CN115400232A - Method for synthesizing radiopharmaceutical - Google Patents

Method for synthesizing radiopharmaceutical Download PDF

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Publication number
CN115400232A
CN115400232A CN202110577060.XA CN202110577060A CN115400232A CN 115400232 A CN115400232 A CN 115400232A CN 202110577060 A CN202110577060 A CN 202110577060A CN 115400232 A CN115400232 A CN 115400232A
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fbat
compound
radiopharmaceutical
synthesized
amount
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田海滨
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Hanzhong Hanhe Medical Technology Co ltd
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Hanzhong Hanhe Medical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/90—Plate chromatography, e.g. thin layer or paper chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
    • G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
    • G01T1/16—Measuring radiation intensity
    • G01T1/17—Circuit arrangements not adapted to a particular type of detector
    • G01T1/178—Circuit arrangements not adapted to a particular type of detector for measuring specific activity in the presence of other radioactive substances, e.g. natural, in the air or in liquids such as rain water
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography

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  • Life Sciences & Earth Sciences (AREA)
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  • Analytical Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • High Energy & Nuclear Physics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The invention discloses a method for synthesizing a radiopharmaceutical, which comprises the following steps: s1: using nitropyridine or fluoropyridine in combination with spirochete to produce unlabeled nitro precursor compound 1 or F-18 reference compound FBAT, and performing mp, NMR and high resolution ms analyses on compound 1 and reference compound FBAT; s2: using a strategy similar to that previously used for F-18-FFDI, we will use either nitropyridine or fluoropyridine binding spirochetes. The invention determines the radiochemical purity of the synthesized F-18-FBAT by using a radioactive thin-layer chromatography and an analytical radioactive high-performance liquid chromatography on a silica gel chromatographic strip, and verifies the identity of the F-18-FBAT by co-injection with a reference FBAT, so that when the specific activity is determined, the quality (mu mol) of the known radioactive F-18-FBAT is compared with a standard curve of the concentration of a known reference compound by using HPLC at 220nm, thereby achieving the aim of better quality control, avoiding the occurrence of redundant steps and ensuring that the synthesized medicine has higher quality.

