RU2841999C1 - Method of producing radioisotopes terbium-155, terbium-152, terbium-149 and strontium-82 - Google Patents

Abstract

FIELD: medical science; nuclear physics.

SUBSTANCE: invention relates to technology of producing radioisotopes for nuclear medicine on charged particle accelerators. Method of producing radioisotopes ¹⁵⁵Tb, ¹⁵²Tb, ¹⁴⁹Tb and ⁸²Sr comprises irradiating a cascade target with gadolinium isotopes and 85Rb isotope by protons on a charged particle accelerator, wherein protons with energy of up to 80 MeV are used to irradiate the target. Target is made from four modules lying in series on the direction of the proton beam. At that, first in beam direction module contains ¹⁵⁵Gd isotope, second module contains ⁸⁵Rb isotope, third module contains ¹⁵⁴Gd isotope, fourth module contains ¹⁵⁶Gd isotope. When target is irradiated with protons during threshold nuclear reactions ¹⁵⁵Gd(p,7n)¹⁴⁹Tb, ⁸⁵Rb(p,4n)⁸²Sr, ¹⁵⁴Gd(p,3n)¹⁵²Tb and ¹⁵⁶Gd(p,2n)¹⁵⁵Tb, in it are simultaneously accumulated target radioisotopes ¹⁵⁵Tb, ¹⁵²Tb, ¹⁴⁹Tb and ⁸²Sr, which are then extracted from target by radiochemical methods.

EFFECT: possibility of simultaneous production of target radioisotopes ¹⁵⁵Tb, ¹⁵²Tb, ¹⁴⁹Tb and ⁸²Sr on a beam of protons with high output, with low content of radionuclide impurities, when using in the target gadolinium isotopes ¹⁵⁵Gd (14.8%), ¹⁵⁶Gd (20.47%), ¹⁵⁴Gd (2.18%) and ⁸⁵Rb (72.2%), characterized by high content in natural mixture.

3 cl, 3 dwg, 5 tbl, 5 ex

Description

The invention relates to the technology of producing radioisotopes for nuclear medicine using charged particle accelerators.

High-tech medical care using diagnostic and therapeutic radioisotopes allows early detection and timely treatment of socially significant oncological and cardiovascular diseases. Various radioisotopes are tested to achieve these goals. In particular, the use of a series of terbium radioisotopes ¹⁴⁹ Tb, ¹⁵² Tb, ¹⁵⁵ Tb, ¹⁶¹ Tb, which combine the possibility of using several diagnostic methods, is currently being actively studied for the diagnosis and treatment of oncological diseases: positron emission tomography ( ¹⁵² Tb), single-photon emission computed tomography ( ¹⁵⁵ Tb) with α-emitter therapy ¹⁴⁹ Tb or β-emitter therapy ¹⁶¹ Tb.

The possibility of simultaneous examination by positron emission tomography (hereinafter PET) and single-photon emission computed tomography (hereinafter SPECT) methods increases the reliability of the result. Being a trivalent metal, terbium easily forms strong bonds with DOTA and DTPA chelators and, thus, makes it possible to incorporate it into conjugates specific to cancer cells. These properties allow the use of terbium radioisotopes in theranostics: in radionuclide therapy with simultaneous visualization by different methods of terbium isotope distribution and, accordingly, cancer cells in the patient's body.

For diagnostics of myocardial perfusion, the most informative method is recognized to be the PET method using the radioisotope Rb-82, which is obtained using the Sr-82/Rb-82 isotope generator. This method has long been widely used abroad. In our country, due to the lack of available opportunities for the production of ⁸² Sr, this method has not yet found wide application.

The radioisotope ¹⁶¹ Tb is usually obtained in a reactor by the reaction ¹⁶⁰ Gd(n,γ) ¹⁶¹ Gd → ¹⁶¹ Tb. The radioisotopes ¹⁴⁹ Tb, ¹⁵² Tb, ¹⁵⁵ Tb are obtained in accelerators by irradiating europium or gadolinium targets with ¹ H, ² H, ³ He, ⁴ He nuclei, or by spallation reactions by irradiating a tantalum target with protons with an energy of ~1.4 GeV, or as a result of other inelastic scattering reactions by irradiating a wide range of targets with heavy ions.

