RU2542733C1 - Method of producing lutetium-177 radioisotope - Google Patents

Abstract

FIELD: physics, atomic power.

SUBSTANCE: invention relates to a method of producing isotopes for radiation medicine. The method includes irradiating a target with neutrons and separating ¹⁷⁷Lu from the irradiated target. The target used is the ¹⁷⁶Yb isotope. The target is irradiated with a stream of neutrons from a nuclear reactor. During the irradiation process, as a result of the nuclear reaction ¹⁷⁶Yb(n,γ)¹⁷⁷Yb, ¹⁷⁷Yb is generated in the target, the decay product of which is the desired ¹⁷⁷Lu (without a carrier), which is then separated by a chromatographic technique on an ion-exchange column. The eluent used to wash off ¹⁷⁷Lu from the column is a 0.07 N solution of α-isobutyric acid. The product is cleaned from α-isobutyric acid traces on a second ion-exchange column. The eluate is acidified to pH=1-2. ¹⁷⁷Lu is collected on the column and the eluate with α-isobutyric acid is discharged as wastes. The column is then washed with 100 ml of distilled water, followed by elution of ¹⁷⁷Lu with 10 ml of 0.5 N HCl. The eluate is evaporated dry and the residue is washed with HCl with pH=5.1.

EFFECT: producing the ¹⁷⁷Lu radioisotope without a carrier in significant amounts (tens of curies) on standard research reactors, using domestic raw materials and chemicals to produce, separate and clean the ¹⁷⁷Lu radioisotope, providing labelling quality during synthesis of radiopharmaceutical agents based on ¹⁷⁷Lu.

6 cl, 1 dwg

Description

The invention relates to reactor technology for producing radioisotopes for nuclear medicine.

Currently, one of the most promising and dynamically developing areas of nuclear medicine is radioimmunotherapy using targeted delivery vehicles and β-emitters as therapeutic agents.

Among the most promising β-emitting radioisotopes for cancer therapy, lutetium-177 ( ¹⁷⁷ Lu) can be distinguished, which has optimal characteristics for use in nuclear medicine: a convenient half-life (T _1/2 = 6.71 days), acceptable energy of β-particles ( E _max = 0.497 MeV), soft accompanying γ-radiation (E _γ = 113 keV (6.4%) and 208 keV (11%)). The decay product of ¹⁷⁷ Lu is the stable isotope ¹⁷⁷ Hf. The relatively short path length of the ¹⁷⁷ Lu β-particle in biological tissues (<2 mm) when a significant number of radioisotope atoms are localized in the immediate vicinity of the tumor cell provides selective destruction of the tumor with minimal damage to surrounding tissues.

Since ¹⁷⁷ Lu emits simultaneously β-particles and γ-quanta, it is ideally suited for both diagnosis and localization, and for the treatment of malignant neoplasms.

It is expected that radiopharmaceuticals (RFPs) based on ¹⁷⁷ Lu will become highly effective therapeutic agents in the treatment of cancer of the liver, prostate and skin integument, as well as other diseases, including rheumatoid arthritis and hemophilia.

Intensive search work in the field of obtaining and using drugs based on ¹⁷⁷ Lu is being carried out all over the world. The relevance of these studies is evidenced by the fact that more than 50 reports presented at the last congress of the European Association of Nuclear Medicine EANM'12 (Milan, October 2012) are devoted to the development and study of drugs for various purposes labeled with lutetium-177.

The present invention can be used for the production of the Lu-177 radioisotope in practically significant quantities in standard research reactors with a thermal neutron flux of up to 10 ¹⁴ sec ^-1 cm ^-2 , and domestic raw materials can be used to produce, isolate and purify the Lu-177 radioisotope and chemicals.

State of the art

At present, Lu-177 is obtained either as a result of the direct reaction of ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu, or through the intermediate nucleus of ¹⁷⁷ Yb by neutron irradiation of the ytterbium target by the reaction of ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb → ¹⁷⁷ Lu.

A known method for producing ¹⁷⁷ Lu by reaction ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu (Journal of Radioanalytical and Nuclear Chemistry, Vol. 277, No.3, 2008, 663-673).

The isotope ¹⁷⁶ Lu is irradiated in the reactor and ¹⁷⁷ Lu is produced by the direct reaction of ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu. The thermal neutron capture cross section for the ¹⁷⁶ Lu isotope exceeds 2 bar; the resonance integral is about 1 bar. As a result, ¹⁷⁷ Lu of sufficiently high specific activity can be obtained: by the radiation capture reaction of ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu, almost 28% of ¹⁷⁶ Lu atoms are converted to ¹⁷⁷ Lu.

However, this method has several significant disadvantages:

- this method allows to obtain the target radioisotope ¹⁷⁷ Lu with a carrier (in the raw material isotope ¹⁷⁶ Lu), which significantly reduces the scope of its application in nuclear medicine;

- the use of this method inevitably leads to the appearance in the target radioisotope ¹⁷⁷ Lu impurity long-lived activity ^177m Lu with a half-life of 160 days.

