Method of producing radioactive, fluorine-labelled organic compound

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing a radioactive, fluorine-labelled organic compound of formula , involving a step of heating a compound of formula at temperature of 40-90°C (where R1 denotes a linear or branched alkyl with 1-10 carbon atoms or an aromatic substitute; R2 denotes a linear or a branched halogen-alkylsuphonic acid substitute with 1-10 carbon atoms, a linear or branched alkylsulphonic acid substitute with 1-10 carbon atoms, a fluorosulphonic acid substitute or an aromatic sulphonic acid substitute, and R3 denotes a protective group) while stirring in an inert organic solvent in the presence of a phase transfer catalyst, 18F ions and calcium ions for radioactive fluorine labelling, and concentration of the phase transfer catalyst in the inert organic solvent is not less than 70 mmol/l.

EFFECT: disclosed method improves output of radioactive fluorination.

5 cl, 43 ex, 5 tbl, 6 dwg

 

DESCRIPTION

TECHNICAL RATIONALE

The present invention relates to a method for radioactive labeled with fluorine, compounds suitable for use in positron emission tomography and single photon emission computed tomography.

The LEVEL of TECHNOLOGY

Radionuclide medical research, presents positron emission tomography (hereinafter referred to as PET) and single photon emission computed tomography (hereinafter referred to here called SPECT), is effective in the diagnosis of several diseases, including heart disease and cancer. Such methods include the introduction of an agent labeled with a specific radioisotope (hereinafter referred to here called radiopharmaceuticals), with subsequent detection of γ-rays, directly or indirectly emitted by the agent. Radionuclide medical research differs in that it not only has such excellent characteristics, such as high specificity and sensitivity to diseases, but also the advantage of providing information on the functionality of the lesions, compared with other research methods.

For example, [18F]-2-fluoro-2-deoxy-D-glucose (hereafter called "18F-FDG"), one of the radiopharmaceuticals used for PET studies, has tended to concentrate in areas with a high metabolism who m glucose, thereby allowing specific to detect tumors, in which glucose metabolism is increased.

Radionuclide medical study carried out by recording the distribution of introduced radiopharmaceutical and the findings vary depending on the nature of the radiopharmaceutical. Therefore, for various diseases developed various radiopharmaceuticals, and some of these drugs have found clinical application. For example, a variety of agents for the diagnosis of tumors, agents for the diagnosis of bloodstream and agents for the mapping of receptors.

In recent years, as new radiopharmaceuticals developed a number of radioactive labelled by halogen, amino acid compounds, including [18F]-1-amino-3-fertilisation acid (hereafter called [18F]FACBC), and discusses the clinical use of such drugs (patent document 1 and non-patent documents 1 and 2). [18F]FACBC is effective diagnostic agent for vysokopolimernyh tumors because it has the ability to specifically absorbed amino acid Transporter.

As for ways to get [18F]FACBC, the methods include obtaining ester 1-(N-(tert-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]CYCLOBUTANE-1-carboxylic key is lots as a precursor for labelling, by replacing triflate group in position 3 of the predecessor radioactive fluorine and unprotect the compounds obtained in acidic conditions (patent document 1 and non-patent documents 1 and 2).

Patent document 1: laid Japan patent No. 2000-500442.

Non-patent document 1: Jonathan McConathy et al., "Improved synthesis of anti-[18F]FACBC: improved preparation of labeling precursor and automated radiosynthesis.", Applied Radiation and Isotopes, (Netherlands), 2003, 58, p.657-666.

Non-patent document 2: Timothy M. Shoup et al., "Synthesis and Evaluation of [18F]1-Amino-3-fluorocyclobutane-l-carboxylic Acid to Image Brain Tumors.", The Journal of Nuclear Medicine, 1999, 40, p.331-338.

Description of the INVENTION

The PROBLEM addressed by the INVENTION

However, the yield of the product described in this way to obtain [18F]-FACBC (J. McConathy et al., Applied Radiation and Isotopes, 2003, 58, p.657-666), is 12-24%. It is desirable for industrial production of [18F]-FACBC to use terms consistently providing higher output.

Getting [18F]-FACBC includes, as a main stages, the stage of radioactive fluorination, consisting in attaching a radioactive fluorine to the precursor for labeling, and the stage of removing protection, consisting in the implementation unprotect the intermediate obtained in stage radioactive fluorination. According to the conventional method, stage radioactives the fluorination provides access 12-42% (lined with the Japan patent No. 2000-500442 and Timothy M. et al., J. Of Nuc. Med., 1999, 40, p.331-338), and a low output at this stage is one of the reasons for reducing the output of the synthesis of [18F]-FACBC. Thus, to improve the output of the synthesis of [18F]-FACBC should, above all, to improve the stage of radioactive fluorination.

The present invention is made considering the above circumstances, and aims to develop the production method, which consistently provided a radioactive labeled with fluorine, amino acid, in the form of ether [18F]-1-(N-(tert-butoxycarbonyl)amino)-3-forceclosure-1-carboxylic acid (hereafter referred to [18F]Boc-FACBC), as intermediate compounds for [18F]FACBC.

Solutions to PROBLEMS

The study by the present applicants found that the radioactive labeled with fluorine, an amino acid, such as [18F] Boc-FACBC, can be stably obtained with high yield by setting the reaction temperature of 40-90°C and the concentration of the phase transfer catalyst in the reaction solution is not below a certain number, when carrying out the reaction of radioactive fluorination, and thus the present invention was completed.

Thus, according to the present invention, a method of obtaining radioactive labeled with fluorine, organic compounds, which includes stage nahrawan the I connection represented by the following formula (1):

in an inert organic solvent in the presence of a phase transfer catalyst, ion18F and potassium ions, to obtain compounds represented by the following formula (2):

where stage heating performed at a temperature of heating 40-90°C, and the phase transfer catalyst is contained in an inert organic solvent at a concentration of not less than 70 mmol/L.

In the production method of the present invention, potassium ions, used for stage heating, preferably contained in an inert organic solvent at a concentration of at least 27 mmol/L.

Also, in the production method of the present invention, the phase transfer catalyst is used in a molar ratio of at least 0.7 relative to the compound represented by formula (1).

