RU2803641C1 - Method of producing radioisotope i-161 - Google Patents

Abstract

FIELD: nuclear medicine.

SUBSTANCE: invention relates to reactor technology for producing radioisotopes for nuclear medicine and can be used to produce the radioisotope ¹⁶¹Tb in quantities sufficient for therapy in research reactors with a thermal neutron flux of 10¹⁴ s^-1 cm^-2. The method is based on irradiation of enriched gadolinium-160 in a reactor with a neutron flux with an intensity of up to 10¹⁴ s^-1 cm^-2 through the intermediate formation of the short-lived isotope¹⁶¹ Gd according to the reaction¹⁶⁰ Gd(n,γ) ¹⁶¹Gd→ ¹⁶¹Tb followed by dissolving the target material in 7 M HNO₃ and sequentially passing through columns filled with sorbent: (1) based on N,N,N',N'-tetra-n-octyldiglycolamide, (2) di-2-ethylhexylphosphoric acid, (3) N,N,N',N'-tetra-n-octyldiglycolamide and (4) an acrylic ester polymer. The first column is used to concentrate ¹⁶¹Tb and reduce the acidity of the medium to 0.01 M HNO₃. The second column is used for the main separation of Gd and Tb. Elution of Gd is carried out with 0.58 M HNO₃, ¹⁶¹Tb — 0.7 M HNO₃. The third column is used to concentrate ¹⁶¹Tb and remove traces of nitric acid. Elution of ¹⁶¹Tb is carried out with 0.05 M HCl. The fourth column is used to remove traces of organic matter.

EFFECT: technical result is to increase the yield and radionuclide purity of 161Tb without a carrier in research reactors with a thermal neutron flux up to 1,014 s^-1 cm^-2.

3 cl, 3 dwg

Description

Technical field

The invention relates to reactor technology for producing radioisotopes for nuclear medicine and can be used to produce the radioisotope ¹⁶¹ Tb in quantities sufficient for therapy in research reactors with a thermal neutron flux of 10 ¹⁴ s ^-1 cm ^-2 .

State of the art

Currently, approaches involving a combination of therapy and diagnostics are being intensively developed in nuclear medicine. In this case, the role of a therapeutic factor is played by corpuscular radiation, which affects cancer cells, and the role of a diagnostic factor is played by photon radiation, which makes it possible to perform molecular visualization using single-photon emission computed tomography (SPECT). In this regard, radionuclides that combine low-energy beta radiation with soft gamma radiation are of great interest. The radionuclide ¹⁶¹ Tb ideally meets these requirements (T _½ - 6.89 days; E _βav = 154 keV; Eγ = 74.6 keV (10%)). In terms of its nuclear physical characteristics, it is close to ¹⁷⁷ Lu, however, as shown in animal experiments, it is somewhat superior in therapeutic properties. (Eur. J. Nucl. Med. Mol. Imaging (2014) 41:1907-1915) [1]. The advantage of ¹⁶¹ Tb compared to ¹⁷⁷ Lu is its ability to emit Auger electrons during radioactive decay, which act as an additional damaging factor on a cellular scale.

Currently, work on terbium-161 in the world is at the stage of preclinical research; it is expected to be used in the form of targeted drugs based on peptides and antibodies. Similar drugs based on lutetium-177 are in various stages of clinical trials, and one of them has received FDA approval.

Currently, ¹⁶¹ Tb is produced by irradiation with ¹⁶⁰ Gd neutrons through the intermediate formation of ¹⁶¹ Gd according to the reaction ¹⁶⁰ Gd(n,γ) ¹⁶¹ Gd→ ¹⁶¹ Tb (Nucl. Med. Biol. 38 (2011) 917-924). [2].

There is also a known method for the cyclotron production of ¹⁶¹ Tb using the reaction ¹⁶⁰ Gd(d,x) ¹⁶¹ Tb (J. Radioanal. Nucl. Chem. 298 (2013) 1385-1392.) [3]. However, this method has a significant drawback:

- the use of this method inevitably leads to the appearance in the target radioisotope ¹⁶¹ Tb of a long-lived impurity ¹⁶⁰ Tb with a half-life of 72.3 days in an amount of about 20% in activity. Isotopic separation requires electromagnetic separation, which will result in unacceptable costs to produce the product.

