RU2600324C1 - Method of producing terbium-149 radioisotope - Google Patents

Abstract

FIELD: medicine; physics.

SUBSTANCE: invention relates to a method of producing ¹⁴⁹Tb radionuclide, used in nuclear medicine. Method comprises irradiation of the target of metal europium or its compounds on charged particle accelerator by light nuclei ³He (or ⁴He) and operating time in the target as a result of nuclear reactions ¹⁵¹Eu(³He,⁵n)¹⁴⁹Tb and (or) ¹⁵³Eu(³He, 7n)¹⁴⁹Tb (or, respectively, ¹⁵¹Eu(⁴He, 6n)¹⁴⁹Tb and (or) ¹⁵³Eu(⁴He, 8n)¹⁴⁹Tb) of radionuclide ¹⁴⁹Tb, which is removed from the target after irradiation by solid-state extraction, or by electromagnetic separation of isotopes.

EFFECT: possibility of using metal europium or its compounds of natural isotopic composition as the target material, possibility to use for producing ¹⁴⁹Tb relative to accelerators ⁴He and ³He of average energies, possibility to use for extracting ¹⁴⁹Tb without carrier by extraction chromatography or electromagnetic separation of isotopes, possibility to ensure ¹⁴⁹Tb output, acceptable for carrying out preclinical and clinical studies, and for further use.

3 cl, 2 tbl, 2 ex

Description

The invention relates to a technology for producing radionuclides for nuclear medicine on charged particle accelerators.

Currently, for the purposes of radioimmunotherapy, a fairly wide range of radionuclides is considered, which can be conjugated to monoclonal antibodies or peptides and used as therapeutic agents in targeted delivery drugs in the treatment of cancer. In particular, for these purposes, β-emitting radionuclides are mentioned in the literature: ⁹⁰ Y, ¹⁷⁷ Lu and α-emitters: short-lived ²¹² Bi (half-life T _{1 | 2} = 46 minutes) and ²¹³ Bi (T _{1 | 2} = 61 minutes) ; as well as ²²⁵ Ac (T _{1 | 2} = 10 days), which provides a cascade of α-particles taking into account the chain of daughter radionuclides; ²¹¹ At (T _{1 | 2} = 7.21 hours) and a long-lived generator ²¹² Pb / ²¹² Bi (T _{1 | 2} = 10.64 hours).

Due to the physical properties of α-particles: relatively short range and high linear energy loss (compared to β-particles), targeted delivery preparations with α-emitters should be more effective in the treatment of micrometastases, especially in the postoperative period, providing a gentle effect on healthy tissues .

The short-lived α-emitters ²¹² Bi (T _{1 | 2} = 46 minutes) and ²¹³ Bi (T _{1 | 2} = 61 minutes) are not convenient for practical use, both in terms of the time required to prepare a radiopharmaceutical (RP) and with point of view of the time of therapeutic effect.

During the decay of ²²⁵ Ac (or its daughter decay products), as well as ²¹² Pb, the resulting recoil nuclei can acquire energy sufficient to break down the chemical bond of the radionuclide in the conjugate (RFP). As a result, in in vivo experiments, the radionuclide may not be targeted to the cancer cell, but will randomly move through the bloodstream.

As for ²¹¹ At, despite the physical properties convenient for use, the main obstacle to its wide practical application is the in vivo instability of the association of astatine with aromatic hydrocarbons.

In the past few years, mainly abroad, research has been actively conducted on the production and use of ¹⁴⁹ Tb α-emitter for the purpose of radioimmunotherapy. The radionuclide ¹⁴⁹ Tb has a convenient half-life (T _{1 | 2} = 4.15 hours); the yield of α particles with an energy E _α = 3.97 MeV from different sources is 16.7 20%. In contrast to ²²⁵ Ac or ²¹² Pb when using ¹⁴⁹ Tb as a therapeutic agent, there is no risk of the conjugate losing the α-emitting radionuclide due to the destruction of the chemical bond due to the decay of the precursor. Terbium-149 has a line with Ε _γ = 165 keV and a yield of 28.1%, convenient for recording with standard γ-cameras, which makes it possible to use it in the method of single-photon spectroscopy. Terbium-149 has an annihilation line with Ε _γ = 511 keV, which allows its use in the method of positron emission tomography. Being a trivalent metal, terbium easily forms strong bonds with the DOTA and DTPA chelators and, thus, makes it possible to integrate it into conjugates specific to cancer cells. The list of these properties gives reason to use ¹⁴⁹ Tb in theranostics: in radioimmunotherapy with simultaneous visualization of the distribution of ¹⁴⁹ Tb and, accordingly, cancer cells in the patient's body.