Further, in the production method of the present invention, the compound represented by formula (1)is contained in an inert organic solvent at a concentration of not less than 50 mmol/L.

According to a preferred variant implementation of the present invention, a method of obtaining radioactive labeled with fluorine, organic compounds according to this invention includes

the stage of obtaining a mixture of the catalyst interfacial Perrin is sa, ions18F and potassium ions; and

stage radioactive fluorination, comprising adding a compound represented by the formula (1), and an inert organic solvent to the above mixture, and maintaining the resulting reaction solution at a temperature of 40-90°C, with stirring, giving a compound represented by the formula (2).

In the above formulas (1) and (2), R1means a linear or branched Akilova chain with 1-10 carbon atoms or an aromatic Deputy, and, preferably, can mean the Deputy selected from the group including methyl group, ethyl group, tert-boutelou group and phenyl group.

R2selected from the group including linear or branched halogenallylacetic Deputy with 1-10 carbon atoms, a linear or branched alkylsulphonyl Deputy with 1-10 carbon atoms, PERSULPHATES Deputy and aromatic sulfoxylates Deputy, and, preferably, can mean the Deputy chosen from the group comprising methansulfonate acid, toluensulfonate acid, nitrobenzenesulfonic acid, benzosulfimide acid, triftormetilfullerenov acid, persulfonic acid and performancelevel acid.

R3means a protective group and has no specific Ogre is Iceni, provided that has the ability to prevent the interaction between a radioactive fluorine and amino group. More precisely, R3selected from the group consisting of various urethane substituents, various amide substituents, various kidnie deputies and various amine substituents, and preferably a linear or branched allyloxycarbonyl Deputy with 2-7 carbon atoms, linear or branched altneratively Deputy with 3-7 carbon atoms, benzyloxycarbonyl Deputy with 7-12 carbon atoms, which may have a Deputy, alkylpolyoxyethylene Deputy with 2-7 carbon atoms, linear or branched alkylamide Deputy with 1-6 carbon atoms, linear or branched alkanolamines Deputy with 2-6 carbon atoms, benzamidine Deputy with 6 to 11 carbon atoms which may have a Deputy, cyclic kidny Deputy with 4-10 carbon atoms, an aromatic kinowy Deputy with 6 to 11 carbon atoms which may have a Deputy, a linear or branched alkylamino Deputy with 1-6 carbon atoms, linear or branched alkanolamines Deputy with 2-6 carbon atoms and benzylamino Deputy with 6 to 11 carbon atoms, which may have a substituent. More preferably, R3means C is the election agent, selected from the group comprising tert-butoxycarbonyl group, allyloxycarbonyl group, phthalimido group and N-benzylideneamino Deputy, and, most preferably tert-butoxycarbonyl group or phthalimido group.

In the method of obtaining the number of radioactive labeled with fluorine, amino acids, such as described up to the present time [18F]-FACBC, the reaction labeling with radioactive fluorine is carried out, using a phase transfer catalyst at low concentrations, i.e. in a molar ratio of about 0.3 of its predecessor for tagging (lined with the Japan patent No. 2000-500442, Timothy M. et al., J. Of Nuc. Med., 1999, 40, p.331-338 and J. McConathy et al., Applied Radiation and Isotopes, 2003, 58, p.657-666). In contrast, a standard of the open method, the present applicants have found that the concentration of the phase transfer catalyst in an inert organic solvent should be set no lower than 70 mmol/l and, preferably, the phase transfer catalyst used in a molar ratio of at least 0.7 of its predecessor for marking, thus the output when fluoridation is significantly improved, and radioactive labeled with fluorine, organic compound, such as [18F]-FACBC, can stably be obtained with high yield. The amount of the phase transfer catalyst is, preferably, equimolar the th or higher, expressed in molar ratio relative to the predecessor for tagging.

In addition, the present applicants found that out when radioactive fluorination at the stage of radioactive fluorination can be improved by increasing the concentration of the precursor to ringing in the reaction solution. Based on the discovery by applicants found that radioactive labeled with fluorine, an amino acid, such as [18F]-FACBC, can be obtained with a higher yield when using the concentration of the precursor to ringing in the inert organic solvent is not below a certain concentration.

Thus, the method, according to another preferred variant implementation of the present invention includes maintaining the concentration of the precursor to ringing in the inert organic solvent is not lower than a certain concentration to the above-mentioned method of producing radioactive labeled with fluorine, organic compounds. More precisely, the concentration of the precursor in an inert organic solvent is preferably not less than 50 mmol/l, more preferably not less than 60 mmol/l and particularly preferably not less than 70 mmol/L.

The higher the concentration of the precursor to ringing in an inert organic solvent, the greater is the progress on the stage of radioactive fluorination; however, since increasing the concentration of the precursor at a constant number of precursor leads to a reduction of the total amount of solution, the concentration should be such as to ensure a sufficient amount of fluid to perform the reactions of radioactive fluorination. The upper limit of this concentration is dependent on the number of precursor for labelling, the volume of the reaction vessel, etc. for Example, if the retrieval is carried out, using automatic equipment for synthesis, the upper limit of the concentration of the reaction solution is 250 mmol/l, if the lower limit of the liquid volume that can be processed in a reaction vessel, equal to 0.4 ml and the number used to communicate predecessor for marking equal to 0.1 mol. Similarly, the upper limit of the concentration of the reaction solution is 160 mmol/l, if the lower limit of the liquid volume that can be processed in a reaction vessel, 0.5 ml and the number used to communicate predecessor for marking equal to 0.08 mmol.

As indicated above, the reaction temperature when the reaction tagging is 40-90°C. the Reaction temperature reduces the reaction output when too high or too low. A more preferred range of reaction temperatures of 50-80°C and even predpochtitelnei is, 60-70°C.

In this invention, various solvents, does not have reactivity against fluoride ion [18F], phase transfer catalyst, potassium ion and connections predecessor for tagging, useful as an inert organic solvent. Specific examples of the inert organic solvent include organic solvents containing at least one solvent selected from the group comprising tetrahydrofuran, 1,4-dioxane, acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide and acetonitrile, preferably acetonitrile.

