System for producing 44sc solutions and synthesizing radiopharmaceuticals based on them

Abstract

FIELD: medicine.SUBSTANCE: system has been revealed for obtaining 44Sc solutions and synthesizing radiopharmaceuticals based on them, containing a 44Ti / 44Sc radionuclide generator in the form of a chromatographic column as a source of 44Sc, wherein the chromatographic column is made with a solid-phase extractant based on alkyl ammonium chloride as a sorbent for retaining 44Ti. The system contains a container with a solution based on a mixture of oxalic and hydrochloric acids for eluting 44Sc, an additional chromatographic column for carrying out the procedure of post-processing of the generator eluate, which contains a cation exchange resin as a sorbent, with sulfonic acids used as functional groups in it, in addition, the system contains a container with aqueous solutions of sodium salts of carboxylic acids used as an eluent for desorption of 44Sc from an additional chromatographic column, and also contains a container with an aqueous solution of the precursor and a thermostatted reaction container for carrying out the synthesis of radiopharmaceuticals.EFFECT: high operational stability, reproducibility of the main parameters over a long period of time, long service life, ease of operation, high yield of 44Sc and low breakthrough of 44Ti into the eluate.9 cl, 5 dwg, 4 tbl, 3 ex

Description

[0001] The invention relates to medicine, namely to radionuclide generators for producing physiologically acceptable solutions 44 Sc used in the synthesis of radiopharmaceutical drugs (RPDs) used in diagnostics by positron emission tomography (PET) for clinical diagnostics and research purposes.

[0002] Due to its nuclear-physical characteristics It is a promising radionuclide for use in PET diagnostics, enabling the acquisition of high-contrast tomograms at late time intervals (up to 24 hours) after the administration of radiopharmaceuticals containing it. Moreover, the coordination chemistry of scandium is similar to that of lanthanides and yttrium, which explains the similarity in the properties and structure of the radioconjugates. Therefore, 44 Sc can be used as a diagnostic radionuclide in combination with therapeutic radionuclides of rare earth elements ( 90 Y,153 Sm, 161 Tb, 177 Lu). 44 Sc can be produced in a cyclotron by irradiating calcium targets ( 44 Ca(p,n) 44 Sc) and also from a radionuclide generator through the decay of the parent radionuclide which can be obtained by irradiating targets made of scandium of natural isotopic composition There are currently no commercially available radionuclide generators. and all known developments are at the prototype stage.

[0003] So, a radionuclide generator is known from the prior art 44 Ti / 44 Sc based on ZR resin [1]. Sorption 44 Ti (101.2 MBq) in an aqueous solution of 6 M HCl is carried out on ZR hydroxamate resin, using an aqueous solution of 0.05 M HCl as the eluent, with the yield 44 Sc is 82.9±5.3% (for 16 elutions). This generator system allows for the immediate production of solutions physiologically acceptable for the synthesis of RFLPs. 44Sc (without additional conditioning procedures), which can be directly incorporated into the radiopharmaceutical synthesis scheme. The disadvantage of this generator system is the instability of the sorption front of the parent 44 Ti, which is why it is necessary to use a complex method of bidirectional elution of the generator and install additional protective cartridges with inactive ZR resin to reduce the amount of breakthrough 44 Ti (up to 2.3×10 -2 %), which are extremely high for medical applications, as well as in the context of long-term generator operation.

[0004] A radionuclide generator is also known from the prior art 44 Ti / 44 Sc based on an inorganic sorbent - tin dioxide (SnO2) [2]. Sorption 44 Ti (7.4 MBq) on SnO2 is eluted in an aqueous solution of 0.1 M HNO3 for 6.5 hours with a sorption efficiency of ≥91%. A solution of 5 M HNO3 is used for elution, with the yield 44Sc is 84.7±9.5%, and the breakthrough 44 Ti 0.14±0.15%. The use of tin dioxide can prevent sorbent degradation under the influence of ionizing radiation (typical of sorbents based on ion-exchange resins) and maintain a stable sorption front during long-term operation of the generator. However, for this generator 44 Ti / 44 Sc is known for its relatively short operating life (3 months), which is one of the drawbacks of this generator system. Another drawback is that the resulting end product—the eluate—is 44 Sc in 5 M HNO3 does not allow its direct use for the synthesis of RFLP, and the breakthrough value 44 Ti is characterized by an unacceptably high value of 0.14±0.15%.