The only factor holding back the widespread use of ¹⁴⁹ Tb as a therapeutic agent is the difficulty of its preparation.

At present, ¹⁴⁹ Tb are produced by spallation reactions by irradiating targets with protons with energies of ~ 1.4 GeV, or by irradiating targets with heavy ions with energies of more than 100 MeV using expensive, unique high-energy accelerators intended primarily for basic research. Since the spectrum of radionuclides obtained as a result of these reactions is wide enough, an electromagnetic separator must be additionally used to isolate ¹⁴⁹ Tb.

Known methods for producing ¹⁴⁹ Tb by irradiation with protons or nuclei of ³ He ( ⁴ He) isotope ¹⁵² Gd by reactions ¹⁵² Gd (p, 4n) ¹⁴⁹ Tb; ¹⁵² Gd ( ³ He, 6n) ¹⁴⁹ Dy → ¹⁴⁹ Tb and ¹⁵² Gd ( ⁴ He, 7n) ¹⁴⁹ Dy → ¹⁴⁹ Tb. The main disadvantage of these methods is the high cost and complexity of obtaining the target material ( ¹⁵² Gd isotope, the content of which in the natural mixture of isotopes is only 0.2%).

The present invention allows to obtain ¹⁴⁹ Tb in a simpler and cheaper way, compared with the above, in volumes sufficient for both preclinical and clinical studies, and for commercial use. In this case, europium (or its compounds) of a natural isotopic composition ( ¹⁵¹ Eu - 47.81%, ¹⁵³ Eu - 52.19%) is used as a target, and ¹⁴⁹ Tb is generated on the average energy accelerator by the reactions ¹⁵¹ Eu ( ³ He, 5n) ¹⁴⁹ Tb and (or) ¹⁵³ Eu ( ³ He, 7n) ¹⁴⁹ Tb (or respectively ¹⁵¹ Eu ( ⁴ He, 6n) ¹⁴⁹ Tb and (or) ¹⁵³ Eu ( ⁴ He, 8n) ¹⁴⁹ Tb). Since the reaction threshold of ¹⁵¹ Eu ( ³ He, 5n) ¹⁴⁹ Tb is only 29 MeV, ¹⁴⁹ Tb can be produced on compact accelerators with ³ He nuclei up to 50 MeV.

A simple and cheap extraction chromatography method can be used to extract terbium from a target. Obtained in this manner is practically ¹⁴⁹ Tb will not have long-lived radionuclide impurities, besides a number of short-lived radioisotopes of terbium, which, being a + β and (or) ^- β-emitters may simultaneously with ¹⁴⁹ Tb used for therapy and diagnosis of micrometastases.

State of the art

At present, ¹⁴⁹ Tb radionuclide is produced either by spallation, irradiating a tantalum target with protons with an energy of ~ 1.4 GeV, or as a result of other inelastic scattering reactions, irradiating a wide spectrum of targets with heavy ions, or by irradiating with protons or nuclei ³ He ( ⁴ He ) isotope ¹⁵² Gd by reactions ¹⁵² Gd (p, 4n) ¹⁴⁹ Tb; ¹⁵² Gd ( ³ He, 6n) ¹⁴⁹ Dy → ¹⁴⁹ Tb and ¹⁵² Gd ( ⁴ He, 7n) ¹⁴⁹ Dy → ¹⁴⁹ Tb.