The EFFECTS of the INVENTION

According to the method of obtaining of the present invention, when the radioactive fluorination reaction, the temperature is set 40-90°C and the concentration of the phase transfer catalyst support is not less than 70 mmol/l, preferably, the concentration of potassium ion and/or the precursor to ringing in an inert organic solvent, maintained at a certain concentration or higher, and the molar ratio of phase transfer catalyst relative to the predecessor for tagging, maintained at a certain amount or above, thus, the output upon receipt of radioactive labeled with fluorine amino acids, such as [18F] Boc-FACBC, can be improved.

BEST SPO is ABOUT the execution of the INVENTION

Hereafter, the method of obtaining radioactive labeled with fluorine, organic compounds of the present invention are described in detail on the example of the synthesis of [18F]Boc-FACBC using ethyl ester 1-(N-(tert-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]CYCLOBUTANE-1-carboxylic acid as a precursor for labeling.

According to a preferred variant implementation, the method of receiving according to the present invention includes (1) a step for mixtures containing the phase transfer catalyst, ionsl8F and potassium ions, and (2) a step for radioactive labeled with fluorine, organic compounds by reacting the precursor for labeling with the above mixture in order to ensure labeling with radioactive fluorine (stage radioactive fluorination).

In the above stage (1), radioactive fluorine can be obtained in a known manner, for example by way enriched H218O water is used as target and subjected to bombardment by protons. In this case, the radioactive fluorine is present in enriched H218O water used as a target. Enriched with H218O water containing radioactive fluorine is passed through an anion exchange column, so that the radioactive fluorine is adsorbed and collected on the Olonka, thereby standing out from enriched H218O water. Then the potassium carbonate solution is passed through the column for elution of radioactive fluorine, and the eluate by recharge phase transfer catalyst and evaporated to dryness, thereby obtaining a mixture containing a phase transfer catalyst, ion18F and the potassium ion.

The number used here potassium carbonate is preferably adjusted to a value of 27 mmol/l or above in terms of the concentration of potassium ions in an inert organic solvent used for the reaction solution. As clear from the following examples and comparison examples, when the concentration of potassium ion in an inert organic solvent is less than 27 mmol/l, the yield of [18F]-fluorination at the stage of radioactive fluorination increases along with the concentration of potassium ion, and 27 mmol/l or higher output becomes almost constant. Therefore, the use of conditions in which the concentration of potassium ion in an inert organic compound is 27 mmol/l or higher allows more stable to carry out stage radioactive fluorination with high output.

On the other hand, it should be noted that when the amount of potassium carbonate is excessive, the product of the interaction may decompose under the influence of carbonate ions. In a preferred embodiment, Khujand the exercise of, the amount of potassium carbonate in terms of potassium ions can be approximately equivalent relative to the amount of the phase transfer catalyst and, most preferably, the concentration and quantity of a solution of potassium carbonate to adjust so that the amount of the phase transfer catalyst was in a molar ratio of about 1.3 relative to potassium ions.

Various compounds with the ability to form a clathrate with ion18F, can be used as the phase transfer catalyst. In particular, there can be used various compounds used for the preparation of organic compounds labeled with radioactive fluorine; can be used 18-crown-6 and various other simple aminopolyamide. In the most preferred embodiment, can be used KRYPTOFIX 222 (trademark, manufacture Merck & Co., Inc.).

According to the present invention, the amount of the phase transfer catalyst is adjusted to provide a concentration of not less than 70 mmol/l in an inert organic solvent, which is added later. As clear from the following examples and comparison examples, the stage of radioactive fluorination can be stably performed with high yield by setting the amount of phase transfer catalyst in an inert, organic the immediate vicinity of the solvent is not less than 70 mmol/L. The amount of the phase transfer catalyst is preferably not less than 0.7 in terms of molar ratio relative to the predecessor for tagging, which is used later stages of radioactive fluorination. In a further preferred embodiment, the amount of the phase transfer catalyst is equimolar or higher, relative to the precursor for labelling. In this case, the larger the amount of the phase transfer catalyst, the greater the output, but an excessive amount of the phase transfer catalyst is not preferred because it is often difficult to sufficiently remove added in excess of the phase transfer catalyst. In a preferred embodiment, the total amount of the phase transfer catalyst may be 0.2 mmol or less, for example, when the number of precursor labeling is 80 mmol, the molar ratio of phase transfer catalyst and precursor tagging is 2.5 or less. This amount of phase transfer catalyst can be easily removed by cleaning using a column for solid phase extraction or the like at the subsequent stage.

After the mixture containing the phase transfer catalyst, ions [18F] and ions feces is I, obtained in the above manner, the radioactive labeled with fluorine, amino acid synthesized in exercising the above stage (2). At stage (2), the precursor for labelling, ether 1-(N-(tert-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]CYCLOBUTANE-1-carboxylic acid is first added to the mixture containing the phase transfer catalyst, ions [18F] and potassium ions. In the most preferred embodiment, the precursor for labelling first dissolved in an inert organic solvent and then added to the mixture. In this case, it is preferable to adjust the amount of used inert organic solvent so that the concentration of the precursor to ringing in the reaction solution in the radioactive fluorination was not less than 50 mmol/l, since the output when the radioactive fluoridation significantly improved.

After you have finished adding the precursor for labelling and the inert organic solvent of the above reaction solution is subjected to radioactive fluorination by heating under stirring, obtaining radioactive labeled with fluorine organic compound as the target compounds of the present invention. The reaction temperature is 40-90°C, preferably 50 to 80°C and particularly preferably 60-70°C. the Time of the EOI is to interact depends on the reaction temperature, and when the reaction temperature is 40-90°C, the time of interaction is usually 3 minutes or more, preferably 3-15 minutes and, more preferably, 3 to 7 minutes. It is expected that the longer the interaction, the further reaction takes place labeling with radioactive fluorine, but it should be noted that at the same time the decomposition of radioactive fluorine.

After interaction do the cleaning in order to remove unreacted educt and phase transfer catalysts. In the most preferred embodiment, the cleaning perform the following ways. First, get a solution by adding diethyl ether to the reaction solution, which terminates the interaction. The resulting solution was passed through a column of solid phase silica-based (e.g., Sep-Pak (registered trademark), Silica (trade mark, manufactured in Japan Waters), and thus, [18F]Boc-FACBC in the form of diethyl solution.

