The technical FIELD

The present invention relates to methods for the selection and use of radioactive chemicals (radiochemically). In particular, the method according to the present invention is aimed at obtaining sea anemone-225 and its child elements with high radiochemical and radionuclide purity, which can be used to obtain alpha-emitting (alpha-emitting) radiopharmaceuticals, in particular, for compounds with therapeutic drugs, containing antibodies, proteins (proteins), peptides, antisana, a statin, natural substances and hormones. Alpha-emitting radionuclide anemone-225 and its child elements can be used both for therapeutic and diagnostic purposes.

Data about conventional priority

Provisional application U.S. No. 60/167, 910, filed November 30, 1999

PRIOR art

Cancer ranks second after cardiovascular diseases among causes of death in the United States, accounting for one-fourth of the total mortality. Men often suffer from cancer of the lung, prostate, colon and rectum, female breast cancer, lung, colon and rectum.

The method of treatment in such cases often is the surgical removal of the tumor, which is certainly invasive. Chemiotherapy and radiotherapy have an advantage: they are non-invasive; but they have the potential disadvantage is that they too aselective. That is, they achieved a high degree of destruction of cancer cells, but they can produce very serious side effects. In fact, the side effects are the main drawback of these methods of treatment, which the patient often choose the surgical method of treatment, and no chemotherapy or radiotherapy.

These systematic methods using differences between cancerous and healthy cells. For example, uses the difference in the rate of proliferation of the cancerous and normal cells. The higher the rate of proliferation, the more is absorbed toxic substances, and in normal cells this absorption is less. Thus, when the system arrives cellular toxins, cancer cells absorb them faster than normal and thus destroyed to a greater extent. However, anti-cancer therapeutic drugs provide a significant side effect: they kill healthy cells, and this, as mentioned above, is the main reason for failure patients on such therapy.

To improve the selectivity of the destruction of cancer cells has been used successfully a number of ways. These methods often use one or another difference between cancerous and normal cells. With the greatest success are the structural differences of the cells, such as anti the us on the cell surface, receptors or other surface proteins, or molecules, which are differently expressed for different cell types.

For example, compared with normal cells and many tumor cells have an increased number of specific cell-surface antigens.

Target (addressing) substances, such as monoclonal antibodies may be specific for cancer cells and to contact their surface antigens, which allows to achieve a good localization and high absorption of therapeutic agent by the cells. In particular, for localization of cancer cells using such monoclonal antibodies as anti-gp160 against human lung cancer (see Sugiyama and others, "Selective Growth Inhibition of Human Lung Cancer Cell Lines Bearing a Surface Gtycoprotein gp160 by¹²⁵I-Labeled Anti-gp160 Monoclonal Antibody" ("Selective inhibition of growth of lung cancer cells with surface glycoprotein gp160 using¹²⁵I-labeled anti-gp160 monoclonal antibodies"), Cancer Res. 48, 2768-2773 (1988)), monoclonal antibodies FNT-1" (FNT-1) to cervical carcinoma person (see Chen et al, "Tumor Necrosis Treatment of ME-180 Human Cervical Carcinoma Model with¹³¹I-Labeled TNT-1 Monoclonal Antibody (Treatment tumor necrosis model ME-180 cervical carcinoma person using¹³¹I-labeled TNT-1 monoclonal antibodies"), Cancer Res., 49 (16), 4578-85, 1989) and antibodies to receptors of epidermal growth factor in KB carcinoma is (see Aboud-Pirak and others, "Efficacy of Antibodies to Epidermal Growth Factor Receptor Against KB Carcinoma In Vitro and in Nude Mice" ("the Effectiveness of antibodies to receptors of the epidermal growth factor against KB carcinoma in vitro and mice"), J. National Cancer Institute, 80(20), 1605-1611 (1988)).

To combat cancer cells also use different radiotherapy drugs, such as beta-emitters iodine-131, copper-67, rhenium-186 and yttrium-90. However, the disadvantages of beta-emitters are their low specific activity, low power transmission, low doses, which allows the cell to heal radiation damage), they damage the surrounding healthy tissue and some of them do not have detectable photons, giving the opportunity to get the image (for example, yttrium-90).

Alpha emitters are less toxic and more effective for therapy. In contrast to conventional total radiation therapy using gamma emitters in cellular radiation therapy targeted drugs are looking for cancer cells and attach to them radioisotopes. Selective cytotoxicity of radionuclides emitting alpha particles is the result of the transfer of more energy, at least 100 times greater than beta-emitting radionuclides, as well as a shorter run (50-80 micrometers) and the limited ability of cells to repair damaged DNA.

Because the alpha radiation of the radiation is related radionuclides penetrates only to a depth of several cells, it makes less damage to healthy tissues and cells than chemotherapy and radionuclide therapy of beta - and gamma-emitting radionuclides. Short mileage alpha particles allows an accurate "aiming" for cancer cells. Alpha-emitting radionuclides are one of the most effective cytotoxins known today, and be safe for the treatment of humans.

For example, for the treatment of Non-Hodgkin lymphoma, carcinoma of the thyroid and other cancers is applied beta-emitting iodine-131 (half-life - 8.02 days). Despite the fact that iodine is mainly localized in the thyroid tissue, this treatment remains problematic, as the radionuclide penetrates tissue to a depth of 10 mm and can damage healthy tissue. With the introduction in doses sufficient to kill cancer cells (up to 600 millicurie), iodine-131 can destroy the bone marrow, and in this case, patients need to do bone marrow transplantation - a procedure is painful and dangerous. Another radioisotope emitting beta particles and used in radionuclide medicine is yttrium-90, which, with its high energy, also penetrates deep into human tissue and can damage healthy tissue and organs.

For radionuclide therapy are also offered anemone-225, bismuth-212, lead-212, fermium-255, terbium-149, RA is rd-223, bismuth-213 and astatine-211, which are all alpha-emitting radionuclides. All of these radionuclides are the most effective are probably anemone-225 (an alpha emitter with an energy of 5.8 MeV and half-life 10 days) and its child element bismuth-213 (the half - life 46 minutes). Alpha-emitting astatine-211 is also offered as a medical radionuclide, but it is less suitable because of its short half-life (7,21 hours), which makes it difficult delivery.

The bismuth-213 half-life shorter than that of a sea anemone-225, but his physical and biochemical characteristics, its production, and its pharmacological properties make this radionuclide likely candidate for the treatment of humans. Dr. Otto Ganso (Otto Gansow) first developed the ways of the alpha-radioimmune therapy, creating linkers for linking monoclonal antibodies with radioactive bismuth (see U.S. Patent No. 4923985, 5286850, 5124471, 5428154 and 5434287 issued Aganzo and others). Alpha-emitting radioisotope bismuth-213 in connection with target molecules show good results in clinical trials for alpha radioimmune therapy.

At present, the bismuth-213 is undergoing clinical trials for the treatment of acute myeloid leukemia (AML) and could potentially be used for treatment of several other diseases, including T-cell is akosa, Non-Hodgkin lymphoma, metastases associated with prostate cancer and other diseases. It is established that the bismuth-213 can be used to stop the growth of the arterioles that feed the solid tumor, and lung cancer. This therapy is used now for the treatment of tumors liquid phases, such as leukemia. It can also be useful for the treatment of solid tumors and some other diseases, including immune disorders, rheumatoid arthritis, disease, degeneration of the joints, as well as other diseases, including sarcoma Galoshes and infectious diseases associated with AIDS. Cellular radiation therapy using powerful alpha-emitters for precise contact with cancer cells, can minimize the side effects characteristic of traditional chemotherapy and standard radiation exposure (nausea, hair loss, constipation, dry mouth insomnia and vomiting), and become the preferred method of treatment. Patients can be treated on an outpatient basis, and the required dose will be much smaller doses of beta-emitters.

Some ways to get sea anemone-225 is extremely dangerous and have a low yield of product. According to one method, the extraction of the long-lived thorium-229 (half-life-7300 years) anemone-225 receives U.S. Department of Energy. Thorium-229 is extracted in very small number is the operation with the necessary precautions of fissile uranium-233, weapons-grade uranium from natural thorium 20-30 years ago during the cold war. So, from 5 kg of uranium-233 (quantities sufficient to produce one nuclear bomb) receive only 0.5 g or 0.1 CI thorium-229. This quantity is enough to treat only about 10 patients. This high-cost technology when thorium-229, "cow", is a sea anemone generator-225, gives small sea anemone output-225, since the presence of the old thorium-229 and uranium-233 containing thorium-229, which can be extracted is limited.

Even if you take all of the thorium-229 from existing stocks of uranium-233 in the US, you get only a small amount of sea anemone-225, according to the calculations of not more than 3 curies per month. Such quantity of the radionuclide is not even enough for a few small clinical trials, and it would be enough only for those few patients who could afford to buy this radioisotope for the highest price at which the Energy Ministry has him now. The cost of the necessary quantity of the radioisotope would be tens of thousands of dollars.

In U.S. Patent No. 5355394 describes the method of obtaining useful quantities of sea anemone-225 and bismuth-213 with a very high thermal neutron flux in a nuclear reactor. However, according to the patent, to produce usable quantities of the original thorium-229 on reboots years of continuous irradiation of radium-226 in a large nuclear reactor. Thus, this process will be very slow. Another disadvantage of this method of production is that it will also be narabatyvatjsya a large number of detachable part of the thorium-228.