, С.; Zhemosekov, К.;

, U.; Johnston, К.; Dorrer, H.; Hohn, Α.; van der Walt, N.T.;

, Α.; 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, 1951-1959). Мишень из металлического тантала (50 г/см²) облучали протонами высокой энергии ~1.4 ГэВ. После испарения продуктов реакции из нагретой до 2000°С мишени они были ионизованы с помощью лазера, извлечены из ионного источника, ускорены до 50 кэВ и разделены в магнитном поле электромагнитного сепаратора по массам. Продукты с массой 149 были высажены на покрытую золотом цинковую пластинку площадью 70 мм² и затем направлены на радиохимическую очистку.A known method of producing ¹⁴⁹ Tb by the reaction of Ta (p, spallation) (

, FROM.; Zhemosekov, K .;

, U .; Johnston, K .; Dorrer, H .; Hohn, Α .; van der Walt, NT;

, Α .; 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, 1951-1959). A target made of metal tantalum (50 g / cm ² ) was irradiated with high-energy protons of ~ 1.4 GeV. After evaporation of the reaction products from a target heated to 2000 ° С, they were ionized using a laser, extracted from an ion source, accelerated to 50 keV and separated by mass in the magnetic field of the electromagnetic separator. Products weighing 149 were planted on a gold-plated zinc plate with an area of 70 mm ² and then sent for radiochemical cleaning.

This method has significant disadvantages, which are as follows:

- to obtain ¹⁴⁹ Tb, a unique and expensive high-energy proton accelerator is used: ISOLDE (CERN, Geneva, Switzerland), mainly intended for basic research;

- as a result of the cleavage reaction, a wide range of fragments is formed and, as a result, there is a need for the separation of isotopes with atomic number 149 to use a rather expensive and energy-intensive technological operation of electromagnetic separation of isotopes in an electromagnetic separator.

, M.

, D. Soloviev, C. Tamburella, E.

, B. Allan, S.N. Dmitriev, N.G. Zaitseva, G.Ya. Starodub, L.G. Molokanova, S.

, M.Miederer Production routes of the alpha emitting 149Tb for medical application - Radiochimica Acta 90 (5) 247 -, 2002). Облучение проводили на циклотроне тяжелых ионов U-200 (Объединенный институт ядерных исследований, г. Дубна). Энергия ионов ¹²С составляла 108 МэВ. Мишень из ^natNd₂O₃ толщиной 12 мг/см² облучали в течение 1,25 часа. Через 20 минут после окончания облучения в мишени было зарегистрировано 1.2 МБк ¹⁴⁹Tb. Так же, как и в предыдущем примере, для выделения ¹⁴⁹Tb из продуктов неупругих реакций использовали электромагнитный сепаратор с последующей радиохимической очисткой.A known method for producing ¹⁴⁹ Tb by the reaction Nd ( ¹² C, 5n) ¹⁴⁹ Dy → ¹⁴⁹ Tb (GJ Beyer, JJ

, M.

, D. Soloviev, C. Tamburella, E.

, B. Allan, SN Dmitriev, NG Zaitseva, G.Ya. Starodub, LG Molokanova, S.

, M. Miederer Production routes of the alpha emitting 149Tb for medical application - Radiochimica Acta 90 (5) 247 -, 2002). Irradiation was carried out on the U-200 heavy ion cyclotron (Joint Institute for Nuclear Research, Dubna). The energy of ¹² C ions was 108 MeV. A target of ^nat Nd ₂ O ₃ with a thickness of 12 mg / cm ^{2 was} irradiated for 1.25 hours. Twenty minutes after the end of the irradiation, 1.2 MBq ¹⁴⁹ Tb was detected in the target. As in the previous example, to isolate ¹⁴⁹ Tb from the products of inelastic reactions, an electromagnetic separator was used, followed by radiochemical purification.

The disadvantages of this method include:

- the need to use the unique expensive U-200 heavy ion cyclotron (Joint Institute for Nuclear Research, Dubna);

- as in the previous method, due to the presence of a wide range of inelastic reaction products in the target after irradiation, it becomes necessary to isolate isotopes with atomic number 149, use a rather expensive and energy-intensive technological operation of electromagnetic separation of isotopes on an electromagnetic separator, followed by radiochemical cleaning.

, M.

, D. Soloviev, C. Tamburella, E. Hageb_⌀, B. Allan, S.N. Dmitriev, N.G. Zaitseva, G.Ya. Starodub, L.G. Molokanova, S.