EXAMPLE

Hereafter the present invention is disclosed in more detail using examples and comparison examples, not limiting the invention.

Thus, in the examples and the comparison examples, radiochemical purity determined by performing the TLC analysis under the following conditions using the following equation (1).

Conditions TLC-analysis:

Mobile phase: a mixture of diethyl ether/hexane=3/2

Plate for TLC: Silica Gel 60 F254(brand, the thickness of the surface layer: 0.25 mm, manufactured by Merck & Co., Inc.)

Travel length: 10 cm

Scanner for TLC: Rita Star (produced Raytest)

In addition, the output of [18F]fluorination is determined by the following equation (2).

A: the radioactivity of the mixture containing the phase transfer catalyst, ions [18F] and potassium ions (IBC)

B: radioactivity synthesized [18F]-Boc-FACBC (IBC)

Example comparison 1

Synthesis of ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]CYCLOBUTANE-1-carboxylic acid

Hydrolysis of sin-as (FIG. 1, stage 1)

250 ml of a saturated solution of barium hydroxide is added to x 6.15 g (corresponding to 25 mmol) of SYN-5-(3-benzyloxyresorufin)as and refluxed under heating on an oil bath to 114°C for 24 hours or longer. Then, performing the TLC analysis using, as a mobile solvent, two types of systems: a mixture of chloroform/methanol=5/1 (Rf value for sin-as=about 0.6) and a mixture of chloroform/methanol=95/1 (Rf value for sin-as = about 0.3), and confirm the completion of the interaction (staining in the UV and phosphomolybdenum the second acid).

After confirming the completion of the interaction of the reaction solution is cooled to room temperature and add about 24 ml of 1 mol/ml of sulfuric acid to neutralize the reaction solution. After neutralizing the reaction solution further stirred at room temperature for 5 minutes, and the resulting precipitate removed by filtration. The filtrate is concentrated and receiving 5,67 g of SYN-1-amino-3-benzyloxycarbonyl-1-carboxylic acid as white crystals.

Ethyl-esterification (FIG. 1, stage 2)

5,67 g of SYN-1-amino-3-benzyloxycarbonyl-1-carboxylic acid, completely dried to remove water, dissolved in 200 ml of ethanol. To the resulting solution was added to 9.5 ml (corresponding to 75 mmol) of triethylamine and cooled to -78°C for 20 minutes, and then add 4.6 ml (corresponding to 62.5 mmol) of thionyl chloride. The reaction solution was stirred at 0°C for 1 hour and at room temperature for 1 hour, followed by boiling under reflux under heating on an oil bath to 95°C during the night. End interaction confirm the TLC analysis, using a mobile solvent mixture chloroform/methanol=95/1 (Rf value for the target connection = about 0.6) (confirmed by staining in the UV and phosphomolybdenum acid). After confirming the completion of the interaction of reaction is ionic solution concentrated under reduced pressure, getting to 7.64 g of ethyl ester SYN-1-amino-3-benzyloxycarbonyl-1-carboxylic acid as white crystals.

Joining Boc (FIG. 1, stage 3)

of 7.64 g of ethyl ester SYN-1-amino-3-benzyloxycarbonyl-1-carboxylic acid are dissolved in 250 ml of a mixed solvent of ethanol/triethylamine = 9/1. After cooling the solution in an ice bath for 15 minutes to the solution was added 8.6 ml (corresponding to 37.5 mmol) di-tert-BUTYLCARBAMATE and stirred at room temperature overnight. End interaction confirm the TLC analysis, using a mobile solvent hexane/ethyl acetate = 1:1 (Rf value for the target connection = about 0.6) (confirmed by staining in the UV and molybdenum acid). After confirming the completion of the interaction of the reaction solution was concentrated under reduced pressure, obtaining as a remnant of white crystals. To the residue, add 150 ml of cooled ethyl acetate and 150 ml of chilled 0.5 mol/l hydrochloric acid, stirred at room temperature for 5 minutes and leave to stand until separation. The organic layer is extracted and washed with 150 ml of water, twice with 150 ml of saturated aqueous sodium hydrogen carbonate solution, 150 ml of water, twice, and 150 ml of saturated sodium chloride solution, twice, in this order, dried with anhydrous sodium sulfate and to the center under reduced pressure, getting a yellow oily substance. Separately, the aqueous layer was extracted and washed with 150 ml of ethyl acetate, twice 150 ml of water, twice, and 150 ml of saturated solution of sodium chloride, in that order, dried with anhydrous sodium sulfate and concentrated under reduced pressure, producing a small amount of a yellow oily substance. By these operations receive 8,82 g of light yellow oily substance. The residue is purified by chromatography on a column of silica gel (hexane/ethyl acetate = 1/1), receiving of 8.04 g (corresponding to 23 mmol) ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-benzyloxycarbonyl-1-carboxylic acid as white crystals.

Dibenzylamine (FIG. 2, stage 4)

To 8,04 g (corresponding to 23 mmol) ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-benzyloxycarbonyl-1-carboxylic acid, add 150 ml of ethanol and then 960 mg of palladium on charcoal (10% palladium) to effect the substitution of hydrogen with stirring at room temperature over night. After interaction of palladium on charcoal is removed by filtration using celite, and the filtrate concentrated under reduced pressure, obtaining the grade of 5.74 g of white crystals in the form of residue. Interaction is monitored by TLC analysis using the mobile solvent hexane/ethyl acetate = 1/1 (led the rank Rf for target compound interaction = about 0.2) (confirmed by staining in the UV and ninhydrin), to confirm the interaction. Then, the residue is purified by chromatography on a column of silica gel (hexane/ethyl acetate=1/1, hexane/ethyl acetate=4/1)to give are 5.36 g (corresponding to 20.7 mmol) ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-carboxylic acid as white crystals.