This undesirable radioisotope, thorium-228, although it has a shorter half-life, is a powerful deep penetrating gamma emitter, which can damage healthy tissue and will require installation of expensive "hot cell" for the isolation of patients and significant protection in a medical facility. Radioisotopes of thorium-228 and thorium-229 will be intimately mixed with each other and will take about 20 years of storage for decay of thorium-228. This would require substantial lead shielding, and thus produce a lot of radioactive waste and radon gas.

In U.S. Patent No. 5457323 describes another method of obtaining sea anemone-225. This method leads to the formation of gas radon, which is difficult and expensive to remove.

In patent WO 99/63550 proposes a method of obtaining sea anemone-225 by irradiation of radium-226 protons. The main disadvantage of this method is that for acceleration of protons necessary cyclotron.

Thus, the main problem facing doctors and researchers from around the world who wish to apply for the treatment of cancer and other diseases powerful short-lived radionuclide actin is th-225 and its child element bismuth-213, is a limited number of sea anemone-225, insufficient for use in clinics and research. In addition, due to the high cost of this radionuclide its widespread use in the present lie is not possible.

It is for the above reasons there is a need for new methods of obtaining sea anemone-225.

The INVENTION

We propose a method of obtaining sea anemone-225 in sufficient quantities. Substances obtained by means of this invention, particularly useful in radioimmunotherapy for the treatment of cancer, metastases and metastases, located separately from the primary containment.

We propose a method of obtaining sea anemone-225 in quantities sufficient for commercial sale in the form of the original substance, labeled radiopharmaceutical or in the form of a coating.

Offers safe, reliable and effective way of obtaining large quantities of sea anemone-225, not yielding significant quantities of radioactive waste. This method also provides the receiving sea anemone-225 with permanent (repeatable) radiochemical and radionuclide purity.

This invention provides a reliable way to get exposure to radium-226 quantities of sea anemone-225/bismuth-213, exceeding 1000 millicurie, radionuclide purity of <5 µci of radium-225 10 µci sea anemone-225. Anemone-225/bismuth-213 possess the physical properties required for diagnostic and therapeutic radiopharmaceuticals, especially when used in radioimmunotherapy.

Distinguishing features and advantages of the present invention provides his private options for implementation. These options are ways of getting isotopes, including the direction of the electrons on converting (transforming) the substance is covered with a layer of another substance, thus covering substance (coating) has a mass number of an atom is equal to n. When the interaction of electrons with the conversion substance are formed photons, the interaction of which with the substance of the coating leads to the formation of the isotope with the mass number of an atom is equal to n-1.

In one embodiment of the invention, the mass number of the n atom covering substances of radium-226 is 226. In this embodiment, n-1 is equal to 225, and the isotope with mass number 225 is radium-225. Converting substance may contain at least one of the following: copper, tungsten, platinum and tantalum. Covering substance (coating) is applied to the conversion method of electrolytic deposition (galvanothermy). To convert the substance to electrolytic deposition on it of radium-226, may also by electrolytic applied to Nickel. In alternative variants of the e conversion substance is covered with both Nickel and radium-226 by way of electrolytic deposition. The concentration of radium-226 for converting the substance is from about 80 mg/cm²up to 160 mg/cm².

In accordance with the method of the present invention, the electrons are directed to converting substance, covered with a layer of covering material, with the help of electron accelerator in which electrons are in the form of a beam (beam). Converts the substance has a thickness of from about 0.5 mm to about 1.7 mm, and the electron beam current from about 100 microamps to about 1000 microamps. The energy of the electrons is equal to from about 20 MeV to about 25 MeV and photons is from about 10 MeV to about 25 MeV.

The method according to the present invention may additionally include a branch of the sea anemone-225 from radium-225 and radium-226 by a process of chemical separation.

The method according to the present invention relates to isotope production and includes the direction of the electrons on a tungsten plate coated with electrolytic precipitated radium-226; in the interaction of electrons with tungsten are formed photons, interaction of which with radium-226 is obtained radium-225.

Another object of the present invention is a target for the electron beam of an electron accelerator comprising a metal plate coated with electrolytic precipitated radium-226. Atomic number of the substance (material) metal is some of the plates may be equal to 30 or more and the plate may be made of tungsten, tantalum, platinum and/or copper.

The present invention also provides a metal plate coated with a mixture of radium-226, radium-225 and sea anemone-225. The metal plate may be made of metal selected from tungsten, tantalum, platinum, and copper.

Other distinctive features and advantages of the invention will become apparent to specialists after following technical specifications and additional embodiments of the invention.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Figure 1. The resulting activity of radium-225 and sea anemone-225 depending on the time of exposure to the target of radium-226 weighing 1.0 g of the electron beam energy of 25 MeV.

Figure 2. Stream/the spectrum of gamma-radiation induced electrons 20 MeV and 25 MeV, depending on energy (MeV). The curve is calculated on the basis of the Table data.

Figure 3. Profile of radium-226 (gamma, n) depending on energy (MeV).

Figure 4. The radioactive decay of uranium-233 in anemone-225 and bismuth-213.

INFORMATION. CONFIRMING the POSSIBILITY of carrying out the INVENTION

The task of the invention is to obtain radiochemically (radioactive chemicals), in particular sea anemone-225, using radium-226 in the source material. The invention of zaklyuche is to irradiation of radium-226 to receive radium-225, which then beta-decay turns into anemone-225. Anemone-225 can be used to retrieve its child element, bismuth-213. The amounts of sea anemone-225, the product of the present invention may be 100 MCI sea anemone-225 to about 5 MCI of radium-225.

It should be noted that the present invention is used radium-226, natural radium isotope with a half-life of 1600 years. Thus, used in the description of the term radium-226 corresponds radium with natural isotopic composition, and a link to radium-226 as starting material does not imply isotopically pure form of radium-226.

A. Obtaining radionuclides

1. Anemone-225

The invention consists in the transformation (conversion) of radium-226, with photons of high energy, radium-225. This reaction can be described as the reaction of photodecomposition. Radium-225 dissolves in anemone-225, which is then separated in the process of chemical separation.

A. theoretical part

The reaction conversion of radium-226 in the radium-225 is a photodecomposition reaction, in which the absorption of high-energy electromagnetic radiation in the form of photons of gamma radiation causes the emission of a neutron by the nucleus of an atom of radium-226, calling education radium-225. Next, this reaction will be referred to as "gamma, n" or "y,n"-reaction, where "n" represents the IP is usemy neutron.

High-energy photons are formed during irradiation (bombardment) converts substances by high energy electrons (high energy electrons). Converting substance is a substance which when irradiated by electrons emits high-energy photons, and it must be refractory capable of withstanding electron irradiation (bombardment). Such substances are, for instance, tungsten, tantalum, platinum and copper.

High-energy electrons bombarding the conversion substance, must have sufficient energy to generated photons had enough energy for the reaction of photodecomposition. The energy required for the reaction of photodecomposition corresponds to the energy level, which must at least be equal to the threshold (minimum) energy level region of the giant resonance curve of the profile of energy for the reaction isotopic conversion. (Giant resonances is the average energy of the complex resonances of nuclei of a complex system. The width of these resonances is of the order of 1 MeV, and they rely on theory Kapoor-Perls spectrum of a single neutron potential.) It is the energy required for reaction between the photon and radium-226.

The intensity of high-energy photons generated by the envelope is the dominant substance, proportional to the power density (PD) of the electron beam in converting substance. The power density is calculated by the following formula:

PD=E·I/V

where E - energy e-beam, i is the electron beam current and V is the volume of the Converter, through which an electron beam.

Although the minimum energy depends on the level of the threshold energy region of the giant resonance, the maximum energy depends on the conversion of the substance. That is, converts the substance limits the energy introduced into the system. For example, when calculating the energy of high-energy electrons it is necessary to consider the ability of the conversion of a substance to absorb energy. The beam energy should be sufficient to generate photons of energy required for the conversion of isotopes, and at the same time not so large that a large percentage of the energy of the electron beam would pass through the conversion substance.

Also, if the thickness of the conversion layer is too large, then the photons will be degraded when passing through matter. Thus, the optimum thickness for the conversion of a substance depends on the energy of the electron beam, the composition of the conversion of matter and energy threshold region of the giant resonance of radium-226.

B. The manufacture of a solid target

In one embodiment, the implementation of izaberete the Oia radium-226 is applied to convert the substance. Upon irradiation of the conversion of matter with high energy electrons are produced by high-energy photons. Then the high-energy photons collide with radium-226, covering the conversion substance.

1) Converting substance

In the proposed method converts the substance transforms (converts) the high-energy electrons in high-energy photons. Thus, any substance with such ability can be used for this purpose if it is possible to apply a coating of radium-226. In U.S. Patent No. 5949836 issued Lidsky and others, these substances are called substance-"converters".

Converting substance may be any substance having the necessary conversion properties with relative resistance to the process (relative refractory) and which can coat the electrolytic method (galvanizing). Atomic number is the conversion of the substance must be greater than about 30. Examples converts substances are, among others, copper, tungsten, platinum and tantalum. Converting substance in the form of a plate milled, polished, grinded, washed with distilled water and dried. The thickness of the layer converts the substance is from about 0.5 mm to about 1.7 mm, or from about 0.8 is m to about 1.2 mm, or about 1 mm.

2) Application of radium-226 for converting substance

As mentioned above, to obtain the necessary reaction converts a substance covered by the radioisotope radium-226. The coating can be carried out by electrolytic deposition of the radioisotope on converting substance. Radioisotope applied to convert the substance is radium-226, which is in contact with air forms dioxide radium-226.