[0005] Also known about radionuclide generator 44 Ti / 44 Sc, based on Bio-Rad AG 1×8 resin [3]. Sorption 44Ti (185 MBq) in an aqueous solution of 2 M HCl is carried out on an anion exchange resin Bio-Rad AG 1×8, 20 ml of an aqueous solution of a mixture of 0.005 M oxalic and 0.07 M hydrochloric acids is used as an eluent, and elution is carried out by a bidirectional method, with the yield 44 Sc is 97% for 54 elutions carried out over one year. This generator system is characterized by a relatively low breakthrough of the parent 44 Ti (5×10 -5 %), and the loading value 44 Ti (185 MBq) allows for the synthesis of radiopharmaceuticals based on 44 Sc with clinically significant activity values ​​(50-70 MBq). The disadvantages of this technology include the presence of oxalic acid in the eluate, which negatively affects the efficiency of incorporation. 44Sc into the structure of vector molecules, which requires additional solution purification procedures, and the large eluate volume (20 ml) makes their implementation more complex. Furthermore, generator elution 44 Ti / 44 Sc is not performed using a standard bidirectional method, which is difficult to implement in the case of routine clinical use of the generator, and the short operating period (including only 54 elutions) does not guarantee the reliability of this generator. 44 Ti / 44 Sc and its characteristics need to be clarified at later stages of use.

[0006] The closest to the declared technical solution is the generator 44 Ti / 44 Sc, based on TEVA resin (Aliquat® 336) [4], loaded 44 Ti 5 MBq. 1 ml of a 0.1 M oxalic acid solution in 0.2 M hydrochloric acid is used as an eluent, with the yield 44 Sc is 91±6%, and the breakthrough 44 Ti ≤ 1.5×10 -5% for 120 generator elutions. Since the presence of oxalic acid makes direct use of the resulting solutions difficult 44 Sc in the schemes for the synthesis of radiopharmaceuticals, a procedure for conditioning the generator eluate was proposed based on the conversion of the solution 44 Sc using two chromatographic columns: the first was filled with Presep PolyChelate resin (a resin immobilized with carboxymethylated pentaethylenehexamine), and the second with TK-221 resin (based on a mixture of diglycolamide and phosphine oxide on an inert support). As a result of this procedure, a solution was obtained 44 Sc in 0.5 ml of 1 M ammonium acetate solution (pH 4.5) with an efficiency of ≥92%.

[0007] Disadvantages of the well-known generator:

[0008] Short period of generator operation 44 Ti / 44Sc, which includes only 120 elutions during the year, requires clarification of its characteristics at later stages of use, since the presented data do not guarantee the reliability of this generator system when introduced into routine clinical practice.

[0009] Presep PolyChelate resin has been discontinued, requiring the development of a new conditioning procedure and preventing the commercialization of this generator system.

[0010] Two-column generator eluate purification system, which makes the conditioning process complex and time-consuming, resulting in loss of activity 44 Sc, due to the decay of the radionuclide.

[0011] Low activity of loaded motherboard 44 Ti (5 MBq), which limits the use of the generator in routine clinical practice.

[0012] These circumstances presented the authors with the task of developing a system for obtaining solutions 44Sc and the synthesis of radiopharmaceuticals based on them, which meets the following requirements: reliability and long service life, ease of operation, high yield 44 Sc, small slip 44 Ti in eluate, an efficient and fast method for converting solutions 44 Sc into a physiologically acceptable form, allowing solutions to be obtained 44 Sc, suitable for the synthesis of radiopharmaceutical drugs. Thus, the aim of the invention is to eliminate the main drawbacks of the known radionuclide generator 44 Ti / 44 Sc, achieving greater reliability and increased stability of the generator system and reproducibility of the main parameters over a long period of time.