Description

Method for synthesizing radiopharmaceutical
Technical Field
The invention relates to the technical field of medical drug synthesis, in particular to a method for synthesizing a radioactive drug.
Background
The radioactive drug is a special drug containing radionuclide for medical diagnosis and treatment, and can be used for a compound or a biological preparation containing radioactive nuclide markers for medical diagnosis or treatment in a body, and the radioactive drug has certain requirements on the type, energy and radioactive half-life of the emitted nuclear rays according to diagnosis and treatment requirements except that the radioactive drug and general drugs have to meet the requirements of pharmacopoeia such as sterility, no heat source, low chemical toxicity and the like.
Most of the existing synthetic methods for radiopharmaceuticals on the market cannot achieve a good control effect on the synthetic quality, so that the synthetic finished drugs have quality differences, the yield is low, the synthetic process is complicated, repeated steps are required for many times, the operation of workers is not facilitated, and the quality of the synthetic drugs cannot be guaranteed.
Disclosure of Invention
The invention provides a method for synthesizing a radiopharmaceutical, aiming at the defects in the background technology.
In order to solve the above phenomena, the invention adopts the following technical scheme that the synthesis method of the radiopharmaceutical comprises the following steps:
s1, using nitropyridine or fluoropyridine to bind to spirochete to generate unlabeled nitro precursor compound 1 or F-18 reference compound FBAT, and carrying out mp, NMR and high resolution ms analysis on the compound 1 and the reference compound FBAT;
s2, using a strategy similar to that previously used for F-18-FFDI, we will use nitropyridine or fluoropyridine binding spirochetes to generate unlabeled nitro precursor compound 1 or F-18 reference compound FBAT, which compound 1 and reference compound FBAT will be analyzed by mp, NMR and high resolution ms;
s3, directly eluting the mixture into a sealed reaction container by using a solution of potassium carbonate and Kryptofix 2.2.2 with a first amount in 1.5mL of acetonitrile and water;
s4, removing the solvent under vacuum and nitrogen flow, adding a proper amount of dry acetonitrile for 3 times, and then evaporating and drying the mixture;
s5, adding a proper amount of mononitro precursor compound in dimethylformamide into the dry f-18-fluoride-cryptate complex, heating the mixture until the temperature reaches 130 ℃, then cooling, adding 8 ml of water, and transferring the mixture through a C-18Sep-Pak ink box;
s6, f-18-labelled f-18FBAT was screened with the appropriate amount of CH3CN in another sealed vessel, the solvent was removed by rotary evaporation, water and 0.15 m phosphate buffer solution were added to the product and the mixture filtered aseptically to sterile, pyrogen-free bottles, and the final product was subjected to QC testing.
As a further preferred mode of the invention, in step S1, if necessary, a nonradioactive synthesis of different isoquinolinamines and in vitro characterization of F-18-FBAT a) designed synthesis of nitroisoquinolinamine precursors and F-18 reference compounds are required.
As a further preferred form of the invention, in step S2, if desired, different isoquinolinamine analogues will be synthesized and evaluated to optimise binding, and once a lead compound with high binding affinity has been identified, a non-radioactive 19F reference compound will be synthesized for further characterisation.
As a further preferred form of the invention, in step S2, the ogs will be synthesized and evaluated, if necessary, to optimize binding, and once the lead compound with high binding affinity is identified, a non-radioactive 19F reference compound will be synthesized for further characterization.
As a further preferred mode of the present invention, in step S3, the amount of potassium carbonate is 1mg and the amount of kryptofix 2.2.2 is 5mg.
In a further preferred embodiment of the present invention, in step S3, the ratio of acetonitrile to water is 4:1, and the size of the sealed reaction vessel is 10 ml.
In a further preferred embodiment of the present invention, in step S4, the temperature under vacuum is 85 ℃ to 90 ℃ and the amount of dry acetonitrile is 0.8 to 1.0 ml.
As a further preferable mode of the present invention, in step S5, the amount of the mononitro precursor compound in dimethylformamide is 0.25 ml, the heating time is 20 minutes, and the cooling time is 5 minutes.
As a further preferred mode of the invention, in step S5, the cartridge would need to be rinsed 3 times with 10 ml of water and then dried for 2 minutes with a stream of nitrogen.
As a further preferred mode of the present invention, in step S6, the amount of CH3CN was 2.5 ml, while the size of the sealed container was 10 ml.
The invention determines the radiochemical purity of the synthesized F-18-FBAT by using a radioactive thin layer chromatography and an analytical radioactive high performance liquid chromatography on a silica gel chromatographic strip, and verifies the identity of the F-18-FBAT by co-injection with a reference FBAT, so that when the specific activity is determined, the quality (mu mol) of the F-18-FBAT with known radioactivity is compared with a standard curve of the concentration of a known reference compound by using HPLC at 220nm, thereby achieving the aim of better quality control.
Drawings
FIG. 1 is a schematic diagram of the synthesis of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a technical scheme that: a method for synthesizing a radiopharmaceutical comprises the following steps:
s1, using nitropyridine or fluoropyridine to bind to spirochete to generate unlabeled nitro precursor compound 1 or F-18 reference compound FBAT, and carrying out mp, NMR and high resolution ms analysis on the compound 1 and the reference compound FBAT;
s2, using a strategy similar to that previously used for F-18-FFDI, we will use nitropyridine or fluoropyridine binding spirochetes to generate unlabeled nitro precursor compound 1 or F-18 reference compound FBAT, which will be analyzed by mp, NMR and high resolution ms;
s3, directly eluting the mixture into a sealed reaction container by using a solution of potassium carbonate and Kryptofix 2.2.2 with a first amount in 1.5mL of acetonitrile and water;
s4, removing the solvent under vacuum and nitrogen flow, adding a proper amount of dry acetonitrile for 3 times, and then evaporating and drying the mixture;
s5, adding a proper amount of mononitro precursor compound in dimethylformamide into the dry f-18-fluoride-cryptate complex, heating the mixture until the temperature reaches 130 ℃, then cooling, adding 8 ml of water, and transferring the mixture through a C-18Sep-Pak ink box;
s6, f-18-labelled f-18FBAT was screened with the appropriate amount of CH3CN in another sealed vessel, the solvent was removed by rotary evaporation, water and 0.15 m phosphate buffer solution were added to the product and the mixture filtered aseptically to sterile, pyrogen-free bottles, and the final product was subjected to QC testing.
In step S1, non-radioactive synthesis of different isoquinolinamines and in vitro characterization of F-18-FBAT is required if necessary a) designed synthesis of nitroisoquinolinamine precursors and F-18 reference compounds.
In step S2, if desired, different isoquinolinamine analogues will be synthesized and evaluated to optimize binding, and once a lead compound with high binding affinity is identified, a non-radioactive 19F reference compound will be synthesized for further characterization.
In step S2, if desired, the ogs will be synthesized and evaluated to optimize binding, and once a lead compound with high binding affinity is identified, a non-radioactive 19F reference compound will be synthesized for further characterization.
In step S3, the amount of potassium carbonate is 1mg and the amount of kryptofix 2.2.2 is 5mg.
In step S3, the ratio of acetonitrile to water is 4:1, and the size of the sealed reaction vessel is 10 ml.
In step S4, the temperature under vacuum is 85 ℃ to 90 ℃ and the dry acetonitrile content is 0.8 to 1.0 ml.
In step S5, the amount of mononitro precursor compound in dimethylformamide was 0.25 ml, the heating time was 20 minutes and the cooling time was 5 minutes.
In step S5, the cartridge would simultaneously need to be rinsed 3 times with 10 ml of water and then dried for 2 minutes with a stream of nitrogen.
In step S6, the amount of CH3CN was 2.5 ml, and the size of the sealed container was 10 ml.
In conclusion, the invention determines the radiochemical purity of the synthesized F-18-FBAT by the radioactive thin layer chromatography and the analytical radioactive high performance liquid chromatography on a silica gel chromatographic strip, and verifies the identity of the F-18-FBAT by co-injection with a reference FBAT, so that when the specific activity is determined, the quality (mu mol) of the known radioactive F-18-FBAT is compared with a standard curve of the concentration of a known reference compound by HPLC at 220nm, thereby achieving the aim of better quality control, ensuring that the synthesis process of the radiopharmaceutical is smoother, avoiding the occurrence of redundant steps and ensuring that the synthesized drug has higher quality.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims (10)