When the electrolytic deposition of radium-226 for converting the substance is used platinum electrode, although can be used with other types of electrodes. Thus, the electrolytic deposition can be carried out using a platinum electrode in a solution of radium-226, preparing the dissolution of radium-226 in the primary solution of alkali metal hydroxide. Some examples of the hydroxides of alkali metals are sodium hydroxide and potassium hydroxide.

In an alternative embodiment of the invention the metal substrate (converting substance) in the form of plates of such metals as copper, tungsten or tantalum, is placed in the electrolytic solution for the deposition of Nickel and covered them. The plating can be carried out according to the process of the Nickel baths Watts. The deposition process can be carried out at a temperature of about 30-60°C, the stirring solution, the pH is about 3.5 to 5.0. The current density is from about 2 to 7 A/DM². The bath composition: Nickel chloride (40-60 g/l), Nickel sulfate (240-300 g/l) and boric acid (25-40 g/l). In an alternative embodiment, Nickel is deposited by the method described Yoda and others, U.S. Patent No. 5985124.

Then Nickel-plated substrate is placed in the electrolytic solution of the dioxide of radium-226 and covered with radium-226. This process consists in the following.

To obtain a 0.1 M solution of radium-226 required quantity of radium-226 is dissolved in 8-molar HNO₃. Cell for the electrolytic deposition was made according to Krishnaswami and Sarin (see Krishnaswami S. and M.M. Sarin (1976), Anal. Chim. Acta, 83, 143-156). In a device for the electrolytic deposition is placed Teflon rod for mixing. The limit values of the power supply are set at 6 and 0.8 A. the Device installed on razmeshivaem tray, placed in a fume cupboard. Starts mixing with the current power supply is 0.8 A. Upon reaching the desired coating deposition stopped, turning off the power supply and adding concentrated ammonia. The resulting target is washed with distilled water and dried.

Alternatively, the conversion substance is placed in an electrolytic solution containing Nickel, and radium-226. Then p is avodat deposition of Nickel and radium-226 for converting the substance.

In another embodiment, the bromide of radium or radium oxide are mixed in a composition (varnish), which cover plate converts substances, using a process developed for the manufacture of radium watch dials. In another example, radium is applied to converting substance according to the method described by Chan and others in U.S. Patent No. 6103295, "Method of affixing radioisotopes onto a surface of a device" "Method of application of radioisotopes to the surface of the devices").

Regardless of the method of application of radium-226 is deposited on the substrate up until its concentration reaches at least 80 mg/cm². In practice, the concentration of radium-226 may be in the range from about 80 mg/cm²to about 160 mg/cm². The concentration may be lower or higher and depends on various factors, including the energy of the electron beam.

The coating can be applied so that part of the conversion of the substance remained uncovered and contacted with the electron beam. This can be achieved as follows. On the surface of a small area of the plate is filled with the molten plastic having a high melting point, and after hardening, the plate is immersed in the bath. In this case, the electrolytic deposition occurs only on the surface around the site, covered with plastic. Then the plastic is removed and customplugin remains uncovered.

Regardless of the method of manufacturing the target of radium-226 that converts a substance covered with radium-226, ready to irradiation in accordance with the invention.

century Manufacturing a liquid target

In another example embodiment of the invention, using the proposed method, it is possible to achieve conversion of radium-226, which is in solution. A solution of radium-226 is composed of chloride of radium-226, and its concentration is from about 0.5 M to about 1.5 M, or from about 0.75 M to about 1.25 M, or about 1 M In this example embodiment of the invention the solution of radium-226 may be located in a restricted or unrestricted basis.

For example, in the form of an unlimited amount of a solution of radium-226 flows over the conversion substance. Regular samples are taken from the solution originating from the conversion of matter, and solution recycle until then, until you get the desired product.

Target solution radium-226 can also be used in the form of limited volume. For example, a solution of radium-226 is placed in a quartz vial. The solution may be subjected to mixing or not mixed. Then convert the substance is directed electron beam, and formed as a result of this, the photons are directed to a quartz vial with a solution of radium-226, where the photodecomposition reaction.

The Jew is the first target has several advantages. In particular, the advantage is that the final product is obtained already in the solution, i.e. there is no need for additional surgery to separation of the solid product from the solid reagents. In this example, the final product is easily detected by chromatographic separation. The process of this separation is described in more detail below.

g E bombing

Bombardment of the target by the electron beam of an electron accelerator, in particular linear accelerator.

For the layer converts substances thickness of about 1 mm electron beam current should be from about 100 to about 1000 microamps. Or from about 250 to about 750 microamps and may be approximately 500 microamps. Used electron beam continuous or pulsed excitation.

Usually the energy of the electron beam approximately 2-3 times more energy peak of the giant resonance of irradiated isotope. For example, if the isotopic transformation (gamma, n) of radium-226 in the radium-225 a significant portion of high-energy photons will have energy levels that fall into the zone of the giant resonance for this reaction, in particular from about 10 MeV to about 25 MeV or approximately 15 MeV. Thus, the energy of the electrons colliding with the conversion substance is approx the RNO 20 MeV to about 25 MeV.

Irradiation with high energy electrons is in a period of time sufficient to obtain the necessary quantities of the final product, and is approximately from 10 to 30 days, or from about 18 to 23 days. In one embodiment of the invention the exposure time was approximately 20 days. However, the exposure time depends on many factors, including energy electron beam (more energy, less time; less energy - more time), from the conversion of a substance (formed more photons is less time; less photons is longer), the layer thickness converts substances (too little electrons slip - inefficient conversion - more time;

too much ineffective education photons is more time and concentration of the covering substance (less substances involved in the photodisintegration - less time; more matter - more time).

Ideally, the exposure time should not be too large. Therefore, to reduce the reaction time efficiency should be increased to the maximum. As a General rule, applicable to the production of other isotopes, the reaction should occur over a period of time, about 3 times the half-life of the final product, or about 80-90% of the time required to receive the maximum number of product.

It is also necessary to consider that during the conversion of high-energy electrons in high-energy photons in converting substance, a large amount of heat that can limit the speed of the reaction. It is therefore desirable to provide some mechanism for cooling the target, i.e. the conversion of a substance from the coating during the reaction.

In the cooling device can be used the principle of radiative, conductive, or convective heat dissipation, and it should allow to cool a target inside, around or through the target. For example, the target can be done with internal channels for passing refrigerant through the target; it may be integral with the refrigerant around her or porous with refrigerant flowing inside the target. Suitable refrigerants are liquid, such as water or liquid gallium, or gases, such as helium.

Liquid targets are frozen before irradiation or cooled by using a cooling coil immersed in the liquid target or close to it. In another embodiment, the liquid target is circulated through the cooling apparatus, the heat exchanger. In another example embodiment of the invention the liquid target onto the cooled converting substance is irradiated by electrons.

D. Separation of the final products of the reagents

Emitting a beta particle, radium-225 turns into anemone-225. When due to decay produces a sufficient number of sea anemone-225, it is separated by means of chemical separation from other substances.

In one embodiment of the invention irradiated radium-226 and radium-225 is dissolved from the target with a solution of alkali metal hydroxide such as sodium hydroxide solution (5 M)containing equal volumes of 30% H₂O₂and deionized water, with water should be sufficient to cover the target. After dissolving, the solution with the dissolved substances move in the vessel with aluminum powder, and, optionally, purge the air. Then from the target chemical is released and separated anemone-225. For example, after finishing the last volume to the required parameters anemone-225 is passed through a glass filter. Precipitated radium-225 remains in the filter.

In some embodiments of the invention all of radium and anemone associated with converting substance dissolved immediately. In this case, the solution found and radium, and anemones, which should be split. Liquid target is in the same form, i.e. in a combination of sea anemone and radium in solution.

The process of separating the sea anemone and radium involves the dissolution of (dried) sample containing the of Chini-225 and radium-225 in 0.03 M HNO ₃. The dissolved sample is passed through ion-exchange column designed to separate radiochemically, for example, a column with resin LN^®(Eichrom Industries, Inc., The Darien, Illinois, USA). While radium-225 and radium-226 are affluent, and the remaining column radium additionally washed with 0.03 M HNO₃. Associated anemone-225 eluted from the column using 0.35 M HNO₃. Naturally, the above-described column method is applicable to mass production, and to other types of production.

In another embodiment of the method of separation of sea anemone-225 from radium-226 and radium-225 is achieved by crystallization of radium nitrate, when soluble anemone is contained in the residual liquid (supernatant). For example, the sea anemone same structure 2s and 1d orbitals as lanthanum and yttrium. Compared with lanthanum at sea anemone slightly larger ionic radius, and the rest of their chemical composition is very similar. Based branch of the sea anemone-225 from radium lies anionic separation, when the concentration of HNO₃in radium loading is maintained at 5 M and radium is loaded into a column of ion exchange resin. Trivalent iron, chrome and all of divalent and monovalent ions pass through the column. Anemone-225 should be a short delay and is removed separately from impurities. Radium-225 and radium-226 wash from the column using 0.35 M HNO₃and left DL the re-use for the manufacture of targets.

Selected anemone-225 is purified oxalate precipitation followed cationite ion exchange. Briefly the process is as follows. Adding oxalic acid to Actinia-225 he precipitated as oxalate, which is then filtered off and destroy boiling concentrated HNO₃and HClO₄with evaporation HClO₄. Then anemone-225 dissolved in 2 M HCl and loaded into the cationite ion-exchange column. The column is washed with one volume of HCl. Any remaining ferrous ions suiryudan three volumes of 3 M HNO₃. Anemone eluted five volumes of 6 M HNO₃.