[0013] The problem is solved due to the fact that in the system for obtaining solutions 44 Sc and the synthesis of radiopharmaceuticals based on them, containing as a source 44 Sc radionuclide generator 44 Ti / 44Sc in the form of a chromatographic column, according to the invention, the chromatographic column is made with a solid-phase extractant based on alkyl ammonium chloride as a sorbent for retention 44 Ti, wherein the system contains a container with a solution based on a mixture of oxalic and hydrochloric acids for elution 44 Sc, an additional chromatographic column for carrying out the post-processing procedure of the generator eluate, which contains a cation exchange resin as a sorbent, with sulfonic acids used as functional groups in it, in addition, the system contains a container with aqueous solutions of sodium salts of carboxylic acids used as an eluent for desorption 44 Sc with an additional chromatographic column, and also contains a container with an aqueous solution of the precursor and a thermostatted reaction container for carrying out the synthesis of radiopharmaceuticals.

[0014] In this case, the solid-phase extractant can be made on the basis of a quaternary ammonium salt, N-methyl-N,N-dioctyl octane ammonium chloride on an inert carrier.

[0015] Also as an elution solution 44 Sc may contain aqueous solutions of a mixture of 0.1 M oxalic acid in 0.05-0.2 M hydrochloric acid.

[0016] Additional chromatographic column designed for conversion of generator eluate 44 Ti / 44 Sc in a form suitable for the synthesis of radiopharmaceuticals contains a cation exchange resin as a sorbent, which can be silicon dioxide modified with propylsulfone groups.

[0017] At the same time for sorption 44 Sc on a silicon dioxide sorbent modified with propylsulfone groups may contain a generator eluate solution, a mixture of 0.1 M oxalic and 0.05-0.2 M hydrochloric acids.

[0018] Or an additional chromatographic column designed for conversion of the generator eluate 44 Ti / 44 Sc in a form suitable for the synthesis of radiopharmaceuticals contains a cation exchange resin as a sorbent, which can be made from a copolymer of styrene and divinylbenzene modified with sulfone groups.

[0019] In this case, for sorption 44 Sc on a sorbent made of a copolymer of styrene and divinylbenzene modified with sulfone groups may contain a solution of 0.02 M oxalic and 0.01-0.04 M hydrochloric acids.

[0020] In all the described embodiments, the system may contain ethanol or water to wash the sorbent and remove residual eluent from it, regardless of the nature of the sorbent.

[0021] Also a desorption system 44The sorbent may contain aqueous solutions of sodium salts of carboxylic acids, such as acetate, pyruvate, malate, lactate, or sodium succinate, each of which can be used with equal efficiency.

[0022] The technical result is the creation of a system for obtaining solutions 44 Sc, and the synthesis of radiopharmaceuticals based on them, characterized by high reliability (stability of the generator system and reproducibility of the main parameters over a long period of time), long service life and ease of operation, giving a high yield 44 Sc, small slip 44 Ti in the eluate, providing an efficient and rapid method for converting solutions 44 Sc into a physiologically acceptable form and the synthesis of radiopharmaceuticals based on them.

[0023] The following concepts are included in the terms of the technical result:

[0024] Stability. This refers to the stability of the sorption front of the parent radionuclide in the generator column. As the generator system operates, 44 Ti, its sorption front, moves along the carrier inside the column from its beginning to its end (see Figure 1). For the analogue [3], this movement occurs too quickly - with the standard generator elution method, after 50 elutions, the sorption front is destroyed and the parent radionuclide ( 44 Ti) is completely eluted from the generator column. Our solution also exhibits movement, but it is extremely slow, ensuring a stable sorption front in the column, guaranteeing its intended service life (at least two years and 320 elutions).