1. A method for synthesizing a radiopharmaceutical is characterized by comprising the following steps:
s1: using nitropyridine or fluoropyridine in combination with spirochete to produce unlabeled nitro precursor compound 1 or F-18 reference compound FBAT, and performing mp, NMR and high resolution ms analyses on compound 1 and reference compound FBAT;
s2: using a strategy similar to that previously used for F-18-FFDI, we will use nitropyridine or fluoropyridine binding spirochetes to generate unlabeled nitro precursor compound 1 or F-18 reference compound FBAT, which compound 1 and reference compound FBAT will be analyzed by mp, NMR and high resolution ms;
s3: directly eluting with a first amount of potassium carbonate and a solution of Kryptofix 2.2.2 in 1.5mL of acetonitrile and water into a sealed reaction vessel;
s4: removing the solvent under vacuum and nitrogen flow, adding appropriate amount of dry acetonitrile for 3 times, and evaporating to dry;
s5: adding an appropriate amount of mononitro precursor compound in dimethylformamide to the dry f-18-fluoride-cryptate complex, heating the mixture until it reaches 130 ℃, then cooling, adding 8 ml of water, and passing the mixture through a C-18Sep-Pak cartridge;
s6: f-18-labelled f-18FBAT was screened with the appropriate amount of CH3CN into another sealed container, the solvent was removed by rotary evaporation, water and 0.15 m phosphate buffer solution were added to the product and the mixture was sterile filtered to sterile, pyrogen-free bottles and the final product was QC tested.
2. A method for the synthesis of a radiopharmaceutical as defined in claim 1 wherein, in step S1, if necessary, a nonradioactive synthesis of different isoquinolinamines and in vitro characterization of F-18-FBAT a) designed synthesis of nitroisoquinolinamine precursors and F-18 reference compounds is required.
3. A method of radiopharmaceutical synthesis according to claim 1, where in step S2, if desired, different isoquinolinamine analogues will be synthesized and evaluated for optimal binding, and once a lead compound with high binding affinity is identified, a non-radioactive 19F reference compound will be synthesized for further characterization.
4. A method of radiopharmaceutical synthesis according to claim 1, where in step S2, if necessary, an ogs is synthesized and evaluated to optimize binding, and once a lead compound with high binding affinity is identified, a non-radioactive 19F reference compound is synthesized for further characterization.
5. A method of synthesising a radiopharmaceutical as claimed in claim 1 wherein in step S3 the amount of potassium carbonate is 1mg and the amount of kryptofix 2.2.2 is 5mg.
6. The method of claim 1, wherein in step S3, the ratio of acetonitrile to water is 4:1, and the size of the sealed reaction vessel is 10 ml.
7. A method for the synthesis of a radiopharmaceutical as defined in claim 1 wherein, in step S4, the temperature is between 85 ℃ and 90 ℃ under vacuum and the dry acetonitrile content is between 0.8 and 1.0 ml.
8. A method of synthesizing a radiopharmaceutical as defined in claim 1 wherein, in step S5, the amount of the mononitrogen precursor compound in the dimethylformamide is 0.25 ml, the heating time is 20 minutes, and the cooling time is 5 minutes.
9. A method for synthesizing a radiopharmaceutical as defined in claim 1 wherein, in step S5, the cartridge is rinsed 3 times with 10 ml of water and then dried for 2 minutes with a stream of nitrogen.
10. A method for synthesizing a radiopharmaceutical as defined in claim 1 wherein in step S6 the amount of CH3CN is 2.5 ml and the size of the sealed container is 10 ml.
CN202110577060.XA 2021-05-26 2021-05-26 Method for synthesizing radiopharmaceutical Pending CN115400232A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030064978A1 (en) * 2000-02-14 2003-04-03 Christopher Walpole Novel compounds
CN101648027A (en) * 2009-06-09 2010-02-17 王明芳 Positron emission tomography (PET) diagnostic radioactive drug and preparation method thereof
CN102271716A (en) * 2008-12-31 2011-12-07 阿维德放射性药品公司 Synthesis of 18f-radiolabeled styrylpyridines from tosylate precursors and stable pharmaceutical compositions thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030064978A1 (en) * 2000-02-14 2003-04-03 Christopher Walpole Novel compounds
CN102271716A (en) * 2008-12-31 2011-12-07 阿维德放射性药品公司 Synthesis of 18f-radiolabeled styrylpyridines from tosylate precursors and stable pharmaceutical compositions thereof
CN101648027A (en) * 2009-06-09 2010-02-17 王明芳 Positron emission tomography (PET) diagnostic radioactive drug and preparation method thereof

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