, M.Miederer Production routes of the alpha emitting 149Tb for medical application - Radiochimica Acta 90 (5) 247, 2002). В этом способе предлагается нарабатывать ¹⁴⁹Tb облучением изотопа ¹⁵²Gd протонами с энергией ≥50 МэВ. В работе по программе ALICE 91 проведены расчеты функций возбуждения с выходом ¹⁴⁹Tb для нескольких ядерных реакций. Показано, что реакция ¹⁵²Gd(p,4n)¹⁴⁹Tb наиболее удобна как с точки зрения возможности реализации (относительно невысокая энергия протонов), так и с точки зрения величины выхода ¹⁴⁹Tb. Отмечается также, что получение ¹⁴⁹Tb без носителя (выделение ¹⁴⁹Tb из Gd мишени) можно реализовать за приемлемое (с точки зрения последующего использования ¹⁴⁹Tb) время. Основным недостатком прототипа следует считать необходимость использования в качестве мишени изотопа ¹⁵²Gd, содержание которого в природной смеси составляет всего 0.2%. Обогащенный по изотопу ¹⁵²Gd гадолиний получают энергоемким методом электромагнитного разделения изотопов. Вследствие этого цена на ¹⁵²Gd весьма высока. Использование природного Gd сопряжено с существенным снижением выхода ¹⁴⁹Tb и появлением широкого спектра нежелательных долгоживущих радиоактивных примесей.As a prototype, the method of obtaining ¹⁴⁹ Tb by the reaction of ¹⁵² Gd (p, 4n) ¹⁴⁹ Tb described in the above work (GJ Beyer, JJ

, M.

, D. Soloviev, C. Tamburella, E. Hageb _⌀ , B. Allan, SN Dmitriev, NG Zaitseva, G. Ya. Starodub, LG Molokanova, S.

, M. Miederer Production routes of the alpha emitting 149Tb for medical application - Radiochimica Acta 90 (5) 247, 2002). In this method, it is proposed to generate ¹⁴⁹ Tb by irradiating the ¹⁵² Gd isotope with protons with an energy of ≥50 MeV. In the ALICE 91 program, excitation functions were calculated with a yield of ¹⁴⁹ Tb for several nuclear reactions. It was shown that the ¹⁵² Gd (p, 4n) ¹⁴⁹ Tb reaction is most convenient both from the point of view of feasibility (relatively low proton energy) and from the point of view of the yield of ¹⁴⁹ Tb. It is also noted that obtaining ¹⁴⁹ Tb without a carrier (isolation of ¹⁴⁹ Tb from the Gd target) can be realized in an acceptable (from the point of view of subsequent use of ¹⁴⁹ Tb) time. The main disadvantage of the prototype should be considered the need to use as a target isotope ¹⁵² Gd, the content of which in the natural mixture is only 0.2%. Gadolinium-enriched ¹⁵² Gd isotope is obtained by the energy-intensive method of electromagnetic isotope separation. As a result, the price of ¹⁵² Gd is very high. The use of natural Gd is associated with a significant decrease in the yield of ¹⁴⁹ Tb and the appearance of a wide range of undesirable long-lived radioactive impurities.

Disclosure of invention

The technical results of the proposed method for producing ¹⁴⁹ Tb produced by the reactions of ¹⁵¹ Eu ( ³ He, 5n) ¹⁴⁹ Tb and (or) ¹⁵³ Eu ( ³ He, 7n) ¹⁴⁹ Tb (or respectively ¹⁵¹ Eu ( ⁴ He, 6n) ¹⁴⁹ Tb and ( or) ¹⁵³ Eu ( ⁴ He, 8n) ¹⁴⁹ Tb), it should be considered:

1) The possibility of using cheap raw materials as a target material: metallic europium or its compounds of natural isotopic composition.

2) The possibility of using for operation ¹⁴⁹ Tb relatively inexpensive accelerators to operate ⁴ He and ³ Not medium energies.

3) The ability to isolate ¹⁴⁹ Tb without a carrier by the well-known, well-established and widely used method of extraction chromatography.

4) The ability to provide a yield of ¹⁴⁹ Tb, acceptable for both preclinical and clinical studies, and for commercial use.

