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KR-20260064473-A - Preparation of radiopharmaceuticals using the solid phase extraction process

KR20260064473AKR 20260064473 AKR20260064473 AKR 20260064473AKR-20260064473-A

Abstract

The present invention relates to a method for manufacturing a radiopharmaceutical in which purification is performed by solid-phase extraction (SPE) and a cassette configured to perform said method in an automated synthesis module. The method for synthesizing an 18F -labeled radiopharmaceutical according to the present invention utilizes a solid-phase extraction (SPE) process, which improves reproducibility and shortens synthesis time compared to the existing HPLC process, thereby enabling the production of high-purity, high-yield 18F -labeled radiopharmaceuticals. Furthermore, since the 18F -labeled radiopharmaceutical can be conveniently synthesized using a cassette configured to perform said method in an automated synthesis module, it is expected to be usefully utilized in the production of 18F -labeled radiopharmaceuticals.

Inventors

  • 고나래

Assignees

  • 재단법인 아산사회복지재단

Dates

Publication Date
20260507
Application Date
20250630
Priority Date
20241030

Claims (20)

  1. (a) A step of capturing radioactive fluoride [ 18F ] in SPE cartridge 1; (b) a step of introducing eluent 1 into the SPE cartridge 1 to elute the captured radioactive fluoride [ 18 F ] into the reaction vessel; (c) a step of adding a precursor compound to the reaction vessel; (d) a step of adding a reaction solvent to the reaction vessel to react the precursor compound with the radiofluoride [ 18 F ]; (e) a step of hydrolyzing a radiofluoride [ 18 F ]-labeled precursor compound by adding SPE solution 2 to the reaction vessel; and (f) A method for synthesizing an 18 F-labeled radiopharmaceutical using solid phase extraction (SPE), comprising the step of SPE purifying the hydrolysis mixture of step (e) using SPE cartridge 2.
  2. In paragraph 1, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above SPE cartridge 1 is an ion exchange cartridge.
  3. In paragraph 2, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the ion exchange cartridge is a quaternary methylammonium (QMA) cartridge.
  4. In paragraph 1, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above-mentioned eluent 1 is a solution in which a cryptand is dissolved.
  5. In paragraph 4, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the cryptand is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan (Cryptopix 2.2.2).
  6. In paragraph 4, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the solution in which the above-mentioned cryptand is dissolved is a solution dissolved in one or more solvents selected from the group consisting of organic solvents and KOMs buffer.
  7. In paragraph 6, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the organic solvent is one or more selected from the group consisting of methanol, ethanol, n -propyl alcohol, n-butyl alcohol, isopropyl alcohol, isobutanol, isopentanol, acetonitrile ( CH₃CN ), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF).
  8. In paragraph 1, The reaction solvent comprises primary alcohols including methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, and n-octanol; secondary alcohols including isopropanol, isobutanol, isoamyl alcohol, and 3-pentanol; and t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol, 2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-methyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, 1-methoxy-2methyl-2-propanol, and One or more protic solvents selected from the group consisting of tertiary alcohols including 1-methylcycloheptanol; or A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized by using one or more aprotic solvents selected from the group consisting of acetonitrile ( CH₃CN ), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF).
  9. In paragraph 1, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that step (d) above involves heating the reaction vessel to a temperature of 50 to 200°C for 1 to 60 minutes.
  10. In paragraph 1, The above step (e) involves leaving the reaction vessel at a temperature of 50 to 150°C for 1 to 60 seconds; or A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized by heating at a temperature of 50 to 150 ℃ for 1 to 10 minutes.
  11. In paragraph 1, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above SPE solution 2 is a hydrolysis solution in which one or more bases selected from the group consisting of sodium butoxide, sodium hydroxide, potassium hydroxide, sodium hydroxide, sodium methyl mercaptan, sodium thiomethoxide, sodium ethoxide, ammonia/ammonium hydroxide, and sodium methoxide are dissolved.
  12. In paragraph 1, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above SPE cartridge 2 is a reverse phase cartridge.
  13. In Paragraph 12, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above reverse-phase cartridge is selected from the group consisting of a C18 cartridge, a tC18 cartridge, a C8 cartridge, a CN cartridge, an HLB cartridge, a Porapak cartridge, an RDX cartridge, and an NH2 cartridge.
  14. In paragraph 1, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above step (f) comprises the following steps: (f-1) A step of capturing the hydrolysis mixture of step (e) above in SPE cartridge 2; and (f-2) A step of cleaning SPE cartridge 2 by pouring a cleaning solution into the SPE cartridge 2.
  15. In Paragraph 14, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the washing solution is one or more selected from the group consisting of water, ethanol, and acetonitrile.
  16. In paragraph 1, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized by further comprising the following steps: (g) a step of diluting the eluent obtained by passing eluent 2 through the SPE cartridge 2 in a container containing SPE solution 3; and (h) A step of passing the diluted solution of step (g) through SPE cartridge 3.
  17. In Paragraph 16, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above eluent 2 is one or more organic solvents selected from the group consisting of tetrahydrofuran (THF), ethyl acetate, dichloromethane (DCM), dimethylformamide (DMF), acetonitrile ( CH₃CN ), dimethyl sulfoxide (DMSO), acetic acid, t-butanol, isopropanol, n-propanol, ethanol (EtOH), and methanol ( MeOH ).
  18. In Paragraph 16, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above SPE solution 3 is one or more selected from the group consisting of physiological saline, water for injection, Hartmann-D solution, PBS (Phosphate Buffered Saline), HBSS (Hank's Balanced Salt Sol'n), and GBSS ( Gey 's Balanced Salt Sol'n).
  19. In Paragraph 18, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above SPE solution 3 contains one or more stabilizers selected from the group consisting of ascorbic acid, sodium ascorbate, thiamine, and pyridoxine.
  20. In Paragraph 16, A method for synthesizing an 18 F-labeled radiopharmaceutical, characterized in that the above SPE cartridge 3 is a normal cartridge.

