preparation method, that is, using 164 Dy for reactor irradiation, 165 Dy(n,γ) 166 Dy, 166 Dy undergoes - β 166 decay to obtain 164 Ho. The advantage of this method is that the 165 Dy reaction cross-section (2720 barn) and the reaction cross-section of the intermediate product 166Ho, but the production technology of this method is relatively complicated, and Dy / Ho needs to be separated and purified. Since Dy and Ho are adjacent lanthanide elements with extremely similar physical and chemical properties, Dy / Ho separation is very difficult, and due to 166 Ho is a reactor irradiation nuclide with a half-life of 26.8 hours. More than 90% of the 166 Ho decays, and its short half-life limits the spatial distance of its use. 166 Dy / 166 The separation of Ho will also 166 Ho has a short half-life and cannot meet the needs of scientific research and hospital use.

[0004] Considering 166 Ho parent nuclide 166 The half-life of Dy (t 1 / 2 =81.6h) 166 Ho is twice as long, so it is made 166 Dy- 166 Ho generator is a significant expansion 166 The best way to apply spatial distance will also become 166 Ho is an important technical guarantee for large-scale commercial applications. In the prior art, JR Zeevaar et al. first used DOTATOC (DOTA-DPhe 1 -Tyr 3 -octreotide) complex 166 Dy- 166 Ho, then loaded onto a C-18 column and eluted with EDTA (or DTPA) solution to obtain a 166 Dy- 166 Ho generator, the 166 Dy- 166 Ho generators utilize the hot atomic effect, especially 166 Dy decays to 166 Ho * The "post-effect" 166 Ho, its principle is: first 166 Dy through β - Decay to 166 Ho * ,Then 166 Ho * Mainly through the emission of internal conversion electron deexcitation, triggering the Auger cascade, a large number of electrons are stripped off, making 166 Ho is in a highly positively charged state, and the charge redistribution in a very short time makes 166 Ho and complexation 166The DOTA rings of Ho are all in a positive charge state, which in turn causes a Coulomb explosion, resulting in the breaking of the chemical bonds of the DOTA rings, thereby releasing 166 Ho. Complexation 166 Dy / 166 Ho's DOTATOC has a higher affinity for C-18 columns, while 166 Ho-EDTA (or 166 Ho-DTPA) has a weak affinity for C-18 columns, so the difference in polarity can be used to 166 Ho is separated. However, the DOTATOC used in this method is expensive. 166 Ho-EDTA (or 166 Ho-DTPA) has high complex stability and is difficult to convert 166 HoCl3 or 166 Ho(NO3)3 and other easily labeled forms are difficult to meet the needs of further application in scientific research institutions and clinical practice. Summary of the invention

[0005] In view of this, the present invention discloses a method based on 166 Dy- 166 Ho generator separation 166 Ho's method, which first prepares 166 Dy / 166 Ho acid solution, then prepare the complex 166 Dy / 166 Ho-DOTP, and finally by 166 Dy / 166 Ho-DOTP is added to the anion exchange column, and after acid activation, pure water pre-elution, standing, and pure water elution, the radioactive nuclide with a purity greater than 99% is separated. 166 Ho. The separation process of this method is simple, the product radionuclide purity is high and the separation cost is low.

[0006] To achieve this purpose, the present invention adopts the following technical solutions: a 166 Dy- 166 Ho generator separation 166 Ho's method, the method comprising:

[0007] S1: Use acid to dissolve the product of reactor irradiation Dy2O3 at temperature T1 to obtain 166 Dy / 166 Acid solution of Ho;

[0008] S2: Preparation 166 Dy / 166 Complex of Ho and DOTP 166 Dy / 166 Ho-DOTP;

[0009] S3: Load the Dy / Ho-DOTP complex onto an anion exchange column, keep the anion exchange column in an acidic environment after activating it with an acid of volume V1 for time t1, and then pre-rinse it with pure water to remove the excessive acid on the anion exchange column; 166 Dy / 166 Ho-DOTP complex onto an anion exchange column, keep the anion exchange column in an acidic environment after activating it with an acid of volume V1 for time t1, and then pre-rinse it with pure water to remove the excessive acid on the anion exchange column;

[0010] S4: Let the anion exchange column stand still, wait for 166 Ho to grow naturally. Every interval of time t2, rinse it with pure water to obtain 166 Ho solution.

[0011] Preferably, the preparation of the acid solution in S1 is carried out in a hot cell or a shielding work box; the products of irradiating Dy2O3 in the reactor mainly include 166 Dy2O3 and 166 Ho2O3 decayed from 166 Dy2O3; the acid solution includes but is not limited to HCl and HNO3; the temperature T1 is 50 - 60 °C, and here the hot cell refers to a shielding small chamber for carrying out high-radioactivity tests and operations.

[0012] Preferably, the preparation method of the complex 166 Dy / 166 Ho-DOTP in step 2 is as follows: Mix the Dy / Ho acid solution and the DOTP solution according to a certain molar ratio to obtain a mixed solution, and adjust the pH value of the mixed solution with the acid solution and the alkali solution to make 166 Dy / 166 Ho and DOTP undergo a complexation reaction at a certain pH value to form a complex 166 Dy / 166 Ho-DOTP. 166 Dy / 166 Ho-DOTP.