Triflation (FIG. 3, stage 5)

2,07 g (8 mmol) of ethyl ether SYN-1-(N-(tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-carboxylic acid are dissolved in 26 ml of pyridine and stirred in an ice bath for 20 minutes. Then add 2.0 ml (corresponding to 12 mmol) triftormetilfullerenov anhydride and stirred for 30 minutes. Interaction is monitored by TLC analysis using the mobile solvent hexane/diethyl ether = 1/1 (Rf value for the target connection, interaction = about 0.6) (confirmed by staining with ninhydrin), to confirm the completion of the interaction. After confirming the completion of the interaction to the reaction solution add 100 ml of water and 100 ml diethyl ether, and perform the extraction and washing with 100 ml of 1 mol/l hydrochloric acid, twice with 100 ml of water, twice with 100 ml of saturated solution of sodium chloride, twice, in the specified order. After drying with anhydrous sodium sulfate fulfill a concentration under reduced pressure, p is the best 2,78 g of light yellow crystals. The reaction mixture is purified by chromatography on silica gel (hexane/diethyl ether = 3/1)to give white crystals, and the resulting white crystals again recrystallized using a mixture of pentane/diethyl ether, receiving 1.84 g (corresponding to 4.7 mmol) ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]CYCLOBUTANE-1-carboxylic acid.

The comparison examples 1-5, examples 1-8

Contains [18F]-fluoride ion H218O is passed through an anion-exchange column for adsorption and collection of [18F]-fluoride ion on the column. Then, 0.3 ml of potassium carbonate solution at a concentration specified in table 1 was passed through the column for elution of [18F]-fluoride ion, after which 0.3 ml of water is passed through the column and combine with the eluate. To the resulting solution was added to 1.5 ml of the combined acetonitrile solution of Kryptofix 222 (trade mark, manufactured by Merck & Co., Inc.) in the amount indicated in table 1, and measure the radioactivity of the resulting mixture (A: measured radioactivity in table 2).

Then, the mixture is heated to 110°C for evaporation of water and acetonitrile, and subjected to azeotropic distillation with addition of acetonitrile (0.5 ml ×2) followed by evaporation to dryness. To the mixture add a solution of ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]cyclobe the an-1-carboxylic acid (hereafter called Boc-TfACBC), specified in table 1, in acetonitrile, in the amount indicated in table 1, and heated to 83°C for 3 minutes under stirring. Then, the solution is allowed to cool for 5 minutes at room temperature, to the solution add 4 ml of diethyl ether, and the mixture is passed through Sep-Pak Silica (trademark, manufactured by Japan Waters), obtaining a solution of [18F]Boc-FACBC in a mixture of acetonitrile/diethyl ether as labeled with fluorine [18F] connections. Measure the radioactivity and the radioactivity (refer to table 2) is used to calculate the output for the fluoridation of [18F]. Also, spend the TLC analysis of the obtained [18F]Boc-FACBC to determine radiochemical purity using the above equation (1).

In this experiment, each condition performed once in the comparison examples 1 and 3 and example 3, twice in the comparison examples 2 and 4 and example 8, four times in example 4, and three times in the other.

Table 1
The conditions of the experiment in each example and the example of the comparison (the number of each source used substances)
The concentration of carbonate of potassium (mmol/l)The number of Kryptofix 222 (µmol)STA is in Boc-TfACBC (µmol) The ratio of Kryptofix 222/Boc-TfACBCThe quantity added acetonitrile (ml)
Example comparison 12213400,331
Example of comparison 24024800,331
An example of comparison 366,753800,661
Example 4 comparison10060800,751
Example compare 566,753401,31
Example 110079,5601,31
13380801,01
Example 313393801,21
Example 4133106801,31
Example 5133106801,31,5
Example 6133120801,51
Example 71671331001,31
Example 8133160802,01

Table 2
The measured values of radioactivity in each example and the example of comparison (values adjusted for initiation of synthesis)
A (MBq)(MCS)
Example comparison 159,8024,38
Example of comparison 21: 159,84, 2: 149,131: 88,73, 2: 69,59
An example of comparison 3320,11203,06
Example 4 comparison1: 421,71, 2: 347,291: 308,17, 2: 216,28
Example compare 51: 211,91, 2: 187,64,
3: 371,63
1: 122,40, 2: 119,11,
3: 245,90
Example 11: 278,90, 2: 175,47,
3: 356,11
1: 193,63, 2: 117,86,
3: 252,20
Example 21: 500,23, 2: 273,51,
3: 355,39
1: 293,15, 2: 184,08,
3: 239,33
Example 3461,47326,44
Example 41: 11,29, 2: 445,79,
3: 149,01, 4: 126,74
1: 86,33, 2: 332,52,
3: 113,81, 4: 97,44
Example 51: 242,47, 2: 153,66,
3: 135,65
1: 165,59, 2: 101,35,
3: 93,59
Example 61: 123,95, 2: 433,30,
3: 330,94
1: 86,20, 2: 297,44,
3: 245,92
Example 71: 128,58, 2: 123,51,
3: 301,16
1: 98,64, 2: 86,89,
3: 218,30
Example 81: 123,10, 2: 112,361: 93,45, 2: 84,60

The results are shown in table 3 and Fig. 4-6. Calculate the ratio of Kryptofix 222 used as the phase transfer catalyst, and predecessor Boc-TfACBC (hereafter called the ratio of the phase transfer catalyst/precursor), and investigate the relationship with yield, with [18F]-fluorination. The results are shown in Fig. 4. As can be seen from the figures, the conditions under which the ratio of the phase transfer catalyst/precursor is less than 0.7, the output of [18F]Boc-FACBC with [18F]-fluoridation significantly improved with the increase of the ratio of the phase transfer catalyst/precursor. In conditions where the ratio of the catalyst interfacial per the nose/predecessor is not below 0.7, data indicate nearly constant output, although there are data indicating low output with [18F]-fluorination (in the example comparison 5), and exit with [18F]fluorination in these conditions, approximately 30-50% higher than in the conventional method (example of comparison 1).