[0025] Reproducibility. By this we mean that high yields are observed from elution to elution. 44 Sc at low slip 44Ti (from all published studies to date, not just in comparison with an analog) over the entire service life of the generator. That is, this generator system provides the specified values ​​of these two indicators both at the initial and final stages of use (operational life). For the analog, an increase in the number of elutions led to an increase in the breakthrough value. 44 Ti in the eluate, which required the use of special (non-standard) generator elution methods 44 Ti / 44 Sc. Long service life

[0026] Compared to the analog [3], which was used for one year and 54 elutions were carried out, our system can be used for two years with 320 elutions. Our system with such characteristics can be supplied to clinical centers, where it will provide access to 44 Sc for the synthesis of radiopharmaceuticals and the synthesis of radiopharmaceuticals based on them directly in clinical centers in the quantities required for them.

[0027] Ease of operation. Our difference from the comparable system is the use of a unidirectional generator elution method or the standard generator system elution method. This is also illustrated in Figure 2. The comparable system is based on a reversible elution method or bidirectional elution. This requires constantly changing the eluent flow in the column, making the technology more complex to implement than our system. Our solution also eluted 1 ml, compared to 20 ml for the comparable system, which further simplifies the process.

[0028] Regarding the result of "high output 44 Sc» our system demonstrates a high value - 95±3%, not inferior to the analogue [3].

[0029] Under the "small slip" 44 Ti" means an extremely low amount of the parent radionuclide ( 44 Ti), which enters the eluate, which ensures high radionuclide purity of the resulting solutions 44Sc, not contaminated with a long-lived radionuclide. For our system, the breakthrough 44 Ti is (2.5±1.3)×10 -7 % and is not inferior to the analogue [3]. This result is currently the minimum breakthrough value 44 Ti among all known prototypes of radionuclide generators in the world 44 Ti / 44 Sc chromatographic type. By "effective method of solution conversion" 44 Sc" implies that the proposed technological solutions in our system allow for the generator eluate conditioning procedure to be carried out with low losses 44 Sc - less than 20%. This is achieved due to the extremely high sorption yield. 44 Sc on the sorbent is ≥99% (regardless of its nature), with insignificant losses of radionuclide during washing of the sorbent and high desorption yield 44 Sc (up to 95%) obtained using eluents based on aqueous solutions of sodium salts of carboxylic acids.

[0030] Under the "rapid method of conversion of solutions 44 Sc into a physiologically acceptable form” is understood as follows: the conversion process occurs in one stage and does not require working with large volumes (unlike the analogue [3], where the volume of the eluate is 20 ml), therefore it can be performed with minimal losses of the target product ( 44 Sc), caused by the decay processes of the radionuclide.

[0031] The set of elements of the system, interconnected and in constructive unity and functional interrelation, the joint use of which leads to the achievement of the specified technical results, is explained by the following materials below, revealing the essence of the declared technical solution:

[0032] System as source 44 Sc contains a radionuclide generator 44 Ti / 44 Sc, which is a chromatographic column containing as a parent radionuclide 44Ti, sorbent and elution solution 44 Sc, as a sorbent contains a solid-phase extractant based on a quaternary ammonium salt, N-methyl-N,1H-dioctyloctane ammonium chloride, as a solution for elution 44 The system contains an aqueous solution of 0.1 M oxalic acid and 0.05-0.2 M hydrochloric acid. The system also includes an additional chromatographic column filled with a sorbent for converting the generator eluate. 44 Ti / 44 Sc into a form suitable for the synthesis of radiopharmaceuticals, which contains as a sorbent a cation exchange resin, which is silicon dioxide modified with propylsulfone groups, or a copolymer of styrene and divinylbenzene modified with sulfone groups, and also contains solutions for sorption 44Sc - generator eluate, a mixture of 0.1 M oxalic and 0.05-0.2 M hydrochloric acids and a solution of 0.02 M oxalic and 0.01-0.04 M hydrochloric acids for each sorbent, respectively, as a solution for washing the sorbent and removing residual eluent from it contains ethanol or water, regardless of the nature of the sorbent, and for desorption 44 Sc with sorbent contains aqueous solutions of sodium salts of carboxylic acids, such as acetate, pyruvate, malate, lactate and sodium succinate, for the synthesis of radiopharmaceuticals contains an aqueous solution of the precursor and a thermostatted reaction vessel.