The closest in technical essence to the claimed invention is a method for producing ¹⁶¹ Tb by irradiating ¹⁶⁰ Gd with neutrons through the intermediate formation of ¹⁶¹ Gd by the reaction ¹⁶⁰ Gd(n,γ) ¹⁶¹ Gd→ ¹⁶¹ Tb with subsequent isolation ^{of 161} Tb by radiochemical method (EJNMMI Radiopharm. Chem. 4 (2019) 12) [4]. A target weighing about 30 mg of gadolinium oxide, enriched with ¹⁶⁰ Gd to 98.2% in a quartz ampoule, was irradiated with neutrons for 2 weeks at the SAFARI-1 reactor with a neutron flux of up to 1.8⋅10 ¹⁴ s ^-1 cm ^-2 . After holding for 24 hours, the target was dissolved in 2.0 ml of 7.0 M nitric acid, the solution was evaporated at 80°C in a stream of nitrogen, and the residue was dissolved in 0.1 M ammonium nitrate. The separation of a solution of gadolinium and terbium was carried out by solid-phase extraction (SPE) - namely, ion exchange on a 10x170 mm column filled with macroporous Sykam cation exchange resin (Sykam Chromatographie Vertriebs GmbH, Germany) in NH ₄ ⁺ - form with a particle size of 12- 22 microns. Elution was performed with 0.13 M α-hydroxyisobutyric acid (α-HIBA) solution (pH 4.5). In this case, first the terbium was washed off the column, then the gadolinium. Concentration of ¹⁶¹ Tb was carried out using LN3 extraction chromatographic resin based on bis(2,4,4-trimethyl-1-pentyl)phosphinic acid (Triskem International, France) on a 6x5 mm column, followed by elution of the final product ( ¹⁶¹ TbCl ₃ ) in 500 μl of 0.05 M hydrochloric acid.

The disadvantages of this method include the following:

- this separation method uses the principle of solid phase extraction (SPE), namely the ion exchange method, which has low selectivity towards rare earth elements (Gd/Tb separation coefficient on the Sykam cation exchange resin is 1.9 compared to 5.7 for the organophosphorus sorbent di- 2-ethylhexylphosphoric acid (D2EHPA) - in the claimed method, which affects the final yield of the target product and is associated with a labor-intensive process using large-volume columns and high-pressure pumps

- this method uses a lengthy procedure, potentially associated with losses and contamination, of evaporating a radioactive solution containing ¹⁶¹ Tb and gadolinium;

- the method under consideration does not provide for the purification of the target product from contamination with organic substances, including products of radiolysis of the resin used, which reduces the efficiency of labeling biomolecules in the production of radiopharmaceuticals based on ¹⁶¹ Tb.

The technical problem to be solved by the claimed invention is the improvement of the process of production of the radioisotope ¹⁶¹ Tb for medical purposes.

Technical essence of the invention.

The technical result of the claimed invention is the production of the ¹⁶¹ Tb radioisotope without a carrier in higher yield and high radionuclide purity in research reactors with a thermal neutron flux of up to 10 ¹⁴ s ^-1 cm ^-2 .

To achieve a technical result, ^a method for producing the ¹⁶¹ Tb radioisotope is proposed, including neutron irradiation in a nuclear reactor of a target with the ¹⁶⁰ Gd isotope, production of the target 161 Tb radioisotope by the reaction ¹⁶⁰ Gd(n/γ) ¹⁶¹ Gd→ ¹⁶¹ Tb, dissolution of the irradiated target in concentrated nitric acid with obtaining a solution containing gadolinium and ¹⁶¹ Tb, as well as separation of gadolinium and ¹⁶¹ Tb radionuclides and isolation of the target radioisotope, and separation of gadolinium and ¹⁶¹ Tb radionuclides and isolation of the target radioisotope is carried out by the method of solid phase extraction, which consists in sequentially passing a solution of radionuclides through chromatographic columns filled with sorbent, what is new is that to implement the solid-phase extraction method, the resulting solution with ¹⁶¹ Tb and gadolinium is passed through the first extraction column with a resin based on N,N,N',N'-tetra-n-octyldiglycolamide or N,N,N',N'-tetracis-2-ethylhexyldiglycolamide, wash off ¹⁶¹ Tb and Gd from the column with dilute nitric acid, load the wash onto a second column with D2EHPA, elute from the Gd column with a solution of 0.58 M HNO ₃ , after removing Gd, elute from the column with ¹⁶¹ Tb solution 0.7 M HNO ₃ , load the washout from ¹⁶¹ Tb onto the third column with DGA Resin sorbent, remove traces of nitric acid by washing the column with 2 M HCl, wash off the ¹⁶¹ Tb column with 0.05 M HCl, and further purify the solution with ¹⁶¹ Tb from traces of organic compounds by passing it through a fourth column of hydrophilic macroporous Prefilter resin.