To achieve these results, a method for producing the terbium-149 ( ¹⁴⁹ Tb) radionuclide is proposed, which includes irradiating a target with charged particles of ³ He or ⁴ He nuclei and isolating ¹⁴⁹ Tb from an irradiated target, using metal europium or its chemical compounds as the target and get the target isotope ¹⁴⁹ Tb when the target is irradiated as a result of nuclear reactions ¹⁵¹ Eu ( ³ He, 5n) ¹⁴⁹ Tb and / or ¹⁵³ Eu ( ³ He, 7n) ¹⁴⁹ Tb or ¹⁵¹ Eu ( ⁴ He, 6n) ¹⁴⁹ Tb and / or ¹⁵³ Eu ( ⁴ He, 8n) ¹⁴⁹ Tb.

Besides,

- ¹⁴⁹ Tb is isolated from the irradiated target by electromagnetic isotope separation.

- ¹⁴⁹ Tb is isolated from the irradiated target by solid-state extraction (extraction chromatography).

The method is as follows.

A target in the form of a disk of metallic europium or a powdered europium compound is hermetically packed in a thin-walled metal capsule (for example, aluminum). Moreover, europium can be used both of natural isotopic composition and with enrichment of one (of two) isotopes. The capsule is placed in the target device, ensuring proper heat removal using a gas or water coolant, and is irradiated with a ³ He or ⁴ He beam with an energy of a beam of charged particles of ³ He ( ⁴ He) (30 ÷ 100) MeV. As a result of irradiation in the target by the reactions ¹⁵¹ Eu ( ³ He, 5n) ¹⁴⁹ Tb and (or) ¹⁵³ Eu ( ³ He, 7n) ¹⁴⁹ Tb (or respectively ¹⁵¹ Eu ( ⁴ He, 6n) ¹⁴⁹ Tb and (or) ¹⁵³ Eu ( ⁴ He, 8n) ¹⁴⁹ Tb) produce the radionuclide ¹⁴⁹ Tb, which after irradiation is isolated from the target by one of the known methods: by the radiochemical method of solid-state extraction (extraction chromatography), or by the method of electromagnetic isotope separation (electromagnetic separation). The method allows one to isolate ¹⁴⁹ Tb (without carrier) (in combination with other terbium radionuclides) from the original target. The method of electromagnetic isotope separation (electromagnetic separation) makes it possible to isolate isotopes with atomic number 149, thereby separating ¹⁴⁹ Tb not only from the source material of the target (Eu), but also from a wide range of associated terbium radionuclides.

Examples of carrying out the invention

Example 1. Terbium-149 was produced in a natural isotopic composition of europium metal ( ¹⁵¹ Eu — 47.81%, ¹⁵³ Eu — 52.19%) by irradiating it with ³ He nuclei with an initial energy of 70 MeV at the U-150 cyclotron of the Kurchatov Institute Research Center.

The europium sample was disk shaped with a diameter of 18 mm and a thickness of 1.3 mm. The density of the europium sample corresponded to a theoretical density of 5.24 [g / cm ³ ]. The range of ³ He nuclei with an initial energy of 70 MeV in metallic europium was previously calculated using the SRIM program. According to the calculations, the thickness of the metal europium sample, equal to 1.3 mm, provided the energy release of ³ He nuclei from 70 MeV to 29 MeV. The theoretical reaction threshold of ¹⁵¹ Eu ( ³ He, 5n) ¹⁴⁹ Tb is 29.2 MeV. In addition to this reaction, the ¹⁴⁹ Tb production was carried out by the reaction ¹⁵³ Eu ( ³ He, 7n) ¹⁴⁹ Tb, which has a higher threshold - 44.4 MeV. Therefore, the irradiated metal europium sample 1.3 mm thick for the purpose of producing terbium-149 can be considered a “thick” target.

The europium sample was irradiated with a beam of ³ He nuclei at a current of ~ 0.1 μA for 470 seconds. The integral flux of ³ He nuclei per sample during the irradiation time was 1.125 × 10 ^{14 3} He nuclei (3605 pulses). The average power of energy release in the sample was ~ 4 W. The sample was cooled during irradiation with a flow of ⁴ He. The presence of ¹⁴⁹ Tb and other associated terbium radionuclides in the irradiated sample was determined by the activation method using an ORTEC γ-spectrometer with a crystal of ~ 100 cm ³ from ultrapure germanium.