The radioisotope ^82Sr (the precursor of ^82Rb in ^{the 82Sr} / ^82Rb isotope generator) is produced by irradiating metallic rubidium or RbCl with protons of up to 70 MeV. In addition, ^82Sr can be produced by irradiating gaseous krypton targets with ^3He or ^4He nuclei of up to 60 MeV.

Currently, the production of medical radioisotopes at cyclotrons operated in the Russian Federation is limited by the upper proton energy level of 30 MeV.

With the commissioning of the C-80 cyclotron at the National Research Center "Kurchatov Institute" - PNPI named after B.P. Konstantinov (St. Petersburg) with a maximum proton energy of 80 MeV, new unique opportunities for the production of medical radioisotopes are opening up, allowing for more efficient methods of obtaining them.

The present invention is focused on proton accelerators with an energy of up to 80 MeV and allows obtaining in a single irradiation on a proton beam simultaneously the target radioisotopes ¹⁴⁹ Tb, ¹⁵² Tb, ¹⁵⁵ Tb and ⁸² Sr with an acceptable level of radionuclide purity in volumes sufficient both for conducting preclinical and clinical studies and for subsequent business turnover. Obtaining radioisotopes ¹⁴⁹ Tb, ¹⁵² Tb, ¹⁵⁵ Tb and ⁸² Sr is carried out by irradiating a cascade target with isotopes ¹⁵⁵ Gd, ⁸⁵ Rb, ¹⁵⁴ Gd, ¹⁵⁶ Gd with protons. To extract terbium radioisotopes from the target, a well-known method of extraction chromatography can be used, and to extract ⁸² Sr - sorption from liquid rubidium on metal surfaces.

A method is known for producing terbium radioisotopes, including ¹⁵² Tb, by irradiating a target with the ¹⁵¹ Eu isotope with ⁴ He nuclei (AN Moiseeva, RA Aliev, VN Unezhev, NS Gustova, AS Madumarov, NV Aksenov, VA Zagryadskiy, “Alpha particle induced reactions on ¹⁵¹ Eu: Possibility of production of ¹⁵² Tb radioisotope for PET imaging” // Nuclear Instruments and Methods in Physics Research B 497 (2021), pp. 59–64). In this method, the cross sections of the corresponding reactions were measured using the “foil stack” method in the energy range of ⁴ He nuclei up to 60 MeV. Based on the measured reaction cross-sections and calculated yields, it is shown that the production of positron emitter ¹⁵² Tb on a beam of ⁴ He nuclei as a result of accompanying reactions leads to the formation of undesirable radionuclide impurities ¹⁵³ Tb and ¹⁵¹ Tb. Moreover, their total activity at the end of irradiation reaches 18% of the activity of ¹⁵² Tb. The saturation yield of 222 MBq/μA given in the article corresponds to a yield of 8.55 MBq/μA×h (in the traditional form of presentation).

The disadvantages of this method include:

- the complexity of implementing the method due to the shortage of accelerators for ⁴ He nuclei up to 60 MeV energy;

- a sufficiently high level of impurity radioisotopes of terbium, from which it is impossible to purify the target product using radiochemical methods;

- low activity yield of the target radionuclide ¹⁵² Tb.

In the work (Müller, C.; Zhernosekov, K.; Köster, U.; Johnston, K.; Dorrer, H.; Hohn, A.; van der Walt, NT; Türler, A.; Schibli, R. A unique matched quadruplet of terbium radioisotopes for PET and SPECT and for α- and β-radionuclide therapy: An in vivo proof-of-concept study with a new receptor-targeted folate derivative. J. Nucl. Med. 2012, 53, p. 1951–1959) the possibilities of obtaining terbium radioisotopes, including ¹⁵⁵ Tb, by the Ta(spallation) reaction were investigated. A metallic tantalum target (50 g/ ^cm2 ) was irradiated with high-energy protons of ~1.4 GeV. After evaporation of the reaction products from the target heated to 2000ºC, they were ionized by a laser, extracted from the ion source, accelerated to 50 keV, separated in the magnetic field of an electromagnetic separator by mass, and then sent for radiochemical purification. This method has significant disadvantages, which are as follows:

- to obtain ¹⁵⁵ Tb, a unique, expensive high-energy proton accelerator is used: ISOLDE (CERN, Geneva, Switzerland), mainly intended for fundamental research;

- as a result of the spallation reaction, a wide range of fragments is formed and, as a consequence, it becomes necessary to use a rather expensive and energy-intensive technological operation of electromagnetic separation of isotopes in an electromagnetic separator to isolate isotopes with atomic number 155.

