Preparation method of Re nuclide and diagnosis and treatment integrated probe based on ammonia water dissolution

Abstract

The invention relates to a preparation method of an Re nuclide and diagnosis and treatment integrated probe based on ammonia water dissolution. The preparation method of the Re nuclide based on ammonia water dissolution comprises the following steps: preparing a target material, oxidizing 182W and / or 186W powder with the enrichment degree of more than 99.5% to prepare tungsten oxide, and performing high-temperature sintering and tabletting on the tungsten oxide to prepare the target material; irradiating, namely irradiating and dissolving the target material by using a proton accelerator, putting the irradiated target material into a mixed solution of ammonia water and hydrogen peroxide, stirring, dissolving and purifying, and separating a purified solution containing Re by passing filtrate through a chromatographic column and anion exchange chromatography; and concentrating. According to the method, the ammonia water alkaline solution is innovatively adopted to replace sodium hydroxide, and the optimized irradiation and separation process is combined, so that efficient and low-pollution 182Re / 186Re preparation is realized. The ammonia water alkaline environment can dissolve tungsten oxide without metal ion interference, the hydrogen peroxide is added to accelerate the dissolution reaction, the dissolution efficiency of the ammonia water combined with the hydrogen peroxide reaches 98%, and the dissolution efficiency is remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of radionuclide production, and in particular to a method for preparing Re nuclides dissolved in ammonia and a diagnostic and therapeutic probe. Background Technology

[0002] Rhenium-186 186 Re is a radioactive isotope with a half-life of approximately 90 hours (3.7 days), emitting both beta and gamma rays. Beta rays (energy approximately 1.07 MeV) can penetrate tissue to a depth of up to 4.8 mm, effectively destroying tumor cells, while gamma rays (energy approximately 137 keV) facilitate real-time monitoring of drug distribution and dosage calculation using imaging technologies such as SPECT / CT, enabling simultaneous optimization of treatment and imaging. This dual characteristic gives it a unique advantage in cancer radiotherapy, particularly for the precision treatment of central nervous system tumors.

[0003] In March 2025, Rhenium-186 (186Re)-labeled liposome therapy, Rhenium obisbemeda, received FDA approval for the treatment of metastatic leptomeningioma of lung cancer. Additionally, Plus Therapeutics, a clinical-stage pharmaceutical company developing targeted radiotherapy drugs for central nervous system cancers using advanced platform technologies, recently announced that the first patient has been dosed in the ReSPECT-GBM Phase 2b dose-escalation clinical trial evaluating Rhenium (186Re) obisbemeda for the treatment of recurrent glioblastoma (GBM). Currently, two 186Re drugs have been approved, and seven clinical trials are underway. It is a very promising therapeutic drug.

[0004] 186 Re can be used to bombard isotopes of tungsten using low-energy (10-13 MeV) proton accelerators. 186 W is used for production. 186 The natural abundance of W is 28.43%, making this isotope relatively easy to obtain. Traditional preparation methods typically involve proton irradiation of a tungsten oxide (W₂O₃) target followed by dissolution with sodium hydroxide solution to obtain a therapeutically usable form. 186 Re solutions. However, existing methods have the following drawbacks:

[0005] (1) The strong alkalinity of sodium hydroxide easily leads to the co-precipitation of Re with impurity metals, reducing the recovery rate of Re.

[0006] (2) Residual sodium ions interfere with the subsequent labeling reaction and the strongly alkaline environment, which can easily lead to precipitation.

[0007] (3) The dissolution efficiency of the target material is low, requiring high temperature conditions and liquid phase extraction to complete the dissolution. The dissolution time is too long, resulting in a reduction in the number of nuclides due to their half-life. Summary of the Invention

[0008] The purpose of this invention is to overcome the above-mentioned shortcomings and provide a method for preparing Re nuclides and diagnostic and therapeutic probes based on ammonia dissolution with high dissolution efficiency and short preparation time.

[0009] To achieve the above objectives, the technical solution of the present invention is: a method for preparing Re nuclides dissolved in ammonia, comprising the following steps:

[0010] To prepare the target material, the enrichment degree of which is greater than 99.5% is used. 182 W and / or 186 W powder is oxidized to prepare tungsten oxide, and the tungsten oxide is sintered at high temperature and pressed into a target material.

