Preparation of radiopharmaceuticals using solid phase extraction (SPE) process

Abstract

The present invention relates to a method for preparing a radiopharmaceutical in which purification is performed by solid phase extraction (SPE) and to a cassette configured to perform the method in an automated synthesis module. By using a solid-phase extraction (SPE) process, the method for synthesizing an 18F-labeled radiopharmaceutical according to the present invention improves reproducibility and shortens synthesis time compared to a conventional HPLC process, thereby enabling production of an 18F-labeled radiopharmaceutical with high purity and high yield. By using a cassette configured to perform the synthesis method according to the present invention in an automated synthesis module, the 18F-labeled radiopharmaceutical can be conveniently synthesized. Accordingly, the method is expected to be advantageously applied to the production of 18F-labeled radiopharmaceuticals.

Description

Manufacturing of radiopharmaceuticals using the SPE (Solid Phase Extraction) process

[0001] 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.

[0002] The present invention claims priority based on Korean Patent Application No. 10-2024-0150896 filed on October 30, 2024 and Korean Patent Application No. 10-2025-0087367 filed on June 30, 2025, and all contents disclosed in the specifications and drawings of said applications are incorporated by reference.

[0003] [ 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 the reabsorption of dopamine from the synaptic cleft into presynaptic neurons, [ 18 F]FP-CIT binds to DAT, enabling the visualization and quantification of DAT levels in the brain. In clinical practice, [ 18 PET imaging using [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.

[0004] [ 18 F]FP-CIT typically transfers F-18s generated in a cyclotron to an automated synthesis module and [ 18 F]-fluorination (capture, elution, drying), [ 18[F]- It is manufactured through a process of precursor labeling, purification, and formulation. Here, the automated synthesis module is a synthesis device that not only secures high-quality radiopharmaceuticals by precisely controlling the addition of reagents, reaction temperature, pressure, and time according to input parameters optimized for 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.). In the case of non-cassette types, cleaning after synthesis is cumbersome because they use reaction vessels and reagent containers fixed to the module; however, cassette types use 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.

[0005] Generally [ 18F]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.

[0006] 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.

[0007] Therefore, the inventors have developed a new automated synthesis process with minimized operator intervention using the SPE process, which improves reproducibility and reduces synthesis time. 18 A method for manufacturing F-labeled radiopharmaceuticals was established, and through this, high-purity 18 F-labeled radiopharmaceuticals were obtained in high yield. In addition, the present invention was completed by developing a new cassette package to carry out this.

[0008] The inventors of the present invention utilize the SPE process 18 As a result of research conducted to synthesize F-labeled radiopharmaceuticals,18 By adding a hydrolysis step to the synthesis of F-labeled radiopharmaceuticals, reproducibility is improved and synthesis time is shortened compared to the existing HPLC process, resulting in high purity and high yield. 18 Using an SPE process capable of obtaining F-labeled radiopharmaceuticals 18 The present invention was completed by developing a method for synthesizing F-labeled radiopharmaceuticals and a cassette configured to perform the synthesis method according to the present invention in an automated synthesis module.

[0009] Therefore, the object of the present invention is to utilize solid-phase extraction (SPE). 18 The present invention provides a method for synthesizing F-labeled radiopharmaceuticals.

[0010] Another objective of the present invention is to utilize solid-phase extraction (SPE). 18 The purpose is to provide a cassette for the synthesis of F-labeled radiopharmaceuticals.

[0011]

[0012] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0013] To achieve the above objective, the present invention provides (a) radioactive fluoride [ 18 (b) a step of capturing [F] in SPE cartridge 1; (b) introducing eluent 1 into the SPE cartridge 1 to capture the captured radioactive fluoride [ 18 A step of eluting [F] into a 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 form the precursor compound and radiofluoride [ 18 Step of reacting F]; (e) adding SPE solution 2 to the reaction vessel to produce radioactive fluoride [ 18F] A step of hydrolyzing a labeled precursor; and (f) a step of SPE purifying the hydrolyzed mixture of step (e) using SPE cartridge 2, using solid-phase extraction (SPE). 18 A method for synthesizing F-labeled radiopharmaceuticals is provided.

[0014] In one embodiment of the present invention, the SPE cartridge 1 may be an ion exchange cartridge, but is not limited thereto.

[0015] In another embodiment of the present invention, the ion exchange cartridge may be a quaternary methylammonium (QMA) cartridge, but is not limited thereto.

[0016] In another embodiment of the present invention, the eluent 1 may be a solution in which a cryptand is dissolved, but is not limited thereto.

[0017] In another embodiment of the present invention, the cryptand may be 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan (Cryptopix 2.2.2), but is not limited thereto.

[0018] In another embodiment of the present invention, the solution in which the cryptand is dissolved may be a solution dissolved in one or more solvents selected from the group consisting of organic solvents and KOMs buffers, but is not limited thereto.

[0019] In another embodiment of the present invention, the organic solvent may be 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), but is not limited thereto.

[0020] In another embodiment of the present invention, the reaction solvent comprises a primary alcohol including methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, and n-octanol; and a secondary alcohol 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 one or more aprotic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), but not limited thereto.

[0021] In another embodiment of the present invention, step (d) may involve heating the reaction vessel to a temperature of 50 to 200°C for 1 to 60 minutes, but is not limited thereto.

[0022] In another embodiment of the present invention, step (e