A method for producing the radioisotope ¹⁵⁵ Tb by the reaction ^nat Gd(α,xn) ¹⁵⁵ Dy → ¹⁵⁵ Tb is known (AN Moiseeva, RA Aliev, EB Furkina, VI Novikov, VN Unezhev, “New method for production of ¹⁵⁵ Tb via ¹⁵⁵ Dy by irradiation of natGd by medium energy alpha particles” // Nuclear Medicine and Biology 106–107 (2022) 52–61). A gadolinium target of natural isotopic composition was irradiated with ⁴ He nuclei with an energy of 60 MeV at the U-150 cyclotron of the National Research Center “Kurchatov Institute”. The radioisotope ¹⁵⁵ Tb was produced by the reaction ^nat Gd(α,xn) ¹⁵⁵ Dy

(T_1/2= 9.9 hours) →¹⁵⁵Tb. Separation of Gd, Tb and Dy was carried out by extraction-chromatographic method using LN Resin sorbent. The isolated fraction with dysprosium was kept for 24 hours, and then the accumulated radioisotope was isolated from it¹⁵⁵Tb in the same way. The release of the radioisotope¹⁵⁵Dy in the "thick" target were calculated using the measured formation cross-sections¹⁵⁵Dy. Exit¹⁵⁵Dy was 35 MBq/µA×h. The stated yield¹⁵⁵Dy allows you to get the output¹⁵⁵Tb in volume ~ 1.7 MBq/µA×h.

The disadvantages of this method include:

- the uniqueness of the cyclotron used and limited access to beams of ⁴ He nuclei accelerated to 60 MeV;

- the need to use complex two-stage radiochemical processing to obtain the target radionuclide ¹⁵⁵ Tb;

- low activity yield of the target radionuclide ¹⁵⁵ Tb.

In the work (AN Moiseeva, KA Makoveeva, EB Furkina, MN German, IA Khomenko, AL Konevega, ES Kormazeva, VI Novikov, NV Aksenov, NS Gustova, RA Aliev, // Co-production of 155Tb and 152Tb irradiating 155Gd/151Eu tandem target with a medium energy α-particle beam, // Nuclear Medicine and Biology 126–127 (2023) 108389) the concept of a tandem target 155Gd/151Eu was proposed. Irradiation of the tandem target 155Gd/151Eu with α-particles with an energy of 54 MeV was carried out on the U-150 cyclotron of the National Research Center "Kurchatov Institute". The rare earth elements were separated using extraction chromatography. ¹⁵⁵ Tb was obtained through the decay of ¹⁵⁵ Dy. The yield of ¹⁵⁵ D on a thick target at an α-particle energy of 54 MeV was 130 MBq/μAh. The specified yield of ¹⁵⁵ Dy allows one to obtain a yield ^{of 155} Tb of ~ 6.3 MBq/μA×h.

The disadvantages of this method include:

- the uniqueness of the cyclotron used and limited access to beams of 4He nuclei accelerated to 60 MeV;

- the need to use complex two-stage radiochemical processing to obtain the target radionuclide ¹⁵⁵ Tb;

- low activity yield of the target radionuclide ¹⁵⁵ Tb.

The method for the simultaneous production of radioisotopes ¹⁵⁴ Tb and ¹⁵⁵ Tb in a cascade target with gadolinium isotopes ¹⁵⁵ Gd and ¹⁵⁶ Gd was chosen as a prototype (Aliev R.A., Zagryadsky V.A., Konevega A.L., Moiseeva A.N., Skobelin I.I., - Method for producing radioisotopes Tb-154 and Tb-155 // Russian Federation Patent No. 2793294 dated 03/31/2023). The cascade target consisted of two modules sequentially located in the direction of the proton beam, wherein the first module in the direction of the beam contained the isotope ¹⁵⁶ Gd, the second module contained the isotope ¹⁵⁵ Gd, and when the target was irradiated in the process of threshold nuclear reactions ¹⁵⁶ Gd(p,3n) ¹⁵⁴ Tb and ¹⁵⁵ Gd(p,2n) ¹⁵⁴ Tb, as well as ¹⁵⁵ Gd(p,n) ¹⁵⁵ Tb and ¹⁵⁶ Gd(p,2n) ¹⁵⁵ Tb, the target radioisotopes ¹⁵⁴ Tb and ¹⁵⁵ Tb were simultaneously accumulated in it, which were then extracted from the target using a radiochemical method.