[0033] The generator is prepared as follows. A sample of the sorbent—a solid-phase extractant based on a quaternary ammonium salt, N-methyl-N,N-dioctyloctane ammonium chloride—is loaded into a polyether ether ketone (PEEK) chromatography column. Next, 1 ml of the sorption solution is passed through the column filled with the sorbent. 44Ti (0.1 M oxalic acid solution). After completion of the preparatory procedures, the generator is left for 24 hours to accumulate the daughter radionuclide ( 44 Sc), and an aliquot is taken from the solution after sorption to control the sorption yield of the parent radionuclide ( 44 Ti). Elution 44 Sc is carried out with an aqueous solution of a mixture of 0.1 M oxalic and 0.05-0.2 M hydrochloric acids, at a flow rate of 0.3 ml / min. An additional chromatographic column is also made of PEEK and contains either a sample of silicon dioxide modified with propylsulfone groups or a sample of a styrene-divinylbenzene copolymer modified with sulfone groups. Depending on the nature of the sorbent, the sorption solution is passed through the prepared column. 44Sc at a rate of 0.3 ml / min, which is either the generator eluate, a mixture of 0.1 M oxalic and 0.05-0.2 M hydrochloric acids, or a solution obtained by diluting the generator eluate - a mixture of 0.02 M oxalic and 0.01-0.04 M hydrochloric acids. After sorption 44 The Sc chromatographic column is washed with ethanol or water at a rate of 1 ml / min, regardless of the nature of the sorbent, and then desorption is carried out. 44 Sc for which aqueous solutions of sodium salts of carboxylic acids are passed through a chromatographic column at a rate of 0.3 ml / min. Next 44 Sc in aqueous solutions of sodium salts of carboxylic acids are mixed in a thermostatted reaction vessel with an aqueous solution of the precursor, where the synthesis of radiopharmaceuticals is carried out: the reaction mixture is heated to 95°C for 15 minutes.

[0034] The invention is illustrated by the following examples:

[0035] Example 1. 147 mg of sorbent - a solid-phase extractant based on a quaternary ammonium salt, N-methyl-N,N-dioctyloctane ammonium chloride, was placed in a chromatographic column made of PEEK (length - 150 mm, ∅ 2.1 mm), after which 1 ml of the sorption solution was passed through the column. 44 Ti (50 MBq) - 0.1 M oxalic acid solution, resulting in quantitative sorption 44 Ti on sorbent (≥99%). Elution of the finished radionuclide generator 44 Ti / 44 Sc was carried out with 1 ml of a mixture of 0.1 M oxalic and 0.2 M hydrochloric acids.

[0036] During operation for two years and 320 elutions, the radionuclide generator 44 Ti / 44 Sc was characterized by high stability and reproducibility of its target parameters: high values ​​of daughter yield were obtained 44 Sc (95±3%) at extremely low breakthrough 44 Ti in eluate ((2.5±1.3)×10 -7%). Table 1 presents a series of experimental yield data 44 Sc and breakthrough 44 Ti obtained for several first and later elutions of the radionuclide generator 44 Ti / 44 Sc.

[0037]

[0038] As the number of elutions increased, migration of the sorption front was observed 44 Ti along the generator column, however, it was only 20 mm, which, taking into account the column length (150 mm), is an acceptable value and allows us to talk about stable retention 44 Ti in the generator and the absence of destruction of the radionuclide sorption front. The generator was operated using the standard method of unidirectional passage of the eluent solution through the generator column, with the final product being the eluate. 44 Sc was obtained in a small volume (1 ml), which has a positive effect on the effectiveness of the subsequent conditioning procedure.

