RU2210125C2 - Method of preparing radionuclide thorium-229 - starting material for preparation of therapeutic agent based on radionuclide bismuth-213 - Google Patents

Abstract

FIELD: nuclear medicine. SUBSTANCE: target containing naturally occurring thorium isotope ²²⁹Th is irradiated by proton beam in cyclotron. Desired isotope thorium- 229 accumulates in target during threshold nuclear reaction of ²³⁰Th (p, pn). Target material is, in particular, ²³⁰Th or ²³⁰ThF₄, or yet metallic thorum-230. EFFECT: retention of high specific activity and radioisotope purity of ²³⁰ThO₂. 2 cl, 1 dwg

Description

Technical field
The invention relates to reactor technology for producing radionuclides for nuclear medicine.

 In the diagnosis and treatment of cancer, α-emitting radionuclides are increasingly used. This is primarily due to the nuclear physical properties of these nuclides - the large initial energy of α particles (5-8 MeV), the short range of these particles in biological tissues (tens of microns) and the high level of energy release in the region of localization of decaying nuclides. Carriers of α-emitting radionuclides (monoclonal antibodies, peptides) with high specificity allow them to be delivered exactly to the tumor node or metastatic focus. It is possible to selectively irradiate pathological objects with minimal radiation exposure to surrounding benign tissues.

The present invention can be used to create a generator of α-emitters actinium-225 / bismuth-213 ( ²²⁵ Ac / ²¹³ Bi). Actinium-225 can be obtained in ²²⁹ Th / ²²⁵ Ra / ²²⁵ Ac generators. Thus, the issue of production of ²²⁹ Th is of key importance.

 The prior art.

 Currently, about 200 different radionuclides have been tested in nuclear medicine for diagnostic and therapeutic purposes. They are obtained due to the formation in reactions of the interaction of charged particles or neutrons with the target material. The target for irradiation is placed in various types of accelerators or nuclear reactors.

 One of the most promising areas in nuclear medicine is the use of α-emitters in point radioimmunotherapy. The use of short-lived α-nuclides for the treatment of oncological diseases is of undoubted interest due to the specific nuclear-physical and chemical properties of these nuclides. An intensive search is underway for radionuclides with high linear energy transfer (LET) with a limited path length in biological tissue.

In radioimmunotherapy, especially at the initial stage of the appearance of a malignant tumor, it is effective to use ²¹³ Bi radionuclide, an α-emitter with high LET (~ 80 keV / μm) and a short range of particles in biological tissue (50-90 μm). The predecessor of ²¹³ Bi in the decay chain is a radionuclide of ²²⁵ Ac with a half-life of T _1/2 = 10 days [V.A. Halkin et al. Radionuclides for radiotherapy. Radiochemistry, 1997, vol. 39, 6, pp. 481-490]. The separation of radionuclides ²²⁵ Ac and ²¹³ Bi is carried out using ion exchange resins. The total content of radionuclide impurities in the α-preparation ²¹³ Bi is not more than 20 μg / ml, while the volumetric activity of the drug is provided over a wide range from 1 to 10 mCi / ml [Dubinkin D.O., Smetanin E. Ya. Et al. VI 1st All-Russian (international) scientific conference "Physico-chemical processes in the selection of atoms and molecules", October 1-5, 2001, Zvenigorod, p. 42].

In turn, ²²⁵ Ac is a daughter decay product of the radionuclide ²²⁹ Th. Thus, to produce the ²¹³ Bi radionuclide, it is necessary to create a ²²⁹ Th / ²²⁵ Ac / ²¹³ Bi generator system. Therefore, the process of obtaining ²²⁹ Th as a starting material acquires decisive importance.

Two methods for producing ²²⁹ Th in significant quantities are known:
- radiochemical separation from the "old" reserves of ²³³ U;
- in high-flow reactors.

For the prototype, a method was chosen for producing ²²⁹ Th in a nuclear reactor by irradiating a launch target with a radionuclide ²²⁶ Ra due to multiple neutron capture [V.Yu. Baranov, N.S. Marchenkov. Nuclide program of the Russian Research Center "Kurchatov Institute": past, present, future. Conversion in mechanical engineering, 2000, 3, pp. 38-47].

However, this method has significant disadvantages:
- obtaining ²²⁹ Th from ²²⁶ Ra is a multi-stage process due to triple neutron capture;
- in the finished product there is a large (up to 50%) fraction of an impurity radionuclide of ²²⁸ Th, which significantly complicates the radiochemical stage of preparation of a medicine based on ²¹³ Bi.

Disclosure of Invention
The invention is based on the manufacturability requirements of a new method for producing ²²⁹ Th radionuclide while maintaining high specific activity and radioisotope purity, the possibility of using the natural isotope ²³⁰ Th, a natural decay product of ²³⁸ U, for its production.

The problem is solved in that in the method for producing a ²²⁹ Th radionuclide, which is a starting radionuclide in the manufacture of a ²¹³ Bi therapeutic radiopharmaceutical, including irradiating the target, the natural thorium isotope ²³⁰ Th is used as the target material, the target is placed in a cyclotron and irradiated with a proton beam, and during the threshold nuclear reaction ²³⁰ Th (p, pn) ²²⁹ Th, the target radioisotope thorium-229 is accumulated in it.

Compounds ²³⁰ ThF ₄ , or ²³⁰ ThO ₂ , or metal thorium-230 can be used as the target material.