Department of radium-225 from sea anemone-225 is described in U.S. Patent No. 5809394 issued by Brau and other

2. Bismuth-213

A. theoretical part

As bismuth-213 is considered a "child" element sea anemone-225, it can also be obtained using the present invention. The chain of radioactive decays involving bismuth-213, is well known:

uranium-233 (half-life of 1.62×10⁵years) → thorium-229 (half-life 7300 years) → radium-225 (half-life of 14.8 days) → anemone-225 (half-life 10 days) → bismuth-213 (half-life 46 minutes). The Figure 4 shows the complete decay chain of uranium-233 in anemone-225f in bismuth-213.

B. Elution, separation and purification

Bismuth-213 can be obtained through the radio the passive decay of sea anemone, using anemone as "the cow." The resulting bismuth-213 is separated from other substances by using organic anion-exchange resin which adsorbs the bismuth-213. The possibility of extraction of bismuth as anion depending on the concentration of HCI are well known and described K.A. Kraus and F. Nelson article Adsorption of the elements from hydrochloric acid (Absorption of elements from hydrochloric acid), Proceedings of the International Conference on the Peaceful Uses of Atomic Energy, Nuclear Chemistry and the Effect of Irradiation (Proceedings of the International conference on peaceful uses of atomic energy, nuclear chemistry and radiation effect), Vol. VII, p. 837, Geneva, 8-20 August, 1955

The distribution of anionic complex of bismuth chloride in HCL increases with decreasing acid concentration. Other ions of interest related complexing agents, i.e. rare earth metals, radium and sea anemone, not extracted as chloride anions through anion-exchange resin. Therefore, the anion exchange resin can effectively separate the bismuth-213 from these and other ions, not extragenomic as anions of chloride anion.

Department of bismuth-213 from other substances are described, for example, in U.S. Patent No. 5749042 issued by Bray and others, in the article by Wu and others, "An improved Generator for the Production of Bi-213" ("Advanced generator to produce Bi-213), the Conference of the American Chemical Society (1996) and in article Ramirez and other Generator System Devlopment of Ra-223, Bi-212 and Bi-214 Therapeutic Alpha-Emitting Radionuclides" ("development of the generating system for a therapeutic alpha-emitting radionuclides Ra 223, 212 Bi and 214 Bi"), the Conference of the American Chemical Society (1996).

C. Application of radionuclides obtained in accordance with the present invention

Anemone produced in accordance with the invention, is obtained in sufficient quantities and with good radiochemical and radionuclide purity, which is especially important for a number of applications. For example, this substance is especially necessary in medicine, including radioimmunotherapy, radiation therapy, and to detect metastases, in particular for the detection of latent cancer during surgery intubation. The medical use of radionuclides produced by the present invention include their use in radiopharmaceutical preparations and/or radiochemically; the values of these terms are experts know. Non-medical applications include use as standards or labels (radioactive tracers).

1. Isolated use (in pure form)

In medicine radionuclides can be used alone (in isolation or in conjunction with another substance. Examples of individual use of radionuclides are getting images in medical applications, radiation (l the key) synovectomy and other

For example, anemone-225, bismuth-213, or their mixture are embedded in the hydrogel. Such alpha-emitting radioactive gel can be used for internal injection in the treatment of sarcomas, carcinomas and diseases of the prostate;

or when outside of its use for the treatment of Kaposi's sarcoma or other diseases. Anemone-225, bismuth-213, or their mixture can be combined with compounds that are not targeted to specific cells, such as styrene or stranovye polymers, acrylic polymers, biorstwami or bioerodible substances, hydrogels or other substances that can exist in the form of colloidal dispersions or particles, and to use radiation synovectomy.

When connecting samoudalyayushcheisya drugs with radioactive polymers or gels, the invention is also capable of optimizing the care of patients after the procedure and to improve the efficiency and safety of their treatment.

A. Manufacturing pharmaceuticals

The radionuclide preparation of pharmaceutical products depends on how the purpose and nature of the disease. However, General recommendations will be given below. These recommendations are valid for complex compounds of the radionuclide with the target molecules, described below.

Examples of pharmaceutical compositions are a radionuclide chelate complex of a radionuclide helathy complex of a radionuclide, attached to the target molecule, in some embodiments of the invention, the linker or any other connection, including radionuclide obtained by the present invention together with a pharmaceutically acceptable carrier, diluent, carrier or transporting agent. To pharmaceutically acceptable carriers, solvents, fillers, and transporting substances include, among others, neutral buffered saline or saline solution. In addition, the pharmaceutical composition may contain other components such as buffers, carbohydrates such as glucose, sucrose or dextrose, preservatives, and other stabilizers and / or fillers.

The methods of preparation of such drugs are well known. The product (composition) may be in the form of suspensions, injectable solution or other convenient form. Can be used physiologically acceptable suspension with or without adjuvants. The composition of the products obtained according to the present invention is a solid or liquid form, containing the active radionuclide and, if necessary, integrated/linker/target agent. Such drugs can be delivered in the form of a set of two components (for example, compound, radionuclide, the linker and the target agent), which is s are mixed at an appropriate time before use. Regardless, does the drug in pre-mixed or as a set, it may contain a pharmaceutically acceptable carrier.

Other examples of sets are sets in which anemone-225, bismuth-213, or their mixture is embedded in the steroid group, aryl group, substituted aryl group, vinyl group, isothiocyanato or isocyanato groups which are able to bind with the antibodies. Anemone-225, bismuth-213, or their mixture can also be incorporated in the aromatic amine, an aromatic isocyanate, an aromatic carboxylic acid, aromatic isocyanates, benzoic acid, substituted group of benzoic acid or vinylacetylene group. This set can be used by any person, including the researcher, pharmacist, physician, and even the end user - the patient.

For injectable compositions of the products of the invention can be supplied in the form of a suspension or solution. When delivered in the form of a solution of complex (or, if desired, the individual components) is dissolved in a physiologically acceptable carrier. Such media typically contain a suitable solvent, preservatives (if necessary), such as benzyl alcohol and buffers. Suitable solvents are, for example, water, aqueous solutions of alcohols, glycols, phosphonate or carbonate complex is the ethers. The content of organic solvents in such aqueous solutions is typically less than 50 percent by volume.

Injectable suspensions are the compositions according to the present invention, including a liquid suspension medium, with or without adjuvants, as a carrier. The suspension medium can be, for example, aqueous polyvinylpyrrolidone, inert oil, such as vegetable oil, or a well-refined mineral oil, or aqueous carboxymethylcellulose. If you want to keep the complex in the form of a suspension, you can choose suitable physiologically acceptable adjuvant among the thickeners, such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin, or alginates. Many surfactants can also be used as suspendida agents, for example lecithin, alkylphenol, polietilenoksidnoy adducts, naphthalenesulfonate, alkylbenzenesulfonate and esters of polyoxyethylenesorbitan. In some cases injectable suspensions may be used a variety of substances that affect the hydrophobicity, density and surface tension of the liquid suspension medium. For example, silicone Antiprotozoal, sorbitol and sugar are good suspendresume agents.

Radionuclides can be connected with transporting substance and for local use. Such substances include solutions, and can also be used gels, lotions, creams or ointments. If necessary, the radionuclides can be entered in oral dosage form, varieties are too numerous to enumerate. Essentially, assign no limit if the radionuclide can be effectively delivered to the desired area of the body.

Anemone-225, bismuth-213, or their mixture can be embedded in the hydrogel. Such alpha-emitting radioactive gel can be used for internal injection in the treatment of sarcomas, carcinomas and diseases of the prostate or to the outside of its use for the treatment of Kaposi's sarcoma or other diseases. Anemone-225, bismuth-213, or their mixture can be combined with compounds that are not targeted to specific cells, such as styrene or stranovye polymers, acrylic polymers, biorstwami or bioerodible substances, such as hydrogels, or other substances that can be converted into a colloidal dispersion or particle, and use them to radiation synovectomy. When combining samoudalyayushcheisya drug radioactive polymers or gels of the invention can also be applied for the optimization of patient care after the procedure and to improve the efficiency and safety of their treatment.

B. Introduction drug</>

For treatment use "effective amount" of the drug. The dosage depends on the disease. Although the analysis of the products obtained according to the present invention, is carried out in an artificial in vitro conditions, it is also planned to use them for diagnosis in a living organism (in vivo).

Although the required dose is determined by experimental testing, the individual can enter about 5×10¹⁰up to 5×10¹¹complex systems on a 70 kg adult human, believing that the ratio of the target agent and an alpha emitter is approximately 1:1. However, the number and frequency of injection will of course depend on many factors, such as the patient's condition, the nature and severity of the disease and the condition of the disease. In addition, first it is desirable to make the mask prior to the introduction of a targeting agent without radionuclide to minimize nonspecific binding of the radionuclide and damage to normal healthy tissues.

2. The use of radionuclide associated with the target agent

Usually it is desirable to connect the radionuclide with another substance to be delivered (target) in a specific area of the body of man or animal. For example, to target radionuclide in the cancer, it is associated with prophetic is the your, which specifically interacts only with this cancer education rather than with other parts of the body. Examples when used radionuclide combined with another substance, are the treatment and diagnosis of all types of cancer and many other diseases.

In the synthesis of labeled organic molecules anemone-225 first trail passed through the ion exchange column to remove salts and trace metals. For labeling organic compounds, such as proteins, monoclonal antibodies and natural substances, solutions of radionuclides must be chemically pure.