[0013] Preferably, the 166 Dy / 166 molar ratio of Ho and DOTP is 1∶1 - 1∶1.1; the acid solution is HCl, the alkali solution is NaOH; the certain pH value is 11 ± 0.5; the reaction temperature of the complexation reaction is 80 - 100 °C, and the reaction time is 30 - 60 min.

[0014] Preferably, in S3, the filling material of the anion exchange column includes but is not limited to anion exchange resin and acidic aluminum trioxide.

[0015] Preferably, in S3, the acids used include but are not limited to HCl and HNO3, the concentration of the acid is 0.01 - 0.1 M, and the volume can make the amount of hydrogen ions in the acid be the same as that loaded onto the anion exchange column 166Dy / 166 2 to 5 times the amount of substance of the Ho-DOTP complex; the time t2 is 15 to 60 min; the pure water has a volume ≥ 10 times the column volume.

[0016] Preferably, the pure water in S3 and S4 has a conductivity less than 5.1 μS / cm at 25 °C.

[0017] Preferably, in S4, the ambient temperature for the static placement of the anion exchange column is room temperature, and the time t3 is 1 to 2 days.

[0018] The beneficial effects of the present invention are as follows: The method for separating 166 Dy- 166 Ho from the 166 Dy-Ho generator provided by the present invention mainly utilizes the significant difference in the chemical valence states of the two substances to achieve 166 the separation of Ho, where the complex formed by the raw material and DOTP 166 Dy / 166 Ho-DOTP has a valence of -5, and the product 166 Ho has a valence of +3; the process for achieving 166 the separation of Ho by this method is simple; this method uses pure water for elution, and the 166 Ho eluted has no carrier, does not contain complexing molecules, and does not require further purification. The radionuclide purity of the product 166 Ho is greater than 99%; the DOTP used in this method is a commonly used chemical reagent, and the cost is significantly reduced compared to DOTATOC. Description of the Drawings

[0019] Figure 1 is the gamma energy spectrum of the raw material 166 Dy / 166 Ho;

[0020] Figure 2 is the gamma energy spectrum of the product 166 Ho. Detailed Embodiments

[0021] Those of ordinary skill in the art will realize that the embodiments described herein are for the purpose of assisting the reader in understanding the principles of the present invention, and it should be understood that the protection scope of the present invention is not limited to such specific statements and embodiments. Those of ordinary skill in the art can make various other specific deformations and combinations that do not deviate from the essence of the present invention based on the technical revelations disclosed in the present invention, and these deformations and combinations are still within the protection scope of the present invention.

[0022] The present invention will be described in detail below with reference to the drawings and specific embodiments.

[0023] A method based on 166 Dy-166 Separation of Ho generator 166 Method for Ho, the method comprising:

[0024] First step: Using an acid solution in a hot cell or a shielded work box to dissolve the product of reactor-irradiated Dy2O3 at a temperature of 50 - 60 °C to obtain 166 Dy / 166 An acid solution of Ho, wherein the product of Dy2O3 mainly comprises 166 Dy2O3 and 166 Ho2O3 decayed from 166 Dy2O3;

[0025] Second step: Prepare 166 Dy / 166 Complex of Ho and DOTP 166 Dy / 166 Ho-DOTP, the specific process is: Mixing the 166 Dy / 166 Ho acid solution and the DOTP solution respectively in a molar ratio of 1:1 to 1:1.1 to obtain a mixed solution, adjusting the pH value of the mixed solution to 11 ± 0.5 using HCl and NaOH, so that 166 Dy / 166 Ho and DOTP undergo a complexation reaction at this fixed pH value, the reaction temperature is 80 - 100 °C, the reaction time is 30 - 60 min, and finally the complex 166 Dy / 66 Ho-DOTP is formed;

[0026] Third step: Loading the 166 Dy / 166 Ho-DOTP complex onto an anion exchange column, the packing material of the anion exchange column includes but is not limited to anion exchange resin and acidic aluminum oxide; then activating with an acid of volume V1 for 15 - 60 min to keep the anion exchange column in an acidic environment, wherein the acid includes but is not limited to HCl and HNO3 with a concentration of 0.01 - 0.1 M, and the volume V1 is such that the amount of hydrogen ions in the acid is 2 - 5 times the amount of substance of the 166 Dy / 166 Ho-DOTP complex loaded onto the anion exchange column; finally pre-rinsing with pure water with a volume ≥ 10 times the column volume and having a conductivity less than 5.1 μS / cm at 25 °C to remove the excess acid on the anion exchange column;

[0027] Fourth step: Let the anion exchange column stand at room temperature, wait for 166 Ho to grow naturally, and every 1 - 2 days, rinse with pure water having a conductivity less than 5.1 μS / cm at 25 °C to obtain 166 Ho solution, rinse with pure water166 The power sources of Ho include, but are not limited to, gravity, vacuum, or peristaltic pumps.