The method proposed in the prototype is oriented towards proton accelerators up to 30 MeV, which does not allow producing both diagnostic radioisotopes ¹⁵² Tb and ¹⁵⁵ Tb and the therapeutic α-emitter ¹⁴⁹ Tb in a single proton irradiation. In addition, the positron emitter ¹⁵⁴ Tb produced in the prototype has a fairly low yield ^{of +} β (2.8%) and has not yet found wide practical application.

The technical result of the proposed method is to provide the possibility of obtaining in a cascade target with a high yield of four target radioisotopes at once: ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr, with a low proportion of radionuclide impurities, with the possibility of using in the target relatively inexpensive isotopes of gadolinium with a high content in the natural mixture: ¹⁵⁵ Gd (14.8%), ¹⁵⁶ Gd (20.47%), ¹⁵⁴ Gd (2.18%) and ⁸⁵ Rb (72.2%).

In order to achieve the specified technical result, a method is proposed for producing radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr, including irradiation in an accelerator with protons with an energy of up to 80 MeV of a target with isotopes of gadolinium and ⁸⁵ Rb, which is made in a cascade of four modules sequentially located in the direction of the beam of charged particles, wherein the first module in the direction of the beam contains the isotope ¹⁵⁵ Gd, the second module contains the isotope ⁸⁵ Rb, the third module contains the isotope ¹⁵⁴ Gd, the fourth module contains the isotope ¹⁵⁶ Gd, and when irradiating the target in the process of threshold nuclear reactions ¹⁵⁵ Gd (p, 7n) ¹⁴⁹ Tb, ⁸⁵ Rb (p, 4n) ⁸² Sr, ¹⁵⁴ Gd (p, 3n) ¹⁵² Tb, as well as ¹⁵⁶ Gd (p, 2n) ¹⁵⁵ Tb, in which target radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr are simultaneously accumulated, which are then extracted from the target using radiochemical methods.

It is advisable to increase the thickness of modules with isotopes¹⁵⁶Gd,¹⁵⁵Gd,¹⁵⁵Gd and⁸⁵Rb should be chosen such that the proton range in the module with the isotope¹⁵⁵Gd provided proton braking from a starting energy of 80 MeV to 60 MeV, the proton range in the module with the isotope⁸⁵Rb provided proton braking from 59 MeV to 34 MeV, the proton range in the module with the isotope¹⁵⁴Gd provided proton braking from an energy of 33 MeV to 24 MeV, and the proton range in the module with the isotope¹⁵⁶Gd provided proton braking from 23 MeV to 15 MeV. It is assumed that in the partitions between the modules, protons will drop energy of 1 MeV. Further proton braking from 15 MeV will be carried out in an aluminum substrate cooled by running water. The established boundaries between the modules allow to develop significant activities of target radionuclides and minimize the presence of accompanying radioactive impurities. Thus, in each module of the cascade target one of the target radioisotopes with a level of radioactive impurities acceptable for practical use will be developed.

It is preferable to extract terbium radioisotopes from the target by solid-state extraction chromatography, and to extract ⁸² Sr sorption from liquid rubidium on metal surfaces.

The method is carried out as follows.

The target, which is a cascade of four modules with the isotopes ¹⁵⁵ Gd, ⁸⁵ Rb, ¹⁵⁴ Gd and ¹⁵⁶ Gd (each module contains only one isotope) arranged sequentially in the direction of the proton beam, is hermetically packed in a thin-walled metal capsule (for example, made of aluminum). The module with the isotope ¹⁵⁵ Gd is installed first in the capsule in the direction of the proton beam, then with the isotope ⁸² Rb, then sequentially with the isotopes ¹⁵⁴ Gd and ¹⁵⁶ Gd. The boundaries between the modules are made of thin-walled aluminum. The capsule is placed in the target device, ensuring proper heat removal using a gas or water coolant, and is irradiated in the accelerator with a proton beam. As a result of irradiation, the radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr are produced in the target by the reactions 155 Gd(p,7n) ¹⁴⁹ Tb, 85 Rb(p,4n) ⁸² Sr, ¹⁵⁴ Gd(p,3n) ¹⁵² Tb ^, and ¹⁵⁶ Gd(p,2n) ¹⁵⁵ Tb ^. Terbium radioisotopes are isolated from the target by the radiochemical method of solid-state extraction chromatography. The radioisotope ⁸² Sr is isolated from the target by sorption from liquid rubidium on metal surfaces.