The relationship between the concentration of potassium ions in acetonitrile to the reaction solution, and exit with [18F]-fluoridation shown in Fig. 5. As follows from Fig. 5, in the conditions in which the concentration of potassium ions is less than 27 mmol/l, exit with [18F]-fluorination improves significantly with increasing concentration of potassium ions, and at concentrations above specified, the output is almost constant. The relationship between the concentration of Kryptofix in acetonitrile to the reaction solution, and exit with [18F]-fluoridation shown in Fig. 6. As follows from Fig. 6, in the conditions in which the concentration of Kryptofix in acetonitrile, the reaction solution (indicated as the concentration of the phase transfer catalyst in Fig. 6) is less than 70 mmol/l, the yield of [18F]Boc-FACBC with [18F]-fluorination increases significantly with increasing concentration Kryptofix, and at concentrations above specified, the output is almost constant. Thus, it is shown that [18F]Boc-FACBC can be obtained with a high yield of the m with [ 18F]fluorination in the conditions in which the concentration of potassium ions is not less than 27 mmol/l and the concentration of the phase transfer catalyst is not less than 70 mmol/L. Also shown that when you set the conditions specified in addition to the above condition, in which the ratio of the phase transfer catalyst/precursor is at least 0.7, condition (example comparison 5), giving a low output when the ratio of the phase transfer catalyst/precursor is at least 0.7, can be eliminated, and, thus, can be made more stable high output when [18F]-fluorination.

Based on the above results, it was established that [18F]Boc-FACBC can stably be obtained with high yield, with [18F]-fluorination, combining the condition under which the ratio of the phase transfer catalyst/precursor is at least 0.7, a condition in which the concentration of potassium ions is not less than 27 mmol/l, and the condition in which the concentration of the phase transfer catalyst is not less than 70 mmol/L.

Table 3
Exit with [18F]-fluorination and radiochemical purity of the compounds obtained in each example and comparison example to
Exit with [18F]fluorination in %Radiochemical purity in %
Example comparison 124,1659,27
Example comparison 138,1374,77
An example of comparison 354,7586,32
Example 4 comparison59,8088,24
Example compare 556,6690,65
Example 165,9595,33
Example 261,3995,36
Example 364,8791,70
Example 473,5396,52
Example 565,3396,43
Example 667,9895,92
Example 768,3893,37
Example 870,7393,57

Examples 9-43

The following experiments are performed with the reaction temperature 40-100°C to prove that [18F]Boc-FACBC can be obtained with a good yield according to the method of receiving according to the present invention.

Contains [18F]-fluoride ion H218O is passed through an anion-exchange column for adsorption and collection of [18F]-fluoride ion on the column. Then, 0.3 ml of a solution of potassium carbonate at a concentration of 133 mmol/l pass through the column for elution of [18F]-fluoride ion, after which 0.3 ml of water is passed through the column and combine with the eluate. To the resulting solution was added 106 µmol Kryptofix 222 (trade mark, manufactured by Merck & Co., Inc.) in 1.5 ml of acetonitrile.

The mixture is then heated to 110°C for evaporation of water and subjected to azeotropic distillation with addition of acetonitrile (0.5 ml ×2) followed by evaporation to dryness. To the resulting mixture add a solution of 80 mmol of Boc-TfACBC in 1 ml of acetonitrile, and the reaction solution is stirred for a time period specified in tables 4a-4d at the temperature indicated in tables 4a-4e, ensuring the flow of radioactive fluorination. Received reactions the config solution analyzed by TLC analysis, determine % of the area of [18F]Boc-FACBC and used as a measure of output with [18F]-fluorination.

While the radioactivity used in each experiment is 414-759 MBq.

Conditions TLC-analysis:

Plate for TLC: Silica Gel 60 F254(trade mark; manufactured by Merck & Co., Inc.)

Mobile phase: a mixture of diethyl ether/hexane = 1/1

Detector: Rita Star (trade mark; manufactured Raytest)

Table 4a
The reaction temperature and the time of interaction in each example
Example 9Example 10Example 11Example 12Example 13Example 14Example 15
The reaction temperature,°C405060708090100
The time inter-actions, min33333 33

Table 4b
The reaction temperature and the time of interaction in each example
Example 16Example 17Example 18Example 19Example 20Example 21Example 22
The reaction
e-perature, °C
405060708090100
The time of interaction, min5555555

Example 25
Table 4c
The reaction temperature and the time of interaction in each example
Example 23Example 24Example 26Example 27Example 28Example 29
Reaction-perature, °C405060708090100
The time of interaction, min7777777

Table 4d
The reaction temperature and the time of interaction in each example
Example 30Example 31Example 32Example 33Example 34Example 35Example 36
The reaction temperature, °C40506070 8090100
The time of interaction, min10101010101010

Table 4e
The reaction temperature and the time of interaction in each example
Example 37Example 38Example 39Example 40Example 41Example 42Example 43
The reaction temperature,
°C
405060708090100
The time of interaction, min15151515151515

the results are shown in tables 5a-5e. As follows from the above results, in the conditions, when the reaction time is from 3 to 15 minutes, exit with [18F]-fluoridation has good size, at least 62%, at all reaction temperatures. Also, no significant change is observed in the output, with [18F]-fluorination, the reaction temperature is not lower than 90°C, and, thus, it was established that a good exit with [18F]-fluorination can be obtained when the reaction temperature of 40-90°C.

Also, the conditions under which the reaction temperature is 50-80°C, with [18F]-fluoridation reaches not less than 70% at all times of interaction, and the conditions under which the reaction temperature is 60-70°C, with [18F]-fluoridation reaches not less than 80% at all times of interaction.

On the other hand, as for the time of interaction, especially good yield with [18F]-fluoridation get when interaction time is 3-7 minutes

Thus, it is shown that at the time of interaction 3-15 min good yield with [18F]-fluorination can be achieved in the conditions, when the reaction temperature is 40-90°C or higher, a greater output with [18F]-fluorination can be achieved in terms of 50-80°C and especially good yield with [18F]-fluorination can be achieved in terms of 60-70°C./p>

In addition, it is shown that the interaction time is not less than 3 minutes is sufficient and the time of interaction between 3-7 minutes is preferable.