[0028] Example 1

[0029] S1: Dissolve the product of reactor-irradiated Dy2O3 with 2M HCl at 50 °C in a shielding workbox 166 Dy2O3 and 166 Ho2O3 decayed from 166 Dy2O3 to obtain 166 Dy / 166 an acid solution of Ho. The raw material 166 Dy / 166 The gamma energy spectrum of Ho is as Figure 1 shown;

[0030] S2: Prepare 166 Dy / 166 a complex of Ho and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP) 166 Dy / 166 Ho-DOTP;

[0031] 166 Dy / 166 The molar ratio of Ho to DOTP is 1:1.05. The reaction pH is adjusted to 11 with NaOH and HCl. The reaction temperature is 80 °C, and the reaction time is 60 min;

[0032] S3: Take 20 mmol of Dy / Ho-DOTP obtained in S2 (calculated based on 166 Dy / 166 Ho) and load it onto an acidic aluminum oxide column. Then add 1 ml of 0.05M HCl to activate for 30 min, and then wash with 10 column volumes of pure water; 166 Dy / 166 Ho) and load it onto an acidic aluminum oxide column. Then add 1 ml of 0.05M HCl to activate for 30 min, and then wash with 10 column volumes of pure water;

[0033] S4: Let the anion exchange column treated in S3 stand at room temperature until 166 Ho grows naturally. Every 2 days, pure water can be used to wash by gravity to obtain 166 a Ho solution. The gamma energy spectrum of the product 166 Ho is as Figure 2 shown. After quantitative analysis, 166 the radionuclide purity of Ho is greater than 99%.

[0034] Example 2

[0035] S1: Dissolve the product of reactor-irradiated Dy2O3 with 1M HCl at 60 °C in a shielding workbox. The product mainly includes 166 Dy2O3 and 166 Ho2O3 decayed from 166 Dy2O3 to obtain 166 Dy / 166 Ho acid solution;

[0036] S2: Prepare 166 Dy / 166 complex of Ho and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP) 166 Dy / 166 Ho-DOTP;

[0037] 166 Dy / 166 The molar ratio of Ho to DOTP is 1:1.1. The reaction pH is adjusted to 10.5 with NaOH and HCl, the reaction temperature is 90 °C, and the reaction time is 45 min;

[0038] S3: Take 10 mmol of 166 Dy / 166 Ho-DOTP (calculated based on 166 Dy / 166 Ho) and load it onto an anion exchange resin column. Then add 1 ml of 0.05M HCl to activate for 15 min, and then wash with 15 column volumes of pure water;

[0039] S4: Let the anion exchange resin column treated in step S3 stand at room temperature. Wait for 166 Ho naturally grown from the decay of 166 Dy. Every 1 day, pure water can be used to wash and collect the 166 Ho solution with a vacuum bottle.

Claims

1. A method based on - generator separation is characterized in that The method includes: S1: Dissolve the products irradiated by the reactor with acid solution at a temperature to obtain an acid solution of / / ; S2: Preparation / Complex with DOTP / -DOTP S3: Load the / -DOTP complex onto an anion exchange column. After acid activation for a volume of acid activation time , keep the anion exchange column in an acidic environment, and then pre-rinse with pure water to remove the excessive acid on the anion exchange column; S4: Let the anion exchange column stand still until natural growth occurs, and at each interval , rinse with pure water to obtain solution.

2. According to claim 1, based on - generator separation The method is characterized in that The preparation of the acid solution in S1 is carried out in a hot cell or a shielding work box; the products of the reactor irradiation mainly include and those decayed from ; the acid solution includes HCl and ; the temperature is 50-60 ; .

3. According to claim 1, based on - generator separation The method is characterized in that The complex in S2 / The preparation method of -DOTP is as follows: / Mix an acid solution and a DOTP solution according to a certain molar ratio to obtain a mixed solution, and adjust the pH value of the mixed solution with an acid solution and an alkali solution to make / and DOTP undergo a complexation reaction at a certain pH value to form a complex / -DOTP.

4. According to claim 3, the method based on - generator separation is characterized in that The / molar ratio of and DOTP is: 1:1 to 1:1.1; the acid solution is HCl, the alkali solution is NaOH; the certain pH value is 11 ± 0.5; the reaction temperature of the complexation reaction is 80 to 100 , and the reaction time is 30 to 60 min.

5. According to claim 1, based on - generator separation the method is characterized in that In S3, the filling material of the anion exchange column includes anion exchange resin and acidic aluminum trioxide.

6. According to claim 1, based on - generator separation the method, characterized in that In S3, the acids used include HCl and , the concentration of the acid is 0.01 - 0.1 M, and the volume is such that the amount of substance of hydrogen ions in the acid is 2 to 5 times the amount of substance of the / -DOTP complex loaded onto the anion exchange column; the time is 15 - 60 min; the volume of the pure water is ≥ 10 times the column volume.

7. According to claim 1, based on - generator separation The method is characterized in that The pure water in S3 and S4 has a conductivity of less than 5.1 μS / cm at 25 degrees Celsius.

8. According to claim 1, based on - generator separation The method is characterized in that In S4, the ambient temperature for the anion exchange column to stand still is room temperature, and the time is 1 to 2 days.

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