[0039] The operation of the claimed invention is illustrated in Fig. 1, which shows scans of the chromatographic column of the radionuclide generator 44 Ti / 44 Sc demonstrating the migration of the parent radionuclide sorption front along the column. Column scan after titanium-44 sorption upon reaching secular equilibrium in the generator (shaded area), as well as scans of every twenty-fifth elution, up to the 320th (dark gray area).

[0040] For the conditioning procedure, a PEEK chromatographic column (50 mm long, 2.1 mm diameter) was prepared and loaded with 100 mg of cation exchange resin based on silica modified with propylsulfone groups. 1 ml of the generator eluate was passed through the column. 44 Ti / 44 Sc - solution 44 Sc in a mixture of 0.1 M oxalic and 0.2 M hydrochloric acids, resulting in quantitative sorption 44 Sc (≥99%) on the sorbent. Desorption 44Sc was carried out with 1 ml of 1 M sodium acetate solution (pH 4-4.5). As a result, experimental data were obtained (presented in Table 2), which show that this procedure allows for the conversion of solutions 44 Sc with high efficiency.

[0041]

[0042] Next 1 ml of solution 44 Sc in 1 M sodium acetate (pH 4-4.5) was mixed in a thermostatted reaction vessel with 2 ml of an aqueous solution of the PSMA-617 precursor (C = 5 μg / ml). The radiopharmaceutical was then synthesized [ 44 Sc]Sc-PSMA-617 by heating the reaction mixture at 95°C for 15 minutes. Experimental data showed that the synthesized radiopharmaceutical [ 44Sc]Sc-PSMA-617 is characterized by high radiochemical purity (≥95%). The radiochemical purity analysis was performed by thin-layer chromatography, the obtained experimental data are presented in the Table in Fig. 2 (Table - data of thin-layer chromatography analysis of the radiopharmaceutical drug [ 44 Sc]Sc-PSMA-617).

[0043] The invention is also explained in Fig. 3, which shows a simplified diagram of the processes for conditioning the generator eluate. 44 Ti / 44 Sc and the synthesis of radiopharmaceuticals based on the obtained solutions 44 Sc, and for conditioning, a cation exchange resin based on silicon dioxide modified with propylsulfonic groups is used, where 1 is a container with a solution based on a mixture of oxalic and hydrochloric acids for elution of the radionuclide generator 44 Ti / 44 Sc; 2 - radionuclide generator 44 Ti / 44Sc; 3 - additional chromatographic column filled with cation exchange resin based on silicon dioxide modified with propylsulfonic groups; 4 - additional capacity with aqueous solutions of sodium salts of carboxylic acids used as an eluent for desorption 44 Sc from an additional column; 5 - container with an aqueous solution of the precursor; 6 - thermostatted reaction container for the synthesis of radiopharmaceuticals; LRW - liquid radioactive waste.

[0044] Example 2. 44 Sc was obtained from a radionuclide generator 44 Ti / 44 Sc, for which development and operational data are described in Example 1. Next, a PEEK column (50 mm long, 2.1 mm diameter) was prepared, into which 56 mg of a sulfone-modified styrene-divinylbenzene copolymer-based cathine exchange resin was loaded. 5 ml of the sorption solution was prepared. 44Sc - a mixture of 0.02 M oxalic and 0.04 M hydrochloric acids, obtained by diluting the generator eluate with water, and as a result of passing it through the column, quantitative sorption was observed 44 Sc (≥99%). The column was then washed with 1 ml of ethanol to remove residual eluent. Desorption 44 Sc was carried out with a 1 M sodium acetate solution (pH 4-4.5). As can be seen from the obtained experimental data (presented in Table 4), this procedure allows for the conversion of solutions 44 Sc with high efficiency.