The target agent can serve only for delivery of the radionuclide in the desired location, or he can possess pharmacological activity. For example obtained by using the present invention anemone-225 and bismuth-213 can be used for the treatment of acute myeloid leukemia (AML). In this example embodiment of the invention anemone-225 and bismuth-213 is combined with anti-angiogenic agent for adjuvant therapy. Such agents are, among others, endostatin, angiostatin and complestatin.

Other specific targeting agents with pharmacological activity and without it, are described below.

A. Targeting agents

Radionuclides produced using the present invention can remove the identification of the destination, if they connect with the target agent. Targeting agents are substances having specific affinity, for example, molecules or subcellular structure, such as a receptor. Such targeting agents carry the radionuclide in a specific place. In an alternative embodiment, first enter the target agent, and then the radionuclide, the agent captures and holds the radionuclide. Usually the target agent holds the radionuclide up until the last will not disintegrate. Therefore, the interaction of the target agent with the target usually lasts longer half-life of the radionuclide.

There are a number of substances that can be used as targeting agents. Along with other target molecules are proteins and enzymes, including monoclonal antibodies, secretory proteins of the prostate, as well as statins, Taxol, tamoxifen, Thaksin and the estrogen receptor modifiers. These substances very much, and for brevity, only some of them will be described in more detail.

1) Antibodies

The radionuclides produced using the present invention, it is possible to attach both monoclonal and polyclonal antibodies. In contrast to polyclonal antibodies, which are heterogeneous mixtures of immunoglobulins, monoclonal antibodies represent them is noglobulin with distinct chemical structure. A characteristic feature of monoclonal antibodies is a functional reproducibility and specificity, and such antibodies can be created and already created for a wide range of antigens, including cancer cells. Chimeric monoclonal antibodies are recombinant methods (see Morrison S.L., Hospital Practice (Office Edition) (hospital practice (Office edition)), p.65-80, 1989).

Methods for obtaining monoclonal antibodies and their fragments are widely discussed and well known in the art. Such methods are described in detail in the "Monoclonal Antibodies" ("Monoclonal antibodies") (R.H.Kenneth, .J. & ..Bechtol eds., 1980); see also Koprowski and others (U.S. Patent No. 4196265). For practical use of the invention is the selection of monoclonal antibodies will depend on the ultimate purpose for which the radionuclide is combined with the antibody. This selection is known to experts.

Private examples are antibodies against cancer. Antibodies generated against known tumor marker can be used to combat this cancer. Prostate-specific antigen is one of the examples of the antigen, which may be affected by the antibodies created for him. In this way, the radionuclide is directed specific to cancer education and held there, not spread throughout the body. In the same way can affect other antigens, e is spasseruetsya specific cancer cells.

Obtained by the proposed method radionuclides can also be used against striking the body of fungi, bacteria and even viruses. Specialists are well known antibodies specific to these pathogens. Radionuclide associated with such an antibody can destroy this alien pathogen with which the antibody binds.

Specialists are well known methods for producing antibodies. These methods, for example, refers to the collection of antibodies in humans, cancer or having an alien pathogen. After extraction and purification of antibodies associated with the radionuclide and injected back into the patient. Alternatively, antibodies to create artificial conditions (in vitro) and after extraction and purification connect with radionuclide and administered to a patient in need of treatment.

Radionuclides produced using the present invention can also be used with "humanized" antibodies. Such antibodies are usually of animal origin, but they are modified by replacing part of their structure equivalent to the structure of human antibodies. This antigenic specificity is retained and the immunogenicity to the antibody is reduced.

2) Use of other ligands

Another use of radionuclides produced using the present invention, associated with the target volume of the volume, already present in the body, i.e. with the receptor. As we all know animals are so many different types of receptors, which are known natural and synthetic ligands. There are too many to be listed here, but here is an example of steroid receptors and poignee receptors. For receptors known as natural and synthetic ligands, and binding a radionuclide with these ligands, specific can send it to the receptors. This is especially important for cases when these receptors must be struck with the disease.

In one embodiment of the invention, bismuth-213, anemone-225, or a mixture attached to the secretory protein of the prostate PSP94 and its immunogenic peptides and sent for prostate cancer.

In another example, the number of different types of cancer cells have been identified receptors for regulatory peptides. Some examples of such peptides are somatostatin, vasoactive intestinal peptide, and cholecystokinin. Radionuclide associated with regulatory peptide that is directed primarily to cancer cells.

Radionuclides produced using the present invention can also be associated with the compounds known as growth factors. Like other targeting molecules described above, the growth factors are selected because of their ability to specifically with asiatica with the identified population of cancer cells. The proposed radionuclides can be used with many known growth factors, including platelet-derived growth factors, transforming beta growth factor, interleukins (such as IL-1,IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 or IL-9), granulocyte factor stimulate the formation of colonies by macrophages (granulocyte macrophage colony stimulating factor (GMCSF), erythropoietin, tumor necrosis factor, growth factor endothelial cells, the main protein of platelets, factor in the growth of endothelial cells capillaries, cartilage growth factor, chondrosarcoma growth factor, a growth factor in the retina, the growth factor hepatoma, bombezin and parathyroid hormone, and epidermal growth factor, alpha transforming-growth factor, fibroblast growth factor, insulin-like growth factor I and II and factor in the growth of nerve cells.

Growth factors are usually chosen due to their ability specific contact identified cancer cells, such as, for example, cells in a state of malignant degeneration, the cells in the metastatic status of rebirth and tumor cells (both benign and malignant). As known in the art, identified cancer cells differ from normal presence of a larger number of receptors growth factor on the surface of the CL the weave.

Alternatively, the radionuclide can be associated with a ligand to hormonal receptors to affect cancer cells expressing the hormone receptors. Ligands that are particularly suitable for communication, are hormones, such as estrogens or derivatives of estrogens, androgens and steroids. This can also be used cholesterol and diethylstilbestrol. Other ligands that can be attached, are drugs affecting these receptors. In particular, tamoxifen and Thaksin are examples of such ligands.

Taxol and thalidomide are specific ligands of interest, but not included in the above group.

B. Attaching a drug to a target agent

The accession of the radionuclide to the desired molecules is relatively easily achieved with well-known specialists of ways. Examples of such methods are discussed in U.S. Patent No. 5364613 (Sieving and others) and in U.S. Patent No. 5958374 (Meares, etc).

Because the radionuclide is usually located in the molecular state, i.e. it is not linked covalently to another molecule, it is necessary to attach it as any other way. Because the radionuclide is likely to be a charged metal, it is a good choice helatoobrazovateli, when the radionuclide is inserted into the larger molecule complexone is.

The complexone can be covalently linked to another functional part, for example the target agent. Thus, the growth factor can be covalently linked to the combined, which includes anemone-225 and bismuth-213. Then the radionuclide is transferred from the growth factor in a specific place in the body of the patient.

Targeting agent can be attached to combined in various ways, including the use of the linker. Typically, the linker is covalently attached to the combined one "end"and the other "end" linker covalently connects with the target agent. Thus the combined and the linker can be present in one molecule, one half of which is chelat forming, and the other is reactive.

From the above it follows that the compound containing a radionuclide may include: 1) combined, 2) the linker and/or 3) the target agent. In some embodiments of the present invention the combined will play the role of the target agent, and then not be necessary to separate the target agent and the linker. As an alternative, a combined can covalently bind directly with the target molecule, eliminating the need for a separate linker. The terms "combined", "linker" and "targeting agent" are conceptual and are intended to facilitate the understanding described to the complex connections and should not be considered limiting. Thus, also assumed the combinations in which the considered radionuclides embedded in the target agent, combinations containing several chelating agents, linkers or targeting agents, or combinations, in which there are no chelating agents, linkers or targeting agents. The only thing required is to have built a radionuclide produced using the present invention.

The radionuclide can be attached to the target molecule using two General ways. By the first method the complexone is attached to the targeting agent is usually using the linker. Then the resulting connection captures the radionuclide. In an alternative embodiment, the first linker is attached to the combined, and then there is the preliminary helatoobrazovateli attach radionuclide. Then the complex radionuclide/combined/linker is attached to the target molecule.

1) the Chelating

There are many different organic macrocyclic complexing agents for binding offer alpha sluchayah radionuclides, including the following groups: (1) speranda, (2) KryptoStorage, (3) cryptand, (4) polysterene, (5) carrandi (modified crown ethers) and (6) podany (acyclic matrix) (see Cram, Science 240, 760-67 (1988). These macrocyclic ring of the compound present is a large steropodon organic compounds, reminiscent of cellular structure and ability to hold heavy radionuclide like ligands retain metal ions.

The complexone must be chosen such that it have a high affinity and specificity for the alpha-radiating radionuclides, as well as low toxicity for mammals. High specificity prevents the substitution of other divalent cations (Mg⁺²and CA⁺²), dominant in physiological fluids. In addition, such a connection or contain a functional group, or to have the chemistry that allows you to enter the desired functional group to attach the linker.

Affinity (affinity) complexone to alpha-emitting radionuclide is determined by the energy of the system, see Cram (above). More specifically, according to x-ray crystallography of the complex and nekompaktnykh crown-ethers (macrocyclic ethers) it is believed that the conformations of solutions of non-complex esters are not clear cavity in the associated convergent spaced relationship. When complexation occurs desolate and restructuring of the crown ether, a process requiring energy. If ion meets combined with rigidly-structured and desolvation cavity (which is the case for sperando), the energy normally absorbed by the som desolvatation and transformation manifests itself in a higher binding constant for this ion.