In the proposed method for the production of ²²⁹ Th radionuclide, the existence of a natural radionuclide of ²³⁰ Th, a natural decay product of ²³⁸ U, is used. It is known that during the radioactive decay of ²³⁸ U, in the chain of daughter products, in addition to the ²³⁴ U isotope, long-lived α-emitters are formed: the ²³⁰ Th isotope, and the ²²⁶ Ra isotope with half-lives of 8.1 • 10 ⁴ and 1.59 • 10 ³ years, respectively. The content of these isotopes in natural uranium is estimated by the following figures: radium 352 mg / t of uranium and thorium 17.9 g / t of uranium. In the processing of uranium ores described above, α-radioactive isotopes are isolated as by-products in the production of uranium [V. B. Shevchenko, B.N. Sudarikov. Uranium technology. M .: Gosatomizdat, 1961].

It is known that during the enrichment of uranium hexafluoride UF ₆ thorium is separated and remains in the "cinder" during fluorination [Matveev L.V. et al. The problem of accumulation of ²³² U and ²³⁶ Pu in a nuclear reactor, "Nuclear Technology Abroad", 1980, 4, p. 10-17].

The main source of ²³⁰ Th available for use at present is waste from dump UF ₆ in separation production, where its accumulation occurs during long-term storage [Yu. V. Smirnov and other Processing, disposal and disposal of waste from mining and metallurgical production, "Nuclear Technology Abroad", 1981, 3, pp. 15-20].

When a target containing thorium-230 is irradiated in a cyclotron as a result of a nuclear reaction of ²³⁰ Th (n, pn) ²²⁶ Th, the target radionuclide ²²⁹ Th is accumulated in the target.

Injected into the target ²²⁹ Th has a genetic chain of decay of the elements, leading to the radionuclide ²¹³ Bi, which is used in nuclear medicine [V.A Khalkin et al. Radionuclides for radiotherapy. Radiochemistry, 1997, v. 39, 6, p. 483, fig. 1].

The radionuclide ²²⁹ Th obtained as a result of the nuclear reaction (p, pn) is incubated for a time sufficient for the accumulation of ²²⁵ Ac in the target of its daughter decay product, after which ²²⁵ Ac are extracted from the target by multistage liquid extraction and sorption of thorium, radium and actinium on anion exchange resin . Actinium-225 is quantitatively sorbed on anion exchange resin, and radium and other decay products are separated in the form of a raffinate solution. Received ²²⁵ Ac used to create a medical generator ²²⁵ Ac / ²¹³ Bi.

The proposed method for creating an α-emitting medical generator for radioimmunotherapy has a significant advantage compared to those described in the literature:
- the target radionuclide ²²⁹ Th is obtained as a result of a single neutron capture;
- an admixture of radionuclide ²²⁸ Th is minimized;
- the target radionuclide ²²⁹ Th receive, using as a source material a by-product in the processing of uranium ore ²³⁰ Th.

An example embodiment of the invention
A target containing ²³⁰ Th is mounted in a cyclotron. During the irradiation of the target, as a result of the threshold nuclear reaction ²³⁰ Th (p, pn) ²²⁹ Th, the target radionuclide is accumulated, which is the initial element of the decay chain of the radionuclides, leading to the production of ²¹³ Bi.

After irradiation, the target with the ²²⁹ Th radionuclide obtained in it is removed from the channel and incubated for a month. During radiochemical processing of the target material in strongly acidic solutions, radionuclides are sorbed on anion exchange resin. During sorption, radium and other decay products are separated in the form of a raffinate solution.

 A raffinate containing a large amount of radium is used for additional production and isolation of actinium-225.

 When thorium-229 is used in many cycles, its exposure to actinium-225 accumulation is carried out in an aqueous solution, and not on anion exchange resin, due to its destruction under the influence of short-lived α-emitters.

 To obtain actinium-225 of high nuclide purity, two sorption separation cycles are carried out using columns of different geometries.

In the process of radiochemical redistribution, Actinium-225 is obtained in the form of a nitric acid or hydrochloric acid solution with the following content of radionuclide impurities:
²²⁵ Ra <1 • 10 ^-4 %,
²²⁹ Th <1 • 10 ^-7 %.

 The remaining radionuclides are in equilibrium.

In this case, ²¹³ Bi of high purity are isolated.

The proposed method for producing ²²⁹ Th - a starting nuclide for the subsequent production of an α-emitting medical radionuclide ²¹³ Bi allows, in comparison with the method selected for the prototype, to reduce the complexity of the process, use as a starting material a by-product of uranium production ²³⁰ Th, reduce the content of associated radionuclides, for example ²²⁸ Th. In this case, the process of obtaining the target radionuclide is carried out in a nuclear-safe installation.

Claims (2)

1. A method of producing a thorium-229 radionuclide, a starting material for the production of a therapeutic drug based on bismuth-213 radionuclide, comprising irradiating the target, characterized in that the natural thorium isotope ²³⁰ Th is taken as the target material, the target is placed in a cyclotron and irradiated with a proton beam, and during the threshold nuclear reaction ²³⁰ Th (p, pn) ²²⁹ Th accumulate in it the target radioisotope thorium-229. 2. The method according to p. 1, characterized in that the compounds of ²³⁰ ThF ₄ , or ²³⁰ ThO ₂ , or metal thorium-230 are used as the target material.

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