Table 1 shows the activities of terbium radionuclides (reduced to the end of irradiation) obtained by irradiating a “thick” (for reactions with ¹⁴⁹ Tb yield) target from natural europium metal of natural isotopic composition with ³ He nuclei with an initial energy of 70 MeV.

Subsequent isolation of the ¹⁴⁹ Tb radionuclide without a carrier (in combination with other terbium radionuclides) is carried out by the known radiochemical method of solid-state extraction (extraction chromatography).

Example 2. Terbium-149 was produced in a 4 mm thick Eu ₂ O ₃ target with a diameter of 16 mm and a bulk density of 1.541 g / cm ³ . The target was located in a thin-walled aluminum capsule. The enrichment over the ¹⁵¹ Eu isotope was 97.5%. The target was irradiated with a ³ He beam with an energy of 55 MeV (at the entrance to europium oxide) at the U-150 cyclotron of the Research Center “Kurchatov Institute”.

The range of ³ He nuclei with an initial energy of 55 MeV in Eu ₂ O _{3 was} previously calculated using the SRIM program. According to the calculations, the thickness of the target from Eu ₂ O ₃ , equal to 4 mm, ensured the release of the energy of ³ He nuclei from 55 MeV to the region below the threshold of reactions leading to the formation of ¹⁴⁹ Tb. Therefore, a target of Eu ₂ O ₃ with a thickness of 4 mm with a bulk density of 1.541 g / cm ³ for the purpose of producing terbium-149 can also be considered a “thick” target, as in example No. 1.

Irradiation was carried out on a beam of ³ He nuclei at a current of ~ 0.15 μA for 338 seconds. The integral flux of ³ He nuclei per sample during irradiation was 1.56 × 10 ^{14 3} He nuclei (5000 pulses). The average power of energy release in the target was ~ 4 W. The sample was cooled during irradiation with a flow of ⁴ He. The presence of ¹⁴⁹ Tb and other associated terbium radionuclides in the target was determined by the activation method using an ORTEC γ-spectrometer with a crystal of ~ 100 cm ³ from ultrapure germanium.

Table 2 shows the activities of terbium radionuclides (reduced to the end of irradiation) obtained by irradiating a target from Eu ₂ O ₃ with a thickness of 4 mm with a bulk density of 1.541 g / cm ³ enriched in the ¹⁵¹ Eu isotope to 97.5% with ³ He nuclei with an energy of 55 MeV (at the entrance to europium oxide).

Subsequent isolation of the ¹⁴⁹ Tb radionuclide without a carrier (in combination with other terbium radionuclides) is also carried out by the radiochemical method of solid-state extraction (extraction chromatography).

Thus, the possibility of obtaining ¹⁴⁹ Tb in a simpler and cheaper way, in comparison with the above, in volumes sufficient for both preclinical and clinical studies, and for commercial use, is shown.

Claims (3)

1. A method of producing a terbium-149 radionuclide ( ¹⁴⁹ Tb), comprising irradiating a target with a charged particle accelerator of ³ He or ⁴ He nuclei and isolating ¹⁴⁹ Tb from the irradiated target, characterized in that
europium metal or its chemical compounds are used as the target and the target isotope ¹⁴⁹ Tb is obtained by irradiating the target as a result of nuclear reactions ¹⁵¹ Eu ( ³ He, 5n) ¹⁴⁹ Tb and / or ¹⁵³ Eu ( ³ He, 7n) ¹⁴⁹ Tb or ¹⁵¹ Eu ( ⁴ He, 6n) ¹⁴⁹ Tb and / or ¹⁵³ Eu ( ⁴ He, ⁸ n) ¹⁴⁹ Tb. 2. The method according to p. 1, characterized in that ¹⁴⁹ Tb are isolated from the irradiated target by electromagnetic isotope separation. 3. The method according to p. 1, characterized in that ¹⁴⁹ Tb is isolated from the irradiated target by solid-state extraction (extraction chromatography).