Unlike the prototype, each of the target radioisotopes will be produced in one specific module. Unlike the prototype, in addition to diagnostic terbium isotopes, the method allows for the simultaneous production of therapeutic α-emitter ¹⁴⁹ Tb, as well as ⁸² Sr, used to create ⁸² Sr/ ⁸² Rb isotope generators used in myocardial perfusion diagnostics. By properly selecting the sequence of module arrangement in the direction of the proton beam (first a module with the ¹⁵⁵ Gd isotope, then with the ⁸² Rb isotope, then sequentially with ^{the 154} Gd and ¹⁵⁶ Gd isotopes), the method allows for the simultaneous production of four target radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr with a high yield, with a sufficiently low proportion of radionuclide impurities and in a wide range of proton energies. At the same time, in each of the modules the production of accompanying unwanted radioisotopes is minimized due to optimally selected boundaries between the modules and the starting energy of the protons.

An illustration of the implementation of the method for producing radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr is shown in Fig. 1-3. Fig. 1 shows the schematic diagram of the cascade target. Fig. 2 shows the reaction cross-sections for the formation of target radioisotopes of terbium, ⁸² Sr and associated impurity radionuclides in each of the modules of the cascade target from the TENDL-2023 library (AJ Koning, D. Rochman, J.-C. Sublet, N. Dzysiuk, M. Fleming, S. van der Marck, TENDL: Complete Nuclear Data Library for Innovative Nuclear Science and Technology, Nucl. Data Sheets. 155 (2019)1–55. https://tendl.web.psi.ch/tendl_2023/tendl2023.html), in Fig. 3 shows the yields of radioisotopes in the modules of the cascade target in accordance with Fig. 1-2. The results of applying the method are presented in the examples of implementing the invention given below.

Examples of implementation of the invention

Example No. 1. The yields of radioisotopes of terbium and ⁸² Sr were calculated in a cascade target with modules with isotopes of ¹⁵⁵ Gd, ⁸⁵ Rb, ¹⁵⁴ Gd and ¹⁵⁶ Gd, irradiated with protons with an energy of 80 MeV, sequentially located in the direction of the proton beam. The thickness of the modules with isotopes was chosen such that the proton range in the module with the ¹⁵⁵ Gd isotope ensured proton deceleration from the starting energy of 80 MeV to 60 MeV, the proton range in the module with the ⁸⁵ Rb isotope ensured proton deceleration from the energy of 59 MeV to 34 MeV, the proton range in the module with the ¹⁵⁴ Gd isotope ensured proton deceleration from the energy of 33 MeV to 24 MeV, and the proton range in the module with the ¹⁵⁶ Gd isotope ensured proton deceleration from the energy of 23 MeV to 15 MeV. It is implied that protons will drop energy of 1 MeV in the partitions between the modules. Further proton deceleration from the energy of 15 MeV will be carried out in an aluminum substrate cooled by running water.

The calculation of the yields of terbium radioisotopes was carried out in a multi-group approximation using the formula

where A [Bq/μA×h] is the yield of terbium radioisotope;

T [h] – irradiation time, equal to one hour;

λ [ h ^-1 ] – decay constant of the terbium radioisotope;

N [cm ^-3 ] – the number of gadolinium nuclei per unit volume of the target;

f [ s ^-1 ] – proton flux (6.24×10 ¹² s ^-1 ), corresponding to a current of 1 μA;

σ _i [cm ² ] – cross-section of the reaction of formation of the terbium radioisotope in the i-th energy interval;

l _i [cm] is the proton range in the target, within the energy boundaries of which the average cross section is equal to σ _i .