[0011] Irradiation, using a proton accelerator to irradiate the target material, causing the target material to... 182 W transforms into 182 Re and / or 186 W transforms into 186 Re, the target material is cooled after irradiation;

[0012] Dissolution: The irradiated target material is placed in a mixture of ammonia and hydrogen peroxide and stirred to dissolve. The undissolved residue is filtered to obtain the filtrate.

[0013] Purification: The filtrate is passed through a chromatographic column and separated into a W-containing solution and a Re-containing purified solution by anion exchange chromatography.

[0014] Concentrate, concentrate and purify the solution to obtain a solution containing high activity. 182 Re and / or 186 Re concentrate of Re.

[0015] 186 Re radioactive isotopes have suitable half-lives and moderate beta values. - X-ray energy, a simple decay chain, its decay chain is as follows.

[0016]

[0017] 182 The decay of Re is a positron emission to the electron, with a half-life of 64.2 hours. 182 The decay chain of Re is 100% composed of β+ decaying into β+. 182 W is the primary decay. 182 Re and 186 Re is close to radionuclides that can be used for diagnosis, and 186Re pairing can result in therapeutic pairings of the same element. They also exhibit very simple decay chains.

[0018]

[0019] The raw materials for the two nuclides, 182 W and 186 W has similar natural abundance, therefore the yield and production conditions of the two nuclides are almost identical, making them a highly promising pair of nuclides for integrated diagnosis and treatment. The two nuclides are chemically indistinguishable and have very similar half-lives, offering significant advantages compared to other nuclide pairings. This invention utilizes a small cyclotron accelerator to prepare two radionuclides, providing a significant advantage for integrated medical diagnosis and treatment.

[0020] This invention innovatively uses an alkaline ammonia solution instead of sodium hydroxide, combined with optimized irradiation and separation processes, to achieve high efficiency and low pollution. 182 Re / 186 Preparation of Re. The alkaline environment of ammonia water can dissolve tungsten oxide without introducing metal ion interference. Adding hydrogen peroxide accelerates the dissolution reaction; the dissolution efficiency of ammonia water combined with hydrogen peroxide reaches 98%, significantly improving dissolution efficiency and avoiding the reduction of radionuclide quantity due to half-life. It reduces sodium and potassium cation contamination and improves radionuclide labeling efficiency. Ammonia water is volatile, and the treatment cost of other waste liquids after adsorption is low.

[0021] Preferably, in the target preparation step, the following steps are performed: 182 W and / or 186 W powder is oxidized in hydrogen peroxide to form tungsten oxide. The tungsten oxide is heated, evaporated, and sintered to form tungsten oxide powder. The tungsten oxide powder is pressed into a target material with a diameter of 10 mm and a thickness of 0.5 mm.

[0022] In the irradiation process, the target material is irradiated with a 10 MeV proton beam using a cyclotron, with a proton beam intensity of 30 μA and an irradiation time of 3-10 hours; the target material is then cooled for 1-2 hours after irradiation.

[0023] Preferably, in the dissolution step, the irradiated target material is first placed in ammonia water with a concentration of 0.5–5 mol / L and stirred at 80°C for 20 minutes to dissolve. Then, 1–2.5 times the amount of hydrogen peroxide with a concentration of 3–5% is added to the ammonia water, and the mixture is stirred at 90°C for 3 hours. The alkaline environment of ammonia water can dissolve tungsten oxide, and the addition of hydrogen peroxide can accelerate the dissolution reaction.

[0024] Preferably, in the purification step, the filtrate is passed through an Al2O3 column to adsorb W-containing anions and Re-containing anions.

[0025] The chromatographic column was eluted with ammonia water and potassium tartrate solution with a concentration of 0.5 mol / L to elute the W-containing acid anion from the column and separate the W-containing solution.

[0026] The chromatographic column was eluted with physiological saline to elute Re-containing anions from the column, resulting in a purified solution containing Re. The Al2O3 particles in the Al2O3 column had a particle size of 50–100 μm.

[0027] Preferably, in the concentration step, the purified solution is evaporated to dryness to form a purified product, and the purified product is dissolved in hydrochloric acid with a concentration of 0.1 mol / L to form a Re concentrate.

[0028] Preferably, in the dissolution step, sodium citrate or potassium tartrate is added to the mixture of ammonia and hydrogen peroxide.