[0045]

[0046] Next 1 ml of solution 44 Sc in 1 M sodium acetate (pH 4-4.5) was mixed in a thermostatted reaction vessel with 2 ml of an aqueous solution of the precursor FAP-2286 (C = 5 μg / ml). Then the radiopharmaceutical was synthesized [ 44 Sc]Sc-FAP-2286 by heating the reaction mixture at 95°C for 15 minutes. Experimental data showed that the synthesized radiopharmaceutical [ 44Sc]Sc-FAP-2286 is characterized by high radiochemical purity (≥95%). The radiochemical purity analysis was performed by thin-layer chromatography, the obtained experimental data are presented in the Table in Fig. 4 (data from the analysis by thin-layer chromatography of the radiopharmaceutical drug [ 44 Sc]Sc-PSMA-617).

[0047] The invention is further illustrated by Fig. 5, which also shows a simplified diagram of the generator eluate conditioning processes. 44 Ti / 44 Sc and the synthesis of radiopharmaceuticals based on the obtained solutions 44 Sc, and for conditioning, a cation exchange resin based on a copolymer of styrene and divinylbenzene modified with sulfone groups is used, where 1 is a container with a solution based on a mixture of oxalic and hydrochloric acids for eluting the radionuclide generator 44 Ti / 44 Sc; 2 - radionuclide generator 44 Ti / 44Sc; 3 - additional chromatographic column filled with cation exchange resin based on a copolymer of styrene and divinylbenzene modified with sulfone groups; 4 - additional capacity with aqueous solutions of sodium salts of carboxylic acids used as an eluent for desorption 44 Sc with an additional column, 5 - a container with an aqueous solution of the precursor; 6 - a thermostatted reaction container for the synthesis of radiopharmaceuticals; LRW - liquid radioactive waste.

[0048] Example 3. Desorption 44 Sc (in Example 1 and Example 2) from an additional chromatographic column was carried out using five one-molar solutions of sodium salts of carboxylic acids (pH 4-4.5), such as sodium acetate, pyruvate, malate, lactate and succinate. Experimental data on the desorption yield 44Sc using these solutions are presented in Table 6. It is important to note that the nature of the sorbent (cation exchange resin) did not have a statistically significant effect on the desorption efficiency. 44 Sc.

[0049]

[0050] After desorption, 44 Sc was used to synthesize the radiopharmaceutical [ 44 Sc]Sc-DOTAGA-PSMA. In a thermostatted reaction vessel, which is part of the system for obtaining solutions 44 Sc and the synthesis of radiopharmaceuticals based on them, mixed 1 ml of solution 44 Sc in a 1 M solution of sodium salt of a carboxylic acid (sodium acetate, pyruvate, malate, lactate or succinate with pH 4-4.5) and 2 ml of the DOTAGA-PSMA precursor solution (C = 5 μg / ml). Then the radiopharmaceutical was synthesized [ 44 Sc]Sc-DOTAGA-PSMA by heating the reaction mixture at 95°C for 15 minutes. Experimental data showed that the synthesized radiopharmaceutical [ 44Sc]Sc-DOTAGA-PSMA is characterized by high radiochemical purity (≥95%). Moreover, this result was obtained regardless of the nature of the solution. 44 Sc, i.e. when using 44 Sc in 1 M solutions of acetate, pyruvate, malaga, lactate and sodium succinate with pH 4-4.5 radiopharmaceutical [ 44 Sc]Sc-DOTAGA-PSMA was synthesized with high radiochemical purity (≥95%).

[0051] Thus, a system for obtaining solutions was created 44 Sc and the synthesis of radiopharmaceuticals based on them show high reliability (stability of the generator system and reproducibility of the main parameters over a long period of time), long service life and ease of operation, and provides a high yield 44 Sc, small slip 44 Ti in the eluate provides an efficient and fast method for converting solutions 44 Sc into a physiologically acceptable form, on the basis of which the synthesis of RFLP with high radiochemical purity can be carried out. 【0052 】Small Scale Small Scale

[0053] 1 Benabdallah N. et al. Modular engineering 44 The / 44 Sc generator: eluate evaluation in preclinical models and estimation of human radiation dosimetry. / / EJNMMI Res. Germany, 2023. Vol.13, No1. P. 17.