Based on this fundamental principle of reorganization, Cram provides a list of affinity "owners" to their most complementary "guests":

speranda > CryptoStorage > cryptand > polysterene > Corradi > badandy. The difference in affinity connection of sperando and podango very large, for example, found that the coupling constant in lithium chelat forming speranda 10¹²higher than the corresponding podand with an open circuit (see Cram, above). Thus, although many chelating agents can be used in the context of this invention, it is preferable to use speranda designed and synthesized specifically for linking sea anemone-225 and bismuth-213.

Especially suitable chelating agents as 18-crown-6 or 21-crown-7 esters, including modified crown ethers as, for example, dicyclohexano-21-crown-7 ether (Case and McDowell, Radioact. Radiochem. (Radioactivity and radiochemistry) 1,58(1990); McDowell and other Solvent Extr. Ion Exch. (Ionoobmennaya extraction in solution) 7.377 (1989); on the other crown-esters or the macrocyclic polyethers, see Pedersen, Science 241, 536-540 (1988); U.S. Patent No. 4943375, Eia and others; Heterocicles (Heterocycles) 32(4), 711-722 (1991); Wai and Du, Anal. Chem. (Analytical Chemistry), 62(21 ), 2412-14 (1990); and Wai Tang, Analyst (London) 114(4), 451-453 (1989)). Briefly, AU²⁺link apirat-oxygen network is, consisting of the internal cavity of the spherical molecules crown ether. It is believed that this relationship is pH dependent: AU²⁺forms a complex with a combination of proton and smaller ions of group IA in the place of communication in the cavity of the crown ether. These crown ethers can be further modified polarizable functional groups (like modification of closo - and Nido-carbonyl used in therapy boron neutron capture), acquiring greater solubility in aqueous media (see Mizusawa and others, Inorg. Chem. (Inorganic Chemistry), 24, 1911 (1985). This modification increases the biological specificity after conjugation (merge) and increases the load capacity of the conjugate to a biological agent. These modifications can be done in tandem with the synthesis of the above crown-ethers with the necessary conditions for soft conjugation with biological system delivery.

Other crown ethers suitable for use in this invention can be synthesized or purchased, including the company Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Fluka Chemical Corp. (Ronkonkoma, new York, USA) and Nisso Research Chemicals (Ivai Co. Ltd., Tokyo, Japan). Gelacio alpha-emitting radionuclide can be done, mixing combined with the salt of an alpha-emitting radionuclide dissolved in the solvent. The choice of a particular solvent, of course, depends on tractorist complexone and alpha-emitting radionuclide. For example, Cram with employees prepared sodium complex speranda, just adding a saturated salt solution of acetonitrile to the solution speranda in methylene chloride (see Cram and Lein, J. Am. Chem. Soc. (Journal of the American Chemical Society), 107, 3657-3668 (1985).

The ability of the crown ether to bind or form a complex with alpha-emitting radionuclide is easily determined (see SOH and others, "Rates and Equilibria of Alkaline-Earth-Metal Complexes with Diaza Crown Ethers in Methanol (Speed and equilibrium formation of complexes of alkaline earth metals with diaza crown ethers in methanol"), Inorg. Chem., 27, 4018-4021 (1988); see also Mohite and Khopkar, "Separation of Barium from Alkaline Earths and Associated Elements by Extraction with Dibenzo-18-crown-6 from a Picrate Medium" ("solvent Extraction separation of barium from alkaline earth metals and related elements using dibenzo-18-crown-6 from pirate"), Analytica Chimica Acta (Analytical chemistry), 206, 363-367 (1988). Outlining briefly, to divide the radionuclide in the complex and the free radionuclide using an organic solvent (such as chloroform) and water. The radionuclide will remain in the organic phase, and the free radionuclide will remain exclusively in the aqueous phase. This can also be done using a variety of chromatographic methods such as high performance liquid chromatography (VPGH) or back-phase high-performance liquid is th chromatography (RP-WPGH).

After separation, you can verify the structure of the molecule. Outlining briefly, the cation may have a relationship of two kinds: (1) through an Association (i.e., forming a pair of anion-cation without the creation of the link) or (2) through the coordination of the cation with the oxygen network crown ether. The specificity and strength of relationship required in these applications depend on the last form of communication. Using the method of single crystal x-ray diffraction can uniquely identify the type of interaction for solids and¹⁷O,¹³- And¹NMR can be used to define the structure of the analyte in solution.

Other chelating agents that can form chelates with radionuclides, are Poliana and proximally. Some examples polyazamacrocycles structures are structures derived from such compounds as 1,4,7,0-tetraazacyclododecane-N,N',N",N"'-tetraoxane acid (hereinafter DOTA); 1,4,7,10-tetraazacyclotridecane-N,N',N",N"'-tetraoxane acid (hereinafter TRITA); 1,4,8,11-tetraazacyclotetradecane - N,N',N",N"'-tetraoxane acid (hereinafter THETA) and 1,5,9,13-tetraazacyclotetradecane - N,N',N",N"'-tetraoxane acid (the NET). Other chelating agents having a linear or branched clachnaharry parts include, among others, those obtained from such compounds as ethylendiaminetetraacetic the I acid (hereinafter EDTA) and diethylenetriaminepentaacetic acid (hereinafter DTPA).

In other embodiments of the invention complexone may have pharmacological use only due to the formation of the chelate with the radionuclide. For example, the chelate complex of a radionuclide can give more specific absorption in some parts of the body than if it were a single radionuclide complexone.

2) Linkers

However, usually chelated radionuclide (i.e. chelate complex of a radionuclide) attached to the targeting agent. Join chelate of the radionuclide to the target agents is usually limited to simple chemical reactions between reactive groups. The linker provides a covalent bridge between the combined and the target agent. In the ideal case, the linker does not affect the ability of the combined bind the radionuclide and on the ability of the target agent to correctly communicate with aim. This is achieved in various ways.

If chelate forming part is a macrocyclic, the linker can be attached to any ring atom. For example, if the chelate forming part of polyazamacrocycles, the linker can be attached to a ring carbon atom or ring nitrogen atom. When the linker is attached to the ring nitrogen atom, such compounds are called N-substituted polyazamacrocycles. In chelat forming parts with carboxyl groups, such as DOTA,TRITA, NET, NEH, EDTA and DTPA, you can replace one or more carboxyl groups on the amide group and thereby to provide a place to attach complexone.

At the other end of the linker, i.e. the end for attaching a targeting agent has a functional group that facilitates this connection. Examples of functional groups capable of covalently to contact the target molecules are groups that can be activated by known methods to give them this ability. For example, to form active esters (-C(=O)OR, where R is, for example, Succinimidyl) of the carboxylic acid to form an acidic halide (-C(=O)X, where X is usually Cl or Br) of the carboxylic acid.

Functional group (functional group) of the linker capable (able) covalently contact with the target agent, you can pick in accordance with the target agent, which will eventually be attached complexone. Reactive pairs of functional groups allow you to combine a chelate forming part of the target molecule through a linker, when one group of pairs is combined, and the other on the target molecule. For example, when the target molecule is a protein with a free amino group (-NH₂), the functional group on the linker such as isothiocyanate (-NCS), poses the s to form a connection (in this case timeonline connection) which leads to the formation of complex combined-linker-targeting molecule. Other examples of appropriate reactive functional groups are, for example, -NH₂with-C(=O)OR (active ester) or-C(=O)OC(=O)R (anhydride), or-C(=O)X (acid halide), which give the amide linkage; or-NH₂with-NCO (isocyanate), giving a urea bond. Other reactive pair-NH₂include-NH₂and

-S(=O)₂X (sulfonyl a halide), -NH₂and-C(=NR)OR (imidate ether) and-NH₂and-OC(=O)X (haloforms). Examples of reactive pairs of functional groups are-SH, and-C(=O)CH₂X (haloacetic), giving-SCH₂C(=O)-communication; -SH, and-alkyl-S (alkyl halide), or-SH, and-S(=O)O-alkyl (alkyl sulfonate), giving thioether; and-SH, and-SH (sulphydryl), giving-SS- (disulfide) bond.

The task of the linker is to attach the complexone to the target agent. If complexone already have a reactive group to which you can attach a targeting agent, you need to separate the "linker" no. For example, if complexone is isothiocyanate (-NCS), and the target agent has an amino group (-NH₂), the combined may be attached directly to the target agent. You can use any combination and not to resort to the use of a separate linker. However, such proximity complexone to aim is that the agent should not jeopardize the ability of each of the parts to perform their function. For example, complexone must retain the ability to bind the radionuclide, and the target agent must interact with its biological purpose. If this cannot be achieved, it is possible to use a longer linker molecule.

Thus, in one embodiment of the present invention, in which the targeting agent is a polymer of amino acids (e.g., peptide, polypeptide, protein, etc.), alpha-emitting radionuclide is located in complexone, which in turn binds the linker with the amino (N) and carboxy (C) - group targeting agent. The linker may play a role inert "strip" between biologically active targeting agent and a complex containing alpha-emitting radionuclide. This pad minimizes spatial interaction that violates affinity targeting agent to its target. The optimal length of the strip depends primarily on affinity targeting agent to its target. The higher this affinity, the less is the value of spatial repulsion between the combined and receptor targets. An almost infinite number of linkers can be selected for use in this invention, including disulfides, dicarboxylic acid, paliperidone chain and modified paliperidone chain. Linkers may contain hydrocarbon the chain length of from 4 to 18 carbon atoms, and six or more methylene units, such as hexamethylenediamine were.