[0029] A method for preparing a Re-targeting imaging agent, comprising preparing a Re concentrate using the aforementioned method for preparing Re-isotopes based on ammonia dissolution; using... 182 W prepared 182 Re concentrate;

[0030] 182 Re concentrate, after chelation with a bifunctional chelating agent, is coupled with a targeting carrier probe to generate a Re radionuclide targeting imaging agent. This agent can be used for targeted imaging of lesions.

[0031] A method for preparing a Re-nuclide-based diagnostic and therapeutic probe, comprising preparing a Re-nuclide containing [specific ingredient] using the aforementioned ammonia-based dissolution method. 182 Re and 186 Re concentrate of Re;

[0032] Re solution is chelated with a bifunctional chelating agent (such as DTPA), and then coupled with a targeted carrier probe to generate a therapeutic probe. 186 Re solution-labeled HEDP (hydroxyethylidene diphosphonic acid) is used for the treatment of bone metastases, with a labeling rate >95%.

[0033] By adopting the above technical solution, the beneficial effects of this invention are: This invention innovatively uses ammonia alkaline solution instead of sodium hydroxide, combined with optimized irradiation and separation processes, to achieve high efficiency and low pollution. 182 Re / 186 Re preparation. Its core advantages include:

[0034] (1) The alkaline environment of ammonia water can dissolve tungsten oxide without causing interference from metal ions. At the same time, adding hydrogen peroxide can accelerate the dissolution reaction, significantly improve the dissolution efficiency, and avoid the reduction of nuclide quantity due to half-life.

[0035] (2) Reduce sodium, potassium and other cation pollution and improve the efficiency of radionuclide labeling.

[0036] (3) Ammonia water is volatile, and after adsorption, the cost of treating other waste liquids is low. Attached Figure Description

[0037] Figure 1 These are the characteristic energy peaks of the purified Re from this invention.

[0038] Figure 2 For the present invention 182 Re reaction cross section diagram;

[0039] Figure 3 For the present invention 186 Diagram of the Re reaction cross section. Detailed Implementation

[0040] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0041] Example 1:

[0042] like Figures 1-3 As shown, the present invention provides a method for preparing Re nuclides dissolved in ammonia, comprising the following steps:

[0043] S1 is used to prepare the target material, with an enrichment degree greater than 99.5%. 182 W and / or 186 W powder is oxidized to prepare tungsten oxide. 182 W and / or 186 W powder is oxidized in hydrogen peroxide to form tungsten oxide. The tungsten oxide is heated, evaporated, and sintered to form tungsten oxide (W2O3) powder. The tungsten oxide powder is pressed into a target material with a diameter of 10 mm and a thickness of 0.5 mm.

[0044] S2 irradiation involves irradiating the target material using a proton accelerator and a cyclotron irradiation using a 10 MeV proton beam at a current intensity of 30 μA for 3-10 hours; this process aims to improve the performance of the target material. 182 W transforms into 182 Re and / or 186 W transforms into 186 Re, generating the target nuclide ( 182 W(p,n) 182 Re or 186 W(p,n) 186 Re). The target material is cooled after irradiation; the target material is cooled for 1-2 hours after irradiation.

[0045] 182 The reaction cross section of Re is as follows Figure 2 As shown, 186 The reaction cross section of Re is as follows Figure 3 As shown.

[0046] S3 dissolution involves placing the irradiated target material into ammonia solution with a concentration of 0.5–5 mol / L, while simultaneously adding hydrogen peroxide to accelerate dissolution. The target material is stirred and dissolved in the mixture. A complexing agent (such as sodium citrate or potassium tartrate) is added to improve the dissolution efficiency of W and inhibit the re-adsorption of Re. Undissolved residue is filtered to obtain the filtrate.

[0047] The alkaline environment of ammonia water can dissolve tungsten oxide without introducing metal ion interference. Adding hydrogen peroxide accelerates the dissolution reaction; the combined ammonia and hydrogen peroxide solution achieves a dissolution efficiency of 98%, significantly improving dissolution efficiency and preventing the reduction of radionuclide content due to half-life. This also reduces contamination from sodium, potassium, and other cations, improving radionuclide labeling efficiency.

[0048] S4 purification involves passing the filtrate through a chromatographic column (Al2O3 column) and separating the W-containing solution and the Re-containing purified solution using anion exchange chromatography. The column adsorbs W-containing and Re-containing acid radical anions.

[0049] The chromatographic column was eluted with ammonia water and potassium tartrate solution with a concentration of 0.5 mol / L to elute the W-containing acid anion from the column and separate the W-containing solution.