Description

Preparation of radiopharmaceuticals using the solid phase extraction process The present invention relates to a method for manufacturing a radiopharmaceutical in which purification is performed by solid-phase extraction (SPE), and a cassette configured to perform said method in an automated synthesis module. [ 18 F]FP-CIT is a radiopharmaceutical used to evaluate dopamine transporter (DAT) levels in the brain during PET (Positron Emission Tomography) imaging. DAT is an essential membrane protein responsible for reabsorbing dopamine from the synaptic cleft into presynaptic neurons, and [ 18 F]FP-CIT binds to DAT, allowing for the visualization and quantification of DAT levels in the brain. In clinical practice, PET imaging using [ 18 F]FP-CIT is commonly used to investigate the integrity of the dopamine system and evaluate the effectiveness of therapeutic interventions in various neuropsychiatric disorders, including Parkinson's disease, Lewy body dementia, and depression. [ 18F ]FP-CIT typically involves transferring F-18 generated in a cyclotron to an automated synthesis module for [ 18F ]-fluorination (capture, elution, drying) and [ 18F ]-precursor. The product is manufactured through a process consisting of labeling, purification, and formulation. In this context, the automated synthesis module is a synthesis device that not only ensures high-quality radiopharmaceuticals by precisely controlling reagent addition, reaction temperature, pressure, and time according to optimized input parameters at each stage, but also enhances safety by reducing manual handling of radioactive materials by operators. Commercially available automated synthesis modules include non-cassette types (TracerLab FXFN, GE Healthcare; Modular Lab, Eckert & Ziegler, etc.) and cassette types (TracerLab MX, GE Healthcare; FastLab, GE Healthcare; AIO module, Trasis, etc.). While non-cassette types involve the inconvenience of cleaning after synthesis due to the use of reaction vessels and reagent containers fixed to the module, cassette types utilize disposable cassette packages, eliminating the need for additional cleaning and allowing for increased production cycles through cassette replacement. Furthermore, as they comply with GMP (Good Manufacturing Practice), there is a recent trend in clinical practice to prefer cassette-type automated synthesis modules. Generally, [ 18 F]FP-CIT is manufactured using an automated synthesis module connected to a High-Performance Liquid Chromatography (HPLC) system. While the HPLC process has the advantage of securing high-purity radiopharmaceuticals by separating unreacted substances and impurities based on the principle of separation according to chemical properties, it has difficulties such as: 1) low cost-efficiency compared to high initial equipment investment, continuous use of consumables, and maintenance; 2) labor-intensive and time-consuming optimization of separation parameters; 3) regular cleaning and maintenance to prevent cross-contamination; 4) low reproducibility due to the manual purification process by operators; and 5) increased manufacturing time and the generation of radioactive waste caused by concentrating large amounts of separated liquid. Accordingly, purification processes utilizing SPE (Solid Phase Extraction) cartridges are being developed to overcome the aforementioned problems. SPE cartridges consist of solid adsorbent particles packed into a small column and are primarily used to purify and concentrate compounds from liquid samples. The adsorbent material varies depending on the target compound and the application; as the liquid sample containing the target compound passes through the cartridge, it interacts with the adsorbent through various interactions—such as polarity, non-polarity, and ion exchange—resulting in the solid phase. Simultaneously, unwanted components are washed away, and the residual substances are eluted from the cartridge as a clean target compound using a solvent that interferes with the interaction with the adsorbent. This SPE purification method has the advantages of: 1) being cost-effective in high-volume clinical environments as it requires less maintenance and consumables; 2) being simpler and easier to design and operate; 3) being suitable for routine production in clinical environments with high reproducibility by implementing an automated synthesis process with minimal operator intervention; 4) being able to improve production efficiency by shortening the overall synthesis time by minimizing the need for multiple purification steps; and 5) being easy to expand applications to meet the increasing demand for the production of various radiopharmaceuticals by appropriately utilizing various types of SPE cartridges. Accordingly, the inventors established a method for manufacturing 18F -labeled radiopharmaceuticals with improved reproducibility and reduced synthesis time by developing a new automated synthesis process with minimized operator inter