As a prototype, the method of obtaining ¹⁷⁷ Lu by the reaction of ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb with the formation of ¹¹⁷ Yb, its subsequent beta decay to ¹⁷⁷ Lu and the isolation of ¹⁷⁷ Lu by the radiochemical method of solid-phase extraction (Ketring, AR Production and Supply of High Specific) was chosen Activity Radioisotopes for Radiotherapy Applications. Alasbimn Journal 5 (19): January 2003. Article No. AJ19-2). A target weighing several milligrams of ytterbium nitrate enriched in Yb-176 to 97.6% in a quartz ampoule was irradiated with neutrons in a MURR reactor. After exposure for several hours, the target was dissolved in 500-700 ml of 0.1-0.5 N HCl.

Separation of ytterbium and lutetium was carried out by solid phase extraction using a "Ln spec" resin (50-100 μm) from the manufacturer Eichrom Industries of Darien, IL. The resin is a solution of di (2-ethylhexyl) orthophosphoricacid acid (HDEHP) (40% by weight) in an inert polymer sorbent Amberchrom ™ CG-71 (60% by weight). About 2 grams of resin was placed in a glass column and 0.15 N nitric acid was activated. Separation was controlled using a gamma spectrometer with a crystal from ultrapure germanium. First, the target material (Yb-176) was eluted from the column with small concentration of nitric acid, while the target radioisotope Lu-177 remained on the column. Then, with a small volume of more concentrated nitric acid, Lu-177 was washed off the column, evaporated to dryness and the precipitate was washed off with a weak HCl solution.

The disadvantages of this method include the following:

- in this method of separation of lutetium and ytterbium, specific resin is used that is not available in the public domain on the Russian market;

- in the considered method there is no very important technological operation for cleaning the target product, including from possible contamination with fragments of radiation destruction of the resin used.

Disclosure of invention

The technical result of the invention is to simplify and reduce the cost of production of the Lu-177 radioisotope without carrier in practically significant quantities (tens of curies) in standard research reactors with a thermal neutron flux of up to 10 ¹⁴ sec ^-1 cm ^-2 due to the use of the Lu- radioisotope for production and isolation 177 domestic raw materials and chemicals, which also leads to an increase in the purity of the final product.

To achieve this result, a method for producing a 177Lu radioisotope is proposed, including neutron irradiation in a nuclear reactor of a target with 176Yb isotope, production of the 177Lu target radioisotope 176Yb (n, γ) 177Yb □ 77177Lu of the target radioisotope, dissolution of the irradiated target, direction of the solution from 177Lu and 176Yb to ion exchange column deposition on a column from a solution of 176Yb and 177Lu and subsequent separation of 177Lu and 176Yb, while separating 177Lu and 176Yb by chromatography by initial elution with an 177Lu ion-exchange chromatographic column, leaving ytterbium on column, the direction of the eluate to the second ion-exchange chromatographic column, sorption of 177Lu on the second column, the direction of the eluate to waste, followed by elution from the second column 177Lu.

Wherein:

- ytterbium oxide (176Yb2O3) is used as a target with the 176Yb isotope;

- as an eluent for elution of 177Lu from the first ion exchange column, a 0.07 N solution of α-isobutyric acid is used;

- as an eluent for the elution of 177Lu from the second ion exchange column using 0.5 N HCl;

- as the ion-exchange resin on the first column using cation exchanger KU-2-8 in + NH ₄ form;

- as the ion exchange resin on the second column, KU-2-8 cation exchanger in + H-form is used.

The figure illustrates a schematic diagram of the implementation of the method of production, isolation and purification of 177Lu.

I - The technological operation of the allocation of 177Lu;

II - The technological operation of cleaning 177Lu;

Sorption column No. 1 — ion exchange column with KU-2-8 cation exchange resin in the + NH ₄ form;

Sorption column No. 2 is an ion-exchange column with KU-2-8 cation exchange resin in + H-form.

The method is as follows.

The target charge isotope Yb-176, the target is irradiated with a stream of a nuclear reactor neutrons during irradiation in the nuclear reaction ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb in the target brings ever ¹⁷⁷ Yb, disintegration product of which: the target radioisotope ¹⁷⁷ Lu (without carrier ) then isolated by the radiochemical method.

The proposed method for producing a radioisotope ¹⁷⁷ Lu has significant advantages compared to the analogue and prototype described in the literature:

- the method allows to produce the Lu-177 radioisotope without a carrier in practically significant quantities (tens of curies) on standard research reactors with a thermal neutron flux of up to 10 ¹⁴ sec ^-1 cm ^-2 and use domestic raw materials for production, isolation and purification of the Lu-177 radioisotope and chemical reagents;

- the method includes a technological operation of purification of the target product, which ensures the quality of labeling in the synthesis of radiopharmaceuticals based on Lu-177.