[0050] The chromatographic column was eluted with physiological saline to elute the Re-containing anions from the column, separating the purified Re-containing solution. The characteristic energy spectrum of purified Re is shown below. Figure 1 As shown.

[0051] S5 concentration: The purified solution is concentrated and evaporated to dryness to form the purified product. The purified product is then dissolved in 0.1 mol / L hydrochloric acid to form Re concentrate. Re concentrate contains high activity. 182 Re and / or 186 Re.

[0052] Example 2:

[0053] A method for preparing a Re-nuclide diagnostic and therapeutic probe includes the following steps:

[0054] The method for preparing Re nuclides based on ammonia dissolution produces a product containing... 182 Re and 186 Re concentrate of Re.

[0055] The Re solution is chelated with a bifunctional chelating agent and then coupled with a targeted carrier probe to generate a therapeutic probe.

[0056] Re-isotopes can be used to label targeted molecules (such as peptides, antibodies, or glucose derivatives) to form therapeutic probes that combine the functions of positron emission tomography (PET) and beta-glucan synthesis. - Radiation therapy function.

[0057] Example 3:

[0058] This invention relates to a method for preparing Re nuclides dissolved in ammonia, comprising the following steps:

[0059] S1 is used to prepare the target material, with an enrichment degree greater than 99.5%. 182 W powder is oxidized to prepare tungsten oxide. 182 W powder is oxidized in hydrogen peroxide to form tungsten oxide. The tungsten oxide is heated, evaporated, and sintered to form tungsten oxide powder. The tungsten oxide powder is pressed into a target material with a diameter of 10 mm and a thickness of 0.5 mm.

[0060] S2 irradiation involved irradiating the target material using a proton accelerator and a cyclotron irradiation using a 10 MeV proton beam at a current intensity of 30 μA for 5 hours; this resulted in the formation of S2 irradiation in the target material. 182 W transforms into 182 Re, generating the target nuclide ( 182 W(p,n) 182 Re. Cool the target material after irradiation; cool the target material for 1-2 hours after irradiation. 182 The reaction cross section of Re is as follows Figure 2 As shown.

[0061] For S3 dissolution, the irradiated target material is first placed in ammonia water with a concentration of 0.5–5 mol / L and stirred at 80°C for 20 minutes. Then, 1–2.5 times the volume of hydrogen peroxide with a concentration of 3–5% is added to the ammonia water, and the mixture is stirred at 90°C for 3 hours. A complexing agent (such as sodium citrate or potassium tartrate) is added in 10–15% of the ammonia water at the molar amount of ammonia to improve the dissolution efficiency of W and inhibit the re-adsorption of Re. The undissolved residue is filtered to obtain the filtrate.

[0062] The alkaline environment of ammonia water can dissolve tungsten oxide without introducing metal ion interference. Adding hydrogen peroxide accelerates the dissolution reaction; the combined ammonia and hydrogen peroxide solution achieves a dissolution efficiency of 98%, significantly improving dissolution efficiency and preventing the reduction of radionuclide content due to half-life. This also reduces contamination from sodium, potassium, and other cations, improving radionuclide labeling efficiency.

[0063] S4 purification involves passing the filtrate through a chromatographic column (Al2O3 column) and separating the solution containing W and the purified solution containing Re using anion exchange chromatography. The column adsorbs W-containing and Re-containing acid radical anions.

[0064] The chromatographic column was eluted with ammonia water and potassium tartrate solution with a concentration of 0.5 mol / L to elute the W-containing acid radical anions from the chromatographic column and separate the W-containing solution.

[0065] The chromatographic column was eluted with physiological saline to elute the Re-containing anions from the column, separating the purified Re-containing solution. The characteristic energy spectrum of purified Re is shown below. Figure 1 As shown.

[0066] S5 concentration: The purified solution is concentrated and evaporated to dryness to form the purified product. The purified product is then dissolved in 0.1 mol / L hydrochloric acid to form Re concentrate. Re concentrate contains high activity. 182 Re.

[0067] A method for preparing a Re-nuclide-targeted imaging agent, comprising preparing the Re-nuclide based on ammonia dissolution using the aforementioned method. 182 Re concentrate; 182 Re concentrate is chelated with a bifunctional chelating agent (such as DTPA) and then coupled with a targeting vector probe to generate a Re-isotope targeting imaging agent. The Re-isotope targeting imaging agent can create targeted imaging of lesions.