[0054] 2 Schmidt CE et al. Development of a Sn02-based 44 The / 44 Sc Generator for Medical Applications / / J. Chromatogr. A. 2024. Vol.1732. P. 465245.

[0055] 3 Filosofov DV, Loktionova NS, Rosch FA 44 The / 44 SC Radionuclide Generator for Potential Application of 44 Sc-based PET-radiopharmaceuticals / / Radiochem. Acta. 2010. Vol.98, No3.

[0056] 4 Larenkov AA, Makichyan AG, Iatsenko VN Separation of 44 Sc from 44 Ti in the Context of A Generator System for Radiopharmaceutical Purposes with the Example of [ 10 ]. 44 Sc]Sc-PSMA-617 and 44Sc]Sc-PSMA-I&T Synthesis / / Molecules. 2021. Vol.26, №21. P. 6371.

Claims

1. System for obtaining solutions 44 Sc and the synthesis of radiopharmaceuticals based on them, containing as a source 44 Sc radionuclide generator 44 Ti / 44 Sc in the form of a chromatographic column, characterized in that the chromatographic column is made with a solid-phase extractant based on alkylammonium chloride as a sorbent for retention 44 Ti, wherein the system contains a container with a solution based on a mixture of oxalic and hydrochloric acids for elution 44 Sc, an additional chromatographic column for carrying out the post-processing procedure of the generator eluate, which contains a cation exchange resin as a sorbent, with sulfonic acids used as functional groups in it, in addition, the system contains a container with aqueous solutions of sodium salts of carboxylic acids used as an eluent for desorption 44Sc with an additional chromatographic column, and also contains a container with an aqueous solution of the precursor and a thermostatted reaction container for carrying out the synthesis of radiopharmaceuticals.

2. The system according to paragraph 1, characterized in that the solid-phase extractant is made on the basis of a quaternary ammonium salt, N-methyl-N,N-dioctyl octane ammonium chloride.

3. The system according to claim 1, characterized in that the elution solution 44 Sc contains aqueous solutions of a mixture of 0.1 M oxalic acid in 0.05-0.2 M hydrochloric acid.

4. The system according to item 1, characterized in that the additional chromatographic column, designed for converting the generator eluate 44 Ti / 44 Sc in a form suitable for the synthesis of radiopharmaceuticals contains a cation exchange resin as a sorbent, which is silicon dioxide modified with propylsulfone groups.

5. The system according to paragraph 4, characterized in that for sorption 44Sc on a silicon dioxide sorbent modified with propylsulfone groups contains a generator eluate solution, a mixture of 0.1 M oxalic and 0.05-0.2 M hydrochloric acids.

6. The system according to item 1, characterized in that the additional chromatographic column, intended for the conversion of the generator eluate 44 Ti / 44 Sc in a form suitable for the synthesis of radiopharmaceuticals contains a cation exchange resin as a sorbent, which is a copolymer of styrene and divinylbenzene modified with sulfone groups.

7. The system according to paragraph 6, characterized in that for sorption 44 Sc on a sorbent made of a copolymer of styrene and divinylbenzene modified with sulfone groups contains a solution of 0.02 M oxalic and 0.01-0.04 M hydrochloric acids.

8. The system according to any one of paragraphs 4 or 6, characterized in that it contains ethanol or water, regardless of the nature of the sorbent, for washing the sorbent and removing residual eluent from it.

9. The system according to any one of paragraphs 4 or 6, characterized in that for desorption 44 Sc from the sorbent contains aqueous solutions of sodium salts of carboxylic acids, such as acetate, or pyruvate, or malate, or lactate, or sodium succinate.

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