In addition, hydrochloric acid solutions are used to separate radionuclides on the second column with D2EHPA.

In addition, 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester is used to separate radionuclides on the third column.

In addition, a C18 chromatographic sorbent based on hydrophobized silica gel is used to remove organic impurities.

Description of drawings

In fig. Figure 1 shows a schematic diagram of the implementation of the method for producing, isolating and purifying ¹⁶¹ Tb.

In fig. Figure 2 shows the elution profiles of Gd - Tb on Ln resin in a nitric acid medium with a column load of 10 mg/g.

In fig. Figure 3 shows the elution profile of Tb on a column with a mass of DGA of 0.1 g. Terbium was loaded in a volume of 70 ml, then elution with 0.05 M HCl began.

Carrying out the invention

The essence of the method, the diagram of which is shown in Fig. 1 consists in irradiating a target of ¹⁶⁰ Gd with neutrons and radiochemical separation ^{of 161} Tb from the irradiated target.

The method is carried out as follows.

The target material used is gadolinium oxide Gd ₂ O ₃ , enriched in the ¹⁶⁰ Gd isotope. The target is irradiated with a flow of neutrons in a nuclear reactor, and as a result of the nuclear reaction ¹⁶⁰ Gd(n,γ) ¹⁶¹ Gd, ¹⁶¹ Gd is formed in the target, the decay product of which - the target radioisotope ¹⁶¹ Tb (without a carrier) - is then isolated by solid-phase extraction. A powdered sample of gadolinium oxide ¹⁶⁰ Gd ₂ O ₃ (enriched in ¹⁶⁰ Gd 97.8%) weighing 10 mg in terms of metal was poured into the internal cavity of a quartz ampoule. Ampoule diameter 7.8 mm, length 72.5 mm, wall thickness 1.5 mm. The ampoule was hermetically sealed and placed in a protective aluminum container. A sample of ¹⁶⁰ Gd ₂ O ₃ was irradiated in the horizontal experimental channel of the IR-8 reactor. The neutron flux density at the location of the samples was ~10 ¹³ cm ^-2 s ^-1 . Irradiation time is 18 hours, exposure time after irradiation and cooling of the target is 5 days. The activity of the ¹⁶¹ Tb sample was 2⋅10 ⁷ Bq. Measurement error ±5%.

After irradiation and exposure, the quartz ampoule was mechanically opened, and the irradiated target was ¹⁶⁰ Gd ₂ O ₃ enriched in the ¹⁶⁰ Gd isotope. weighing 10 mg (in terms of metal) was dissolved in 5 ml of 7 M HNO ₃ . The solution was passed through a 2.5 ml column filled with DGA Resin sorbent (Triskem International), which is N,N,N',N'-tetra-n-octyldiglycolamide supported on a styrene copolymer with divenylbenzene. To fill the column, 1 g of dry sorbent was used, which was pre-equilibrated with 7 M HNO ₃ for an hour. Then 0.01 M HNO ₃ was passed through the column, monitoring the yield of ¹⁶¹ Tb by gamma spectrometry. The quantitative yield of ¹⁶¹ Tb was 96±3%). The volume of the fraction containing ¹⁶¹ Tb is about 10 ml. At this stage, only partial separation of the product from the target material is achieved, but the solution acquires the acid concentration required for further procedures. Further separation was carried out on a chromatographic column with an internal diameter of 4 mm and a height of 22 cm, filled with an organophosphorus sorbent based on di-2-ethylhexylphosphoric acid (D2EHP) LN Resin (Triskem International). To fill the column, 1 g of sorbent was used, pre-equilibrated with 0.58 M HNO ₃ . The irradiated target solution was loaded onto the column and eluted with 0.58 M HNO ₃ . Fractions leaving the column were monitored gamma spectrometrically using a spectrometer with an ultrapure germanium detector. The presence of gadolinium was monitored by the peak ¹⁵⁹ Gd 363.543 keV (11.78%). The presence of terbium was monitored by peak 74.567 (10.2%). Gadolinium was washed off the column in a small volume of 0.58 M HNO ₃ . After the ¹⁵⁹ Gd peak was no longer detectable, the concentration of nitric acid was increased to 0.7 M. The quantitative yield of ¹⁶¹ Tb was 85 ± 1%. The volume of the terbium fraction was 50-70 ml. After the terbium fraction had been completely washed away, the nitric acid concentration was increased to 2 M to clear the column of anything that could still be retained by the sorbent (for example, dysprosium formed during the radioactive decay of terbium) in order to prepare it for reuse. The elution profile is illustrated in Fig. 2. After this, the terbium fraction was passed through a small column filled with DGA Resin sorbent (Triskem International). The mass of dry sorbent used to fill the column was 0.1 g. The sorbent was pre-equilibrated with 0.7 M HNO ₃ . Under these conditions, terbium is strongly sorbed on DGA. The column was then washed with 5 mL of 2 M HCl to remove traces of nitric acid. Terbium was then washed off with 12 ml of 0.05 M HCl. The quantitative yield of ¹⁶¹ Tb was 96±3%). The elution profile is shown in Fig. 3. Further purification from traces of organics was carried out on the fourth column using a hydrophilic macroporous Prefilter resin, which is an acrylic ester polymer with a pore size of approximately 25 nm (Triskem International).