An example embodiment of the invention

A powder sample of ytterbium oxide ^l76 Yb ₂ O ₃ weighing 10 mg was poured into the inner cavity of a quartz ampoule. The diameter of the ampoule is 7.8 mm, the length is 72.5 mm, and the wall thickness is 1.5 mm. The ampoule was hermetically sealed and placed in a protective aluminum container. Samples of ¹⁷⁶ Yb ₂ O ₃ were irradiated in a vertical experimental channel VEK 3 located in a stationary beryllium reflector of the IR-8 reactor. The neutron flux density at the location of the samples was 6.5 × 10 ¹² n × cm ² × s ^-1 per 1 MW of reactor power. The exposure time was 1 day. The exposure time after irradiation is 1 day. The reaction rate of ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb → ¹⁷⁷ Lu amounted to 1.86 × 10 ^-11 per nucleus of ¹⁷⁶ Yb in a neutron flux of 6.5 × 10 ¹² cm ^-2 × s ^-1 . The activity of sample ¹⁷⁷ Lu amounted to 5 · 10 ⁷ Bq. Measurement error ± 5%.

After irradiation and exposure, the quartz ampoule was mechanically opened, and the irradiated target ¹⁷⁶ Yb ₂ O ₃ weighing 10 mg (enrichment by ¹⁷⁶ Yb 99.75%) was dissolved in 50 ml of 0.5 N HCl. The solution was evaporated to a wet cake. The precipitate was diluted with distilled water to pH = 2 (0.01 N HCl). The solution with ¹⁷⁶ YbCl ₃ and ¹⁷⁷ LuCl ₃ with a flow rate of 0.5–2.0 cm ³ / min was eluted through an ion exchange column with KU-2-8 cation exchange resin in the ⁺ NH ₄ form. Column height h = 150 mm, diameter d = 5 mm, h / d≈30. In this case, ¹⁷⁶ Yb and ¹⁷⁷ Lu were sorbed on a column. Then, the column was washed with 100 ml of distilled water, after which it was eluted from a column of ¹⁷⁷ Lu with 100 ml of a 0.07 N solution of α-isobutyric acid, while ¹⁷⁶ Yb remained on the column.

To purify Lu-177 from α-isobutyric acid, the eluate was acidified to pH = 1-2 and passed through a second ion-exchange column with KU-2-8 cation exchange resin in ⁺ H-form. Column height h = 75 mm, diameter d = 5 mm. In this case, Lu-177 was sorbed on a column, and the eluate with α-isobutyric acid was sent to waste. Then, the column was washed with 100 ml of distilled water, after which Lu-177 was eluted with ten milliliters of 0.5 N HCl. The eluate was evaporated to dryness and the precipitate was washed with HCl with pH = 5.

The composition of the eluents was monitored by gamma radiation using an ORTEC gamma spectrometer with an ultrapure germanium crystal. The activity of Lu-177 was determined by the line E _γ = 208 keV, the presence of ytterbium was controlled by the line E _γ = 397 keV, belonging to Yb-175, formed upon irradiation as a result of the reaction ¹⁷⁴ Yb (n, γ) ¹⁷⁵ Yb (content of ¹⁷⁴ Yb in the initial sample - 0.12%).

Claims (6)

1. A method for producing a ¹⁷⁷ Lu radioisotope, including neutron irradiation in a nuclear reactor of a target with the ¹⁷⁶ Yb isotope, operating time of the ¹⁷⁷ Lu target radioisotope ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb → ¹⁷⁷ Lu, dissolution of the irradiated target, solution direction with ¹⁷⁷ Lu and ¹⁷⁶ Yb on an ion-exchange column, deposition on a column from a solution of ¹⁷⁶ Yb and ¹⁷⁷ Lu and the subsequent separation of ¹⁷⁷ Lu and ¹⁷⁶ Yb, characterized in that
separated by ¹⁷⁷ Lu and ¹⁷⁶ Yb by chromatography by initial elution from an ¹⁷⁷ Lu ion-exchange chromatographic column, leaving ytterbium on the column, eluate directions to the second ion-exchange chromatographic column, ¹⁷⁷ Lu sorption on the second column, directing the eluate to the waste, followed by elution from the second column ¹⁷⁷ Lu. 2. The method according to claim 1, characterized in that ytterbium oxide ( ¹⁷⁶ Yb ₂ O ₃ ) is used as a target with the ¹⁷⁶ Yb isotope. 3. The method according to claim 1, characterized in that a 0.07 N solution of α-isobutyric acid is used as an eluent for elution of ¹⁷⁷ Lu from the first ion exchange column. 4. The method according to claim 1, characterized in that 0.5 N HCl is used as an eluent for elution of ¹⁷⁷ Lu from a second ion exchange column. 5. The method according to claim 1, characterized in that cation exchanger KU-2-8 in + NH ₄ form is used as the ion-exchange resin on the first column. 6. The method according to claim 1, characterized in that the KU-2-8 cation exchanger in + H form is used as the ion exchange resin on the second column.