The linker can be attached to any of a number of vnekornevyh functional groups on the combined, including carboxy - and amino groups. In one aspect of the present invention, if unconcious functional group is a carboxyl group, the first step of the synthesis is the reaction complexone with hexamethylenediamine were. Subsequent reaction with the ends of the target agent will complete the synthesis of the compounds.

Alternatively, as mentioned above, the linker can be linked with other components of the growth factor, for example N-end. Under this variant of the invention, after the reaction with hexamethylenediamine were can be carried out reaction combined with succinic anhydride. Subsequent connection of the linker with the target agent via the N-end of the target agent.

In another aspect of the present invention, the complex may contain an amino group. In such cases, to attach complexone to the N-end of the target agent can be used decarbonisation linker (for example, duartina acid). On the other hand, if the combined reacts with Ethylenediamine after condensation with dicarboxylic acid, bind to the target agent should be through With the end.

Private is examples of suitable compounds are CNH DTPA-A and CNH DTPA-B. Methods of obtaining these compounds are given in U.S. Patent No. 5286850; 5124471 and 5434287. Here DTPA economy-and DTPA-CHX-B are synonyms of CNH DTPA-A and CNH DTPA-B.

Additional methods of attaching a radionuclide to the target molecules are given in WO 93/09816. Other methods are described in U.S. Patent No. 4923985; 5286850; 5124471; 5428154 and 5434287 issued by Gansow and other

C. Obtaining pharmaceutical compositions

The above-described receiving radionuclide pharmaceutical preparations in the form of "pure" compounds are also suitable for compounds in which the radionuclide is used with the target agent, and will not be described again.

g Introduction preparation

For treatment use "effective amount" of the drug. The dosage depends on the disease. Although the analysis of the products obtained according to the present invention, is carried out in an artificial in vitro conditions, it is also planned to use them for diagnosis in a living organism (in vivo).

Although the required dose is determined by experimental testing, the individual can enter about 5×10¹⁰up to 5×10¹¹complex systems on a 70 kg adult human, believing that the ratio of the target agent and an alpha emitter is approximately 1:1. Nevertheless, the number and frequency of injection is, of course, depend on many factors, such as the standing of the patient, the nature and severity of the disease and the condition of the disease. In addition, first it is desirable to make the mask prior to the introduction of a targeting agent without radionuclide to minimize nonspecific binding and damage to normal healthy tissues.

3. Use with Menzelinsk agent

In addition to the binding of a radionuclide with an agent, which is used for targeting (targeting) on a specific part of the body, it can also be associated with other cellular toxin to increase the efficiency of cell killing. For example, the radionuclide can be associated with antitumor agent, increasing its effectiveness.

Anti-cancer drugs act by a common mechanism, exerting a toxic effect on the cells. However, faster growing cancer cells absorb more of these tools. Antitumor effect can be enhanced even more by attaching an antitumor agent to a radionuclide. Some examples of such anticancer agents are vincristin, vinblastine, methotrexate, cisplatin, fluorouracil, oxyuridine and adriamycin.

4. Other shipping methods

In addition to the above methods of delivery, the products obtained by using the present invention, may be delivered to different devices and/or implants. For example, these drugs can topath with the desired speed of the pump, running on batteries, and delivered to a desired location. Alternatively, by using polymeric materials these drugs can be given properties prolonged, slow steps.

Such preparations can be made in the form of pellets or implants, which are inserted in the desired location. Alternatively, such polymer compositions obtained by the proposed method with radionuclides can be applied to devices such as stents or catheters for delivery to a desired location. The advantage of this application is particularly evident in the treatment of diseases or pathological changes associated with uncontrolled vascular proliferation, such as restenosis.

Methods of forming such polymeric compounds, implants and devices drug delivery are well known in the art and will not be presented here.

C. Examples

The following examples are given to illustrate one variant of the present invention and should not be construed as limiting in any way the scope of the claimed invention.

Example 1. Converting substance

Milled plate of tungsten size 3 mm (width) × 3 mm (height) × 1 mm (thickness). The plate is well polished, washed in distilled water and well dried.

Primer. The application of the radionuclide in the conversion substance

The electrolytic solution for the deposition of Nickel is prepared by mixing of Nickel chloride (40-60 g/l), Nickel sulfate (240-300 g/l) and boric acid (25-40 g/l). The pH of the solution is brought about from 3.5 to 5.0.

Then tungsten plate manufactured as described above, is placed in the solution for the deposition of Nickel in the apparatus for the electrolytic deposition of the platinum electrode, and is the electrolytic deposition of Nickel on tungsten plate. Deposition conditions: temperature 30-60°; the current density 2-7 A/DM²; stirring is carried out air.

Then the resulting plated substrate is placed in an electrolytic solution of dioxide of radium-226 and spend the electrolytic deposition of radium-226. Outlining briefly, a sufficient quantity of radium-226 dissolved in 8-molar HNO₃to obtain a 0.1 M solution of radium-226. Used electrolytic cell design Krishnaswami and Sarin (see Krishnaswami S. and M.M. Sarin (1976), Anal. Chim. Acta (Analytical Chemistry), 83, 145-156). In the apparatus for the electrolytic deposition is placed in a Teflon spatula for mixing. The limiting values of the parameters of the power supply are 6 and 0.8 A.

The apparatus is mounted on the plate stirrers in a fume cupboard. Included agitation, while the current source feed is limited to 0.8 A. After obtaining the necessary coating deposition process stops, when you disconnect the power source and adding concentrated ammonia. Then the target is washed in distilled water and dried. The concentration of radium-226 in the coating on the tungsten plate must be 120 mg/cm².

Example 3. The irradiation of the target

Received the above method, the target is ready for the irradiation of high-energy electron beam.

The target is set on the path of the electron beam of an electron accelerator operating at 10 kW, and is irradiated by high energy electrons. The electron beam current is approximately 500 microamps. The energy of the electron beam incident on the target should be around 25 MeV. The target is bombarded by about 20 days from a distance of 50 cm from the source beam.

The results of the calculation of theoretical yield of the product is shown in Figure 1, where the resulting activity of radium-225 and sea anemone-225 are given depending on the time of irradiation of the target of 1.0 gram of radium-226 by an electron beam of 25 MeV. The values shown in Figure 1 were obtained using the results given in the Table on Figure 2 and Figure 3. In the Table and Figure 2 shows the gamma-ray flux/spectrum produced by electrons with energy (E) 20 MeV and 25 MeV. The Figure 3 shows the curve of the profile of radium-226 (g is MMA, n) from power.

Higher specific activity can be obtained if to bring the target to the Converter, and the use of targets in the shape of a thick wedge gives higher overall activity.

Typically, the profiles of decay electrons is about 100 times less than the profiles of photodecomposition. Because at energies of 20 MeV or more, the conversion efficiency of electrons into photoelectrons is >50%, it is desirable to work with bremsstrahlung. If the optimal target dose rate of bremsstrahlung radiation in the forward direction depends on the electron energy. It should be noted that performance in lektronnom accelerator for energies above 25 MeV increases not much, since the peak "giant resonance" for your target is near 15 MeV (see Figure 3).

Example 4. Isolation and purification of sea anemone-225

Substances on the target, including radium-226, radium-225 and anemone-225, dissolved tungsten plate with a solution containing equal parts of 5M NaOH and 30% H₂O₂. After dissolution of these substances from the target solution is neutralized by adding sufficient HCl to bring the pH to about 7.

Then the whole solution is dried and the residue again dissolved in a solution of 0.03 M HNO₃. The solution is passed through a column of LN^®resin (Eichrom Industries, Inc., The Darien, Illinois, USA), radium-225 and radium-226 passes through the column with effluent, and the remaining radium wash from the column with a solution of 0.03 M HNO₃. Associated anemone-225 eluted from the column using 0.35 M HNO₃.

Example 5. Obtaining a composition with actinium-225 for purpose (creating a complex with the target molecule)

To create complex to remove any unwanted salts and cleaning anemone-225 in 0.35 M HNO₃pass through a cation exchange column.

A. Getting VOS-p-nitro phenylalanine transcellularly monoamide

Dissolve BOC acid, N hydroxysuccinimide and EDC (48 mmol) in ethyl acetate (400 ml). The mixture is stirred for 12 hours. The reaction solution is filtered and fil the rat washed successively with a saturated solution of salt, 1 M HCl, 5% NaHCO₃and again with saturated salt solution (each 200 ml). The organic layer is separated and dried over MgSO₄. After filtration the solution is rotary evaporated to a solid residue. Then the solid residue was dissolved in DMF (200 ml) and the solution added dropwise to the TRANS-1,2-diaminocyclohexane for 18 hours. Besieged diamid filtered and the solution is rotary evaporated to a thick oil. The residue is dissolved in chloroform and washed, as described above, to remove any of the original substance. Then the chloroform solution is dried as indicated above, filtered and concentrated to a gel-like consistency. This gel is poured into the funnel off and triturated with petroleum ether to obtain the product as a solid substance with a light yellow-brown color.

B. Obtaining p-nitrobenzyl-"economy"-Diethylenetriamine

The BOC group is cleaved under stirring over night amide (4.6 g) in dioxane (300 ml), saturated with HCl. Add diethyl ether (200 ml) and then cooled to 4°leads to significant loss of sediment. The dihydrochloride is collected in a Buechner funnel with argon and vacuum dried.