[0068] The above description is merely a preferred embodiment of the present invention and does not limit the scope of the present invention. All equivalent changes and modifications made in accordance with the claims of the present invention should still fall within the scope of the present invention.

Claims

1. A method for the production of a Re nuclide based on the dissolution of aqueous ammonia, characterized in that, The method comprises the following steps: The target is prepared by oxidizing the tungsten powder with an enrichment degree of greater than 99.5% 182 W and / or 186 The tungsten powder is oxidized to prepare tungsten oxide, and the tungsten oxide is sintered at high temperature and pressed into a target Irradiation, the target material is irradiated by a proton accelerator, so that the target material 182 W is converted into 182 Re and / or 186 W is converted into 186 Re, the target material is cooled after irradiation; dissolving, putting the irradiated target into a mixture of ammonia and hydrogen peroxide to stir and dissolve, filtering the undissolved residue to obtain a filtrate; purifying, passing the filtrate through a chromatographic column to separate a W-containing solution and a Re-containing purified solution by anion exchange chromatography; Concentrate, concentrate the purified liquid, to obtain a high activity 182 Re and / or 186 Re concentrate of Re.

2. The method for preparing a Re nuclide based on ammonia aqueous solution dissolution according to claim 1, characterized by In the target preparation step, the powder of W and / or WO3 is oxidized in hydrogen peroxide to form tungsten oxide, the tungsten oxide is heated, the tungsten oxide is evaporated and sintered to form tungsten oxide powder, and the tungsten oxide powder is pressed into a target having a diameter of 10 mm and a thickness of 0.5 mm. 182 W and / or 186 The powder of W and / or WO3 is oxidized in hydrogen peroxide to form tungsten oxide, the tungsten oxide is heated, the tungsten oxide is evaporated and sintered to form tungsten oxide powder, and the tungsten oxide powder is pressed into a target having a diameter of 10 mm and a thickness of 0.5 mm. In the irradiation step, the target is irradiated by a 10 MeV proton beam of a cyclotron, the proton beam intensity is 30 μA, and the irradiation time is 3-10 hours; the target is cooled for 1-2 hours after irradiation.

3. The Re isotope preparation method based on ammonia dissolution according to claim 1, characterized in that, In the dissolving step, the irradiated target is first put into ammonia with a concentration of 0.5-5 mol / L, stirred and dissolved at 80°C for 20 minutes, 1-2.5 times the amount of hydrogen peroxide with a solubility of 3-5% is added to the ammonia, and stirred at 90°C for 3 hours.

4. The Re isotope preparation method based on ammonia dissolution according to claim 1, characterized in that, In the purification step, the filtrate is passed through an Al2O3 chromatographic column to adsorb W-containing and Re-containing anions by the chromatographic column; The chromatographic column is eluted with ammonia with a concentration of 0.5 mol / L and potassium tartrate solution to elute the W-containing anions from the chromatographic column and separate a W-containing solution; The chromatographic column is eluted with physiological saline to elute the Re-containing anions from the chromatographic column and separate a Re-containing purified solution.

5. The Re isotope preparation method based on ammonia dissolution according to claim 1, characterized in that, In the concentration step, the purified solution is evaporated to form a purified product, and the purified product is dissolved in hydrochloric acid with a concentration of 0.1 mol / L to form a Re concentrated solution.

6. The Re isotope preparation method based on ammonia dissolution according to claim 1, characterized in that, In the dissolving step, sodium citrate or potassium tartrate is added to the mixture of ammonia and hydrogen peroxide.

7. A method for preparing a Re nuclide targeting imaging agent, characterized by, comprising the steps of: preparing a Re concentrate solution using the method for preparing a Re radionuclide based on ammonia solution according to any one of claims 1 to 6; and preparing 182 W using the Re concentrate solution 182 Re concentrate solution; 182 After chelation of Re concentrate with bifunctional chelator, coupling with targeting carrier probe, Re radionuclide targeted imaging agent and therapeutic drug are generated.

8. A method for preparing a Re radionuclide diagnosis and therapy integrated probe, characterized in that, comprising the step of preparing a Re concentrate containing 182 Re and 186 Re using the method for the preparation of a Re radionuclide based on ammonia dissolution according to any one of claims 1 to 6. The Re solution is chelated with a bifunctional chelating agent, and then coupled with a targeting carrier probe to generate a diagnosis and treatment integrated probe.

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