The quantitative yield for ¹⁶¹ Tb was 98%.

The final quantitative yield is 77±5%. Using this method, a sample of ¹⁶¹ Tb with an activity of 144 MBq was obtained by irradiating a target with the ¹⁶⁰ Gd isotope weighing 10 mg for 18 hours and cooling the target for 5 days. The activity of ¹⁶¹ Tb in the irradiated target was 188 MBq.

The proposed method for obtaining the radioisotope ¹⁶¹ Tb has significant advantages compared to those described in the prototype and analogue:

- the procedure associated with the evaporation of a solution of radioisotopes ¹⁶¹ Tb and gadolinium in a stream of nitric acid is excluded from the technological chain, which leads to losses of the target product and a change in the acidity of the initial target solution. It is replaced by more technologically advanced steps of concentration on column 1 and elution; this reduces wastage and improves product purity.

- separation of ¹⁶¹ Tb from the target material occurs more efficiently (with a higher yield) due to the replacement of the cation-exchange sorbent in the prototype on an organophosphorus basis in the form of D2EHPA in the claimed method, which has greater selectivity to the Gd/Tb pair;

- the introduction of an additional stage of purification of the target product makes it possible to get rid of organic impurities, including those formed as a result of radiolysis of materials, which increases the degree of purification of the target product, and, consequently, the efficiency of labeling biomolecules in the production of radiopharmaceuticals based on ¹⁶¹ Tb.

Literature

1. Eur. J. Nucl. Med. Mol. Imaging (2014) 41:1907–1915

2. Nucl. Med. Biol. 38 (2011) 917-924).

3. J. Radional. Nucl. Chem. 298 (2013) 1385-1392

4. EJNMMI Radiopharm. Chem. 4 (2019) 12 – prototype.

Claims (3)

1. A method for producing the radioisotope ¹⁶¹ Tb, including neutron irradiation in a nuclear reactor of a target with the isotope ¹⁶⁰ Gd, production of the target radioisotope ¹⁶¹ Tb by the reaction ¹⁶⁰ Gd(n,γ) ¹⁶¹ Gd→ ¹⁶¹ Tb, dissolution of the irradiated target in concentrated nitric acid to obtain a solution , containing gadolinium and ¹⁶¹ Tb, and the separation of gadolinium and ¹⁶¹ Tb radionuclides and the isolation of the target radioisotope, wherein the separation of gadolinium and ¹⁶¹ Tb radionuclides and the isolation of the target radioisotope is carried out by the solid-phase extraction method, which consists in sequentially passing a solution of radionuclides through chromatographic columns filled with a sorbent, characterized in that that to implement the solid-phase extraction method, the resulting solution with ¹⁶¹ Tb and gadolinium is passed through the first extraction column with a resin based on N,N,N',N'-tetra-n-octyldiglycolamide, ¹⁶¹ Tb and Gd are washed off from the column with dilute nitric acid, load the washout onto the second column with D2EHPA, elute from the Gd column with a solution of 0.58 M HNO ₃ , after removing Gd, elute from the ¹⁶¹ Tb column with a 0.7 M HNO ₃ solution, load the washout with ¹⁶¹ Tb onto the third column with DGA Resin sorbent, remove traces of nitric acid, washing the column with 2 M HCl, are washed off from the ¹⁶¹ Tb column with 0.05 M HCl, while the solution with ¹⁶¹ Tb is additionally purified from traces of organic compounds by passing it through the fourth column with hydrophilic macroporous Prefilter resin. 2. The method according to claim 1, characterized in that hydrochloric acid solutions are used to separate radionuclides on the second column with D2EHPA. 3. The method according to claim 1, characterized in that 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester is used to separate radionuclides on the third column.