Amide and the hydrochloride is suspended in THF (50 ml) in a three-neck round bottom flask, placed in an ice bath. A flask equipped with a condenser, a thermometer and a membrane. Into the flask is put on the borane/THF (6 equivalents) and the temperature was raised to 50° With and support her to full recovery. The reaction course is monitored by WPGH using a ten-minute gradient to 100% 0.1 M SPLA in water to 100% 0.1 M SPLA in methanol. Apply column Waters DeltaPack C18.

After completion of the reaction the solution is cooled to room temperature and to decompose the excess hydride is added to the methanol. The solution is evaporated on a rotary evaporator and the residue is dissolved in 100% ethanol (100 ml). This solution is dried (evaporated) by using high-vacuum rotary evaporator. The solid residue is added dioxane (150 ml), previously saturated with HCl, and the suspension obtained is heated with vertical refrigerator for four hours. Finally the suspension obtained is left at a temperature of 4°C for 18 hours. Then the product is collected in a Buchner funnel with argon and subjected to vacuum drying.

C. Obtaining p-nitrobenzyl economy DTPA

Triamine (1.0 g, 2.49 mmol) was dissolved in DMF (25 ml) with sodium carbonate (1,992 g) and added dropwise tert-butyl bromoacetate (2,915 g, 14,95 mmol). The resulting solution is heated overnight to 80°in an argon atmosphere, after which the reaction mixture was poured into H₂O (100 ml) and extracted with CH₂Cl₂(100 ml). The organic layer was washed with water (3×100 ml), separated, dried over MgSO₄, filtered and evaporated in the rotor of the second evaporator to the consistency of oil. Then this oil is more concentrated in high vacuum rotary evaporator before the formation of a thick oil.

The oil is added TFA (25 ml) and left overnight. Then in a rotary evaporator to remove excess reagent. For the separation and collection of the two main peaks are conducting a preliminary WPGH. After completion of the preliminary WPGH using ion-exchange chromatography (AG50 W × 8 200/400 mesh H+ form) to remove WPGH buffer. Obtained two fractions labeled as CNH / CNH-Century

, Obtaining p-aminobenzyl economy DTPA-A.-In

Atmospheric hydrogenation of each fraction are carried out using 100 mg of each nitrocompounds with 10% Pd/C (100 mg) at pH of 8.5. The reaction is carried out as long as you do not stop the absorption of H₂. The reaction mixture is filtered on a fine Frit with Telicom 577. The filtrate lyophilizer, leaving no white residue.

D. Obtaining p-isothiocyanatobenzene economy DTPA-A

Each fraction is dissolved in H₂O (5 ml) and treated with thiophosgene (20 μl) in CHCl₃(10 ml) for two hours in an argon atmosphere at a maximum stirring. The organic layer is removed at room temperature in a rotary evaporator, and the aqueous layer was lyophilizer, remains off-white solid residue.

W. The final complexation

CNH DTPA-A (you can also use-is) dissolved in phosphate buffer saline solution. Anemone-225 in equal molar ratios dissolved in buffer solution. Then in equal molar ratio are added monoclonal antibodies to prostate serum antigen. The mixture is stirred for 4 hours at a temperature of 4°and then subjected to anion-exchange separation to remove unbound sea anemone-225.

Example 6. The appointment of a sea anemone-225 associated with the target molecule

About 5×10¹⁰radionuclide complexes dissolved in one milliliter of sterile saline. Then this solution is mixed with one liter of sterile lactate solution Ringers and received the drug is injected within half an hour.

Example 7. Obtaining bismuth-213

A. Extraction

Anemone-225 obtained in Examples 4 and 5, is placed in a container with a capacity of 20 ml, and dried. This anemone is called "the cow."

3 M anion exchange disk pre-treated with 0.5 M HCl in the following way. The syringe is typed in 0.5 M HCl, to the syringe, attach the drive and press the plunger of the syringe, pass the acid through the membrane (ROM). Acid after pre-processing is poured. In the eyedropper trying to enter 10 ml of 0.5 M HCl and poured them into the jar with "cow", and waiting for the anemone-225 will dissolve. Pre-treated 3 M filter connected to its output side end of a suitable p is almossawi micropipette is fixed on the output hole of the syringe. Through the plastic tip of a pipette dissolved "cow", containing anemone-225 and its child elements (including bismuth-213), is taken into the cylinder of the syringe through 3 M anion exchange filter.

The plastic tip and 3 M anion exchange disk with bismuth-213 in it are removed. A solution of sea anemone-225 in 0.5 M HCl discharged from the syringe back into the original container for reuse.

B. Flushing

Bismuth-213, absorbed on 3 M anion exchange disk contains small traces of sea anemone-225 and HCl (which adhere to the inner surfaces of the resin). To anion exchange disk containing the bismuth-213, join the new syringe and washed the drive, picking through it into the syringe 0.005 M wash solution. Then the disk is detached and acid washing, containing traces of the "mad cow" solution, is poured into the vessel for disposal. Used HCl is removed.

C. Elution of bismuth-213

A solution of 0.05 M NaOAc (pH 5.5) is typed into a new syringe. Washed 3 M disk with bismuth-213 is attached to the syringe and a solution of 0.05 M NaOAc (pH 5.5) passes through the disk with bismuth in cumulative flask.

Example 8. Getting preparation of bismuth-213 for the purpose (the connection with the target molecule)

CNH DTPA-A (prepared as described above in Example 5) dissolved in acetate buffer, pH of 6.0. Bismuth-213 in an equal molar ratio was dissolved in the buffer RA the creators. Then in equal molar ratio are added monoclonal antibodies to prostate serum antigen. The mixture is stirred at a temperature of 4°C for 4 hours and spend cation exchange to remove unbound bismuth-213.

Example 9. The purpose of the bismuth-213 associated with the target molecule

About 5×10¹⁰radionuclide complexes dissolved in one milliliter of sterile saline. Then this solution is mixed with one liter of sterile lactate solution Ringers and received the drug is injected within half an hour.

In summary, the present invention provides a reliable method of obtaining sea anemone-225/ bismuth-213 in quantities exceeding 1000 millicurie, and radionuclide purity of less than 5 µci of radium-225/100 µci sea anemone-225 by irradiation of radium-226. Get anemone-225/bismuth-213 has the physical properties required for diagnostic and therapeutic radiopharmaceuticals, especially when used in radiation therapy.

All contents of all documents cited in this specification is a part of the present description, all the above documents are incorporated into this description by reference.

The above detailed description is given only explanatory (illustrative) purpose. M the OIG changes and improvements can be made in the above-described preferred variants of the invention. Therefore, it should be understood that the following claims, including all equivalents, define the scope of the present invention.

1. The method of producing isotope, including the direction of the electrons on the conversion substance with a coating of a substance with a mass number of atoms is n, the formation of photons resulting from the interaction of electrons with the conversion agent and the formation of an isotope with mass number of atoms equal to n-1 in the interaction of photons with matter coverage.

2. The method according to claim 1, characterized in that n is equal to 226, and coating with a mass number of atoms is n, is radium-226.

3. The method according to claim 2, characterized in that n-1 is equal to 225, and the isotope with the mass number of atoms equal to n-1, is radium-225.

4. The method according to claim 3, characterized in that the conversion substance includes at least one of the following: copper, tungsten, platinum and tantalum.

5. The method according to claim 4, characterized in that the coating is applied to convert the substance by electrolytic deposition.

6. The method according to claim 5, characterized in that the conversion substance before applying to it the galvanic coating of radium-226 covered with the electrodeposited Nickel.

7. The method according to claim 5, characterized in that the electrolytic deposition on converting substance is simultaneously applied Nickel and radium-226.

8. The way pop, characterized in that radium-226 is applied to convert the substance in a concentration of from about 80 to 160 mg/cm².

9. The method according to claim 4, characterized in that the direction of the electrons on the conversion substance, covered with a coating, use an electronic accelerator, and electrons are in the form of a bundle.

10. The method according to claim 9, characterized in that the thickness of the conversion substance is from about 0.5 to about 1.7 mm, and the electron beam current is from about 100 to about 1000 microamps.

11. The method according to claim 10, characterized in that the electron energy is from about 20 to about 25 MeV.

12. The method according to claim 10, characterized in that the energy of the photons is from about 10 to about 25 MeV.

13. The method according to claim 4, characterized in that it further includes the Department of sea anemone-225 from radium-226 using chemical separation.

14. The method of producing isotope, including the direction of the electrons on a tungsten plate coated with electrolytic precipitated radium-226, whereby when the interaction of electrons with tungsten and the photons are generated and whereby when the interaction of the resulting photons with radium-226 is formed radium-225.

15. The target for the electron beam of an electron accelerator comprising a metal plate coated with electrolytic precipitated radium-226.

In indicated in paragraph 15 characterized in that the substance of the metal plate has an atomic number equal to 30 or more.

17. Target on item 16, characterized in that the metal plate is selected from tungsten, tantalum, platinum, and copper.

18. Target by 17, wherein the metal is tungsten.

19. Metal plate covered with a mixture of radium-226, radium-225 and sea anemone-225.

20. Metal plate according to claim 19, wherein the metal is selected from tungsten, tantalum, platinum, and copper.

21. The method of obtaining sea anemone-225, including the direction of the electrons on the conversion substance, whereby when the interaction of electrons with the conversion substance are formed photons directed to the liquid target of radium-226, and interaction of which with the liquid target is formed radium-225, and radium-225 dissolves in anemone-225.

22. The method according to item 21, wherein the liquid target spatially separated from the conversion of a substance.

23. The method according to item 22, wherein the liquid target is limited.

24. The method according to item 21, wherein the liquid target is in contact with the conversion substance.