The proton ranges l _i in the target were calculated using the SRIM program (F. Ziegler, MD Ziegler, JP Biersack, SRIM – The stopping and range of ions in matter (2010), Nucl. Instruments Methods Phys. Res. Sect. B Beam Interact. with Mater. Atoms. 268 (2010) 1818–1823. https://doi.org/10.1016/j.nimb.2010.02.091).

Table 1 shows the results of calculating the yields of terbium radioisotopes in each of the modules of the cascade target at a starting proton energy of 80 MeV, calculated using formula (1). It follows from Table 1 that each of the target radioisotopes is produced predominantly in one specific module, and the yields of impurity radioisotopes (with the selected sequence of arrangement of modules and the selected boundary between modules) are at a fairly low level. Only in the module with¹⁵⁵Gd impurity activities¹⁵⁰Tb and¹⁴⁸Tb is on the same order as the target therapeutic α-emitter¹⁴⁹Tb. However, the half-life¹⁴⁸Tb (T_1/2=60 minutes) is four times shorter than the half-life ¹⁴⁹Tb (T_1/2= 4.15 hours), which allows for a short holding time to reduce impurity activity¹⁴⁸Tb by an order of magnitude. As for¹⁵⁰Tb, then it has a close relationship with¹⁴⁹Tb has a half-life of 3.27 hours and is a positron emitter with a yield of 20.3%. Thus, radioisotopes: target¹⁴⁹Tb and impurity¹⁵⁰Tb may be considered as a convenient theranostic pair allowing for α-emitter therapy¹⁴⁹Tb with simultaneous PET imaging.

Table 1

Outputs of radioisotopes of terbium and ⁸² Sr, MBq/μA×h

Cascade Target Module with 156Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb 152Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 15-23 MeV 4.83E+00 7.52E+
01 1.57E+
01 0 0 0 0 0 0 0 Cascade Target Module with 154Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 24-33 MeV 0 0 3.29E+
01 7.66E+01 7.43E+
02 9.87E+01 0 0 0 0 Cascade target module with 85Rb Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 34-59 MeV 0 0 0 0 0 0 0 0 0 1,14E+01 Cascade target module with 155Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 60-80 MeV 0 0 0 0 0 4.89E+02 3.34E+
03 2.36E+03 2.45E+03 0

Example No. 2. The starting energy of protons was taken to be 80 MeV. The thickness of the modules with isotopes was chosen such that the proton range in the module with the ¹⁵⁵ Gd isotope ensured proton deceleration from the starting energy of 80 MeV to 61 MeV, the proton range in the module with the ⁸⁵ Rb isotope ensured proton deceleration from the energy of 60 MeV to 35 MeV, the proton range in the module with the ¹⁵⁴ Gd isotope ensured proton deceleration from the energy of 34 MeV to 25 MeV, and the proton range in the module with the ¹⁵⁶ Gd isotope ensured proton deceleration from the energy of 24 MeV to 15 MeV. It is implied that in the partitions between the modules the protons will dump energy of 1 MeV. Further deceleration of protons from the energy of 15 MeV will be carried out in an aluminum substrate cooled by running water. The boundary between the aluminum modules provided deceleration of protons by 1 MeV. The calculation was carried out in a multigroup approximation using formula 1. To calculate the proton range in the target, the SRIM program was used, the cross-section values from TENDL-2023. The calculation results are presented in Table 2.

Table 2

Outputs of radioisotopes of terbium and ⁸² Sr, MBq/μA×h

Cascade Target Module with 156Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb 152Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 15-24 MeV 6.31E+
00 9.61E+
01 8.91E+
01 0 0 0 0 0 0 0 Cascade Target Module with 154Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 25-34 MeV 0 0 4.04E+
01 8.67E+
01 8.46E+
02 2.59E+
02 0 0 0 0 Cascade target module with 85Rb Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 35-60 MeV 0 0 0 0 0 0 0 0 0 1.22E+
01 Cascade target module with 155Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 61-80 MeV 0 0 0 0 0 4.89E+
02 3.34E+
03 2.37E+
03 2.45E+
03 0