Table 5a
Exit with [18F]fluorination in each example
Example 9Example 10Example 11Example 12Example 13Example 14Example 15
The reaction temperature,
°C
405060708090100
The time inter-actions,min3333333
Exit with [18F]-fluorination
in %
627482867 7474

Table 5b
Exit with [18F]fluorination in each example
Example 16Example 17Example 18Example 19Example 20Example 21Example 22
The reaction temperature, °C405060708090100
The time inter-actions, min5555555
Exit with [18F]-fluorination
in %
70808384787069

Table 5c
Exit with [18F]fluorination in each example
Example 23Example 24Example 25Example 26Example 27Example 28Example 29
The reaction temperature, °C405060708090100
The time inter-actions, min7777777
Exit with [18F]-fluorination
in %
74818183767273

Table 5d
Exit with [18F]-Porirua the AI in each example
Example 30Example 31Example 32Example 33Example 34Example 35Example 36
The reaction temperature, °C405060708090100
The time inter-actions, min10101010101010
Exit with [18F]-fluorination
in %
76838381766770

Table 5e
Exit with [18F]fluorination in each example
Example 37 Example 38Example 39Example 40Example 41Example 42Example 43
The reaction temperature, °C405060708090100
The time inter-actions, min15151515151515
Exit with [18F]-fluorination
in %
78838182746968

INDUSTRIAL APPLICABILITY

The method of obtaining radioactive labeled with fluorine, organic compounds according to the present invention can be conveniently applied to obtain radioactive labeled with fluorine, organic compounds, including [18F]Boc-FACBC used to produce new diagnosticheskiye.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 represents a scheme of the synthesis of the ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-benzyloxycarbonyl-1-carboxylic acid.

Figure 2 represents a scheme of the synthesis of the ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-carboxylic acid.

Figure 3 presents a scheme of the synthesis of the ethyl ester SYN-1-(N-(tert-butoxycarbonyl)amino)-3-[((trifluoromethyl)sulfonyl)oxy]CYCLOBUTANE-1-carboxylic acid.

Figure 4 is a graph expressing the relationship between the ratio of the phase transfer catalyst/precursor tagging and release when fluoridation (triangle: examples, square: examples of comparison).

Figure 5 is a graph expressing the relationship between the concentration of potassium ions and exit when fluoridation (triangle: examples, square: examples of comparison).

6 is a graph expressing the relationship between the concentration of the phase transfer catalyst and exit when fluoridation (triangle: examples, square: examples of comparison).

1. The method of obtaining radioactive labeled with fluorine organic compounds, including the stage of heating the compound represented by the following formula (I):

where R1 means a linear or branched Akilova chain with 1-10 carbon atoms which kind or aromatic Deputy, R2means a linear or branched halogenallylacetic Deputy with 1-10 carbon atoms, a linear or branched alkylsulphonyl Deputy with 1-10 carbon atoms, PERSULPHATES Deputy or aromatic sulfoxylates Deputy, and R3means a protective group,
in an inert organic solvent in the presence of a phase transfer catalyst, ion18F and potassium ions, to obtain compounds represented by the following formula (2):

where R1means a linear or branched Akilova chain with 1-10 carbon atoms or an aromatic Deputy, R3means a protective group,
where stage heating performed at a temperature of heating 40-90°C and the phase transfer catalyst is contained in an inert organic solvent at a concentration of not less than 70 mmol/L.

2. The method of receiving according to claim 1, in which potassium ions are contained in an inert organic solvent at a concentration of at least 27 mmol/L.

3. The method of receiving according to claim 1, in which the phase transfer catalyst is used in a molar ratio of at least 0.7 relative to the compound represented by formula (1).

4. The method of receiving according to claim 1 in which the compound represented by formula (1)is contained in an inert organic rastvoritelei concentration of not less than 50 mmol/L.

5. The way of getting any one of claims 1 to 4, including:
the stage of obtaining a mixture of a phase transfer catalyst, ion18F and potassium ions and
stage radioactive fluorination, comprising adding a compound represented by the specified formula (1), and an inert organic solvent to the above mixture and maintaining the resulting reaction solution at a temperature of 40-90°C, with stirring, giving a compound represented by the specified formula (2).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a radioactive fluorine-labelled organic compound of formula (3). The method involves a step for splitting an ester of formula (1), where R1 is a straight or branched C1-C10 alkyl and R2 is a protecting group selected from straight or branched C2-C7 alkyloxycarbonyl groups, passed through and held in a reverse phase column containing filler with a structure in which C2-C18 alkyl groups are attached to a substrate by silicon. In order to split said ester, alkali solution is fed into the column, after which alkaline solution is discharged from the column to obtain a compound of formula (2), where X is sodium or potassium and R2 is a protecting group selected from straight or branched C2-C7 alkyloxycarbonyl groups. At the next step, the protecting group R2 of the compound of formula (2), obtained at the ester splitting step, is removed to obtain a compound of formula (3).

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FIELD: medicine.

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EFFECT: improved method of producing a fluorine-containing acylacetic acid derivative.

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EFFECT: high output of the end product.

2 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining precursor compound of radioactive fluorine-tagged compound, of formula , which includes: stage of interaction, providing conditions for interaction of solution, which contains substance with the following chemical formula : where R1 represents protective group of carboxyl group, and R2 represents protective group of aminogroup together with base, selected from group, consisting of alkylamides, from primary to quaternary, with unbranched or branched chain with 1-10 carbon atoms, nitrogen-containing heterocyclic substances with 2-20 carbon atoms and nitrogen-containing heteroaromatic substances with 2-20 carbon atoms, and compound, reacting with OH-group of compound of chemical formula (1), with conversion into leaving group, selected from group, consisting of alkylsulfonic acid with unbranched or branched chain of 1-10 carbon atoms, haloalkylsulfonic acid with unbranched or branched chain of 1-9 carbon atoms, aromatic sulfonic acid and chloride of aromatic sulfonic acid; as well as stage of purification of reaction solution, obtained at the stage of interaction, to obtain practically individual stereoisomer of substance with the following chemical formula (2), where R1 represents protective group of carboxyl group, R2 represents protective group of amino group, and R3 represents leaving group.

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9 cl, 2 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula (I) in which R1 represents -OH; R2 represents radioactive fluorine; R3 represents hydrogen, and R4 represents C1-C6 alkyl; and to their pharmaceutically acceptable salts. Also the invention refers to a pharmaceutical composition showing the property to bind amyloid for detecting amyloid deposits, containing an effective amount of a benzothiazole derivative of formula (I) and a pharmaceutically acceptable carrier, and to a method of detecting amyloid deposits in a mammal by introduction of the evaluated amount of the benzothiazole derivative of formula (I) able for specific binding with amyloid deposits with following detection of the bound amount.

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining carbamide with stable carbon isotope 13C for application in medical diagnostics of gastrointestinal tract diseases. Claimed method has two stages, the first stage includes interaction of labeled carbon dioxide and propylene oxide at temperature 120-130°C and pressure 1.3-1.5 MPa in presence of catalyst with further isolation of labeled propylene carbonate. Catalyst of the first stage is complex of zinc bromide with tertiary organophosphine or 1-butyl-3-methylimidasolium chloride, and mole ratio of propylene oxide to catalyst constitutes 500-2000:1. At the second stage carried out is ammonolysis of isolated liquid propylene carbonate at temperature 130-150°C and pressure 5.0-7.0 MPa with further isolation of target product.

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FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-phenyl-substituted tricyclic nitrogen compounds labelled with tritium and having general formula: ; . The method involve direct phenylation of the heterocyclic nitrogen atom in tricyclic nitrogen compounds (acridine, phenanthridine), uniformly deposited on a stabilising salt KBF4, in a closed system, using nucleogenic phenyl cations generated during beta-decay of tritium in double labelled benzene.

EFFECT: novel, easy to implement single-step method of obtaining novel tritium-labelled N-phenylacridine and phenanthridine derivatives with good output on radioactivity.

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FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a radioactive fluorine-labelled organic compound of formula (3). The method involves a step for splitting an ester of formula (1), where R1 is a straight or branched C1-C10 alkyl and R2 is a protecting group selected from straight or branched C2-C7 alkyloxycarbonyl groups, passed through and held in a reverse phase column containing filler with a structure in which C2-C18 alkyl groups are attached to a substrate by silicon. In order to split said ester, alkali solution is fed into the column, after which alkaline solution is discharged from the column to obtain a compound of formula (2), where X is sodium or potassium and R2 is a protecting group selected from straight or branched C2-C7 alkyloxycarbonyl groups. At the next step, the protecting group R2 of the compound of formula (2), obtained at the ester splitting step, is removed to obtain a compound of formula (3).

EFFECT: method enables to reduce the amount of nonradioactive impurities and obtain a compound of formula (3) with good output.

2 cl, 3 dwg, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel precursor compounds of formula (1), which can be used to produce organic compounds which are labelled with radioactive halogen used in positron emission tomography and single-photon emission computed tomography. In formula (1) , n equals 0; R1 is an ethyl, 1-propyl or isopropyl substitute; X is a group of formula OR2; R2 is a perfluoroalkyl sulphonyl substitute with a straight or branched chain containing 1-7 carbon atoms; and R3 is an alkyloxycarbonyl with a straight or branched chain containing 2-7 carbon atoms.

EFFECT: high efficiency of the compounds.

3 cl, 3 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: novel phenyloxyaniline derivative labelled with radioactive halogen has formula (I), where R1 denotes an unsubstituted alkyl group having 1-10 carbon atoms, X4 denotes a hydrogen atom, and X1, X2 and X3 are identical or different and each denotes a hydrogen atom, an alkoxy group, having 1-5 carbon atoms, a halogen atom, or a radioactive halogen atom selected from a group comprising 121I, 123I, 124I, 125I, 131I, provided that X2 or X3 denote a radioactive halogen atom selected from a group comprising 121I, 123I, 124I, 125I, 131I, which is a compound which is suitable during early detection, prevention and treating diseases such as dementia of the Alzheimer's type.

EFFECT: more effective use of the compounds.

3 cl, 6 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(2-aminoethyl)pyrocatechol of formula (I), which is uniformly labelled with deuterium or tritium, and is used in analytical chemistry and biological research. 4-(2-aminoethyl)pyrocatechol which is uniformly labelled with deuterium or tritium is obtained using nanodiamond powder (NDP).

EFFECT: obtaining 4-(2-aminoethyl)pyrocatechol which is uniformly labelled with deuterium or tritium.

1 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a compound of formula , where: R1 is hydrogen or C1-4alkyl; each of R2 and R4 is independently selected from C1-4alkyl [11C]-C1-4alkyl and [18F]-C1-4fluoroalkyl, provided that at least one of R2 and R4 is [11C]-C1-4alkyl or [18F]-C1-4fluoroalkyl; and R3 is a halogen, used for visualising an NMDA-mediated disease and method of producing said compound.

EFFECT: high accuracy of visualisation.

11 cl, 10 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to radiopharmaceutical composition for determination of presence, localisation and/or quantity of one or more amyloid deposits on an organ or area of subject's body. Claimed composition contains compound of formula

:

Z represents S, NR', O or C(R')2, where each R' independently represents H or C1-6alkyl, Y represents hydrogen, halogeno, OR' or SR', (R1 = H or C1-6alkyl), or Y represents -NR1R2; and each R1-10 is independently selected from group, consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, C1-6alcoxy, C4-6cycloalkyl, hydroxyl, C1-6hydroxyalkyl, C2-6hydroxyalkenyl, C2-6hydroxyalkinyl, thiol, C1-6thioalkyl, C2-6thioalkenyl, C2-6thioalkinyl, C1-6thioalkoxy, halogeno, C1-6halogenoalkyl, C2-6halogenoalkenyl, C2-6halogenoalkinyl, C1-6halogenoalkoxy, amino, C1-6aminoalkyl, C2-6aminoalkenyl, C2-6aminoalkinyl, C1-6aminoalkoxy, cyano, C1-6cyanoalkyl, C2-6cyanoalkenyl, C2-6cyanoalkinyl and C1-6cyanoalkoxy; nitro, C1-6nitroalkyl, C2-6nitroalkenyl, C2-6nitroalkinyl and C1-6nitroalkoxy. Composition also contains biocompatible carrier-medium and 0.05-5.0% wt/vol of polysorbate at pH from 4.0 to 10.5. One atom of said formula I compound represents radioactive isotope, suitable for visualisation in vivo. Also claimed is method of obtaining said radiopharmaceutical composition.

EFFECT: invention ensures reduced loss of derivatives of thioflavin derivatives and high radioactivity.

22 cl, 5 ex

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