Example No. 3. The starting energy of protons was taken to be 80 MeV. The thickness of the modules with isotopes was chosen such that the proton range in the module with the ¹⁵⁵ Gd isotope ensured proton deceleration from the starting energy of 80 MeV to 59 MeV, the proton range in the module with the ⁸⁵ Rb isotope ensured proton deceleration from the energy of 58 MeV to 33 MeV, the proton range in the module with the ¹⁵⁴ Gd isotope ensured proton deceleration from the energy of 32 MeV to 23 MeV, and the proton range in the module with the ¹⁵⁶ Gd isotope ensured proton deceleration from the energy of 22 MeV to 15 MeV. Further proton deceleration from the energy of 15 MeV will be carried out in an aluminum substrate cooled with running water. The boundary between the aluminum modules provided proton deceleration by 1 MeV. The calculation was performed in a multigroup approximation using formula 1. The SRIM program was used to calculate the proton range in the target, and the cross-section values from TENDL-2023. The calculation results are presented in Table 3.

Table 3

Outputs of radioisotopes of terbium and ⁸² Sr, MBq/μA×h

Cascade Target Module with 156Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb 152Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 15-22 MeV 4.63E+
00 7.15E+
01 1.30E+
01 0 0 0 0 0 0 0 Cascade Target Module with 154Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 23-32 MeV 0 0 4.14E+
01 1.40E+
02 7.46E+
02 1.06E+
02 0 0 0 0 Cascade target module with 85Rb Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 33-58 MeV 0 0 0 0 0 0 0 0 0 1.12E+
01 Cascade target module with 155Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 59-80 MeV 0 0 0 0 0 4.89E+
02 3.34E+
03 2.36E+
03 2.45E+
03 0

Example No. 4. The starting energy of protons was taken to be 80 MeV. The thickness of the modules with isotopes was chosen such that the proton range in the module with the ¹⁵⁵ Gd isotope ensured proton deceleration from the starting energy of 80 MeV to 62 MeV, the proton range in the module with the ⁸⁵ Rb isotope ensured proton deceleration from the energy of 61 MeV to 36 MeV, the proton range in the module with the ¹⁵⁴ Gd isotope ensured proton deceleration from the energy of 35 MeV to 26 MeV, and the proton range in the module with the ¹⁵⁶ Gd isotope ensured proton deceleration from the energy of 25 MeV to 15 MeV. Further proton deceleration from the energy of 15 MeV will be carried out in an aluminum substrate cooled with running water. The boundary between the aluminum modules provided proton deceleration by 1 MeV. The calculation was performed in a multigroup approximation using formula 1. The SRIM program was used to calculate the proton range in the target, and the cross-section values from TENDL-2023. The calculation results are presented in Table 4.

Table 4

Outputs of radioisotopes of terbium and ⁸² Sr, MBq/μA×h

Cascade Target Module with 156Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb 152Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 15-25 MeV 6.38E+
00 1.02E+
02 9.08E+
01 0 0 0 0 0 0 0 Cascade Target Module with 154Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 26-35 MeV 0 0 4.13E+
01 8.90E+
01 8.61E+
02 2.69E+
02 0 0 0 0 Cascade target module with 85Rb Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 36-61 MeV 0 0 0 0 0 0 0 0 0 1.24E+
01 Cascade target module with 155Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 62-80 MeV 0 0 0 0 0 4.89E+
02 3.34E+
03 2.37E+
03 2.45E+
03 0

Example No. 5. The starting energy of protons was taken to be 80 MeV. The thickness of the modules with isotopes was chosen such that the proton range in the module with the ¹⁵⁵ Gd isotope ensured proton deceleration from the starting energy of 80 MeV to 58 MeV, the proton range in the module with the ⁸⁵ Rb isotope ensured proton deceleration from the energy of 57 MeV to 32 MeV, the proton range in the module with the ¹⁵⁴ Gd isotope ensured proton deceleration from the energy of 31 MeV to 22 MeV, and the proton range in the module with the ¹⁵⁶ Gd isotope ensured proton deceleration from the energy of 21 MeV to 15 MeV. Further proton deceleration from the energy of 15 MeV will be carried out in an aluminum substrate cooled with running water. The boundary between the aluminum modules provided proton deceleration by 1 MeV. The calculation was performed in a multigroup approximation using formula 1. The SRIM program was used to calculate the proton range in the target, and the cross-section values from TENDL-2023. The calculation results are presented in Table 5.

Table 5

Outputs of radioisotopes of terbium and ⁸² Sr, MBq/μA×h

Cascade Target Module with 156Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb 152Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 15-21 MeV 4.58E+
00 7.06E+
01 1.24E+
01 0 0 0 0 0 0 0 Cascade Target Module with 154Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 22-31 MeV 0 0 3.90E+
01 1,180E+
02 7.43E+
02 1.03E+
02 0 0 0 0 Cascade target module with 85Rb Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 32-57 MeV 0 0 0 0 0 0 0 0 0 1.09E+
01 Cascade target module with 155Gd Radioisotopes ¹⁵⁶ Tb ¹⁵⁵ Tb ¹⁵⁴ Tb ¹⁵³ Tb ¹⁵² Tb ¹⁵¹ Tb ¹⁵⁰ Tb ¹⁴⁹ Tb ¹⁴⁸ Tb ⁸² Sr 58-80 MeV 0 0 0 0 0 4.89E+
02 3.34E+
03 2.36E+
03 2.45E+
03 0

It follows from the given examples that the use of relatively inexpensive isotopes of gadolinium ¹⁵⁶ Gd, ¹⁵⁵ Gd, ¹⁵⁴ Gd and rubidium isotope ⁸⁵ Rb in the cascade target modules, with a high content in the natural mixture, as well as the selected sequence of arrangement of modules with the said isotopes, make it possible to obtain a yield of ¹⁵⁵ Tb in the cascade target that exceeds the yields of all variants of ¹⁵⁵ Tb production in the prototype to varying degrees (Examples 2 and 4). At the same time, unlike the prototype, the method makes it possible to produce a large amount of the radioisotope ¹⁵² Tb, which can be used in diagnostic studies by the PET method and the yield of which can exceed the yield of the alternative ¹⁵⁴ Tb produced in the prototype. In addition, unlike the prototype, the method allows for the simultaneous production of a large amount of therapeutic α-emitter ¹⁴⁹ Tb and ⁸² Sr, used to create ⁸² Sr/ ⁸² Rb isotope generators used for myocardial perfusion diagnostics. At the same time, the accompanying radionuclide impurities during the production of isotopes are at a sufficiently low level, and the possibility of shifting the boundary between the modules allows for the optimization of their relative quantity.

Claims (3)

1. A method for producing radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr, including irradiating a cascade target with gadolinium isotopes with protons in a charged particle accelerator, characterized in that protons with an energy of up to 80 MeV are used to irradiate the target, in addition to gadolinium isotopes, the target contains the isotope ⁸⁵ Rb, the cascade target is made of four modules sequentially located in the direction of the proton beam, wherein the first module in the direction of the beam contains the isotope ¹⁵⁵ Gd, the second module contains the isotope ⁸⁵ Rb, the third module contains the isotope ¹⁵⁴ Gd, the fourth module contains the isotope ¹⁵⁶ Gd, and when irradiating the target with protons in the process of threshold nuclear reactions ¹⁵⁵ Gd(p,7n) ¹⁴⁹ Tb, ⁸⁵ Rb(p,4n) ⁸² Sr, ¹⁵⁴ Gd(p,3n) ¹⁵² Tb and ¹⁵⁶ Gd(p,2n) ¹⁵⁵ Tb, in which the target radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb and ⁸² Sr are simultaneously accumulated, which are then extracted from the target using radiochemical methods. 2. The method according to claim 1, characterized in that the thickness of the modules with the isotopes ¹⁵⁵ Gd, ⁸⁵ Rb, ¹⁵⁴ Gd, ¹⁵⁶ Gd is selected such that the proton range in the module with the isotope ¹⁵⁵ Gd ensures the deceleration of protons from the starting energy to 60 MeV, the proton range in the module with the isotope ⁸⁵ Rb ensures the deceleration of protons from the energy of 59 MeV to 34 MeV, the proton range in the module with the isotope ¹⁵⁴ Gd ensures the deceleration of protons from the energy of 33 MeV to 24 MeV, and the proton range in the module with the isotope ¹⁵⁶ Gd ensures the deceleration of protons from the energy of 23 MeV to 15 MeV. 3. The method according to item 1, characterized in that the extraction of terbium radioisotopes ¹⁵⁵ Tb, ¹⁵² Tb, ¹⁴⁹ Tb from the target modules is carried out by the method of solid-state extraction chromatography, and ⁸² Sr - by sorption from liquid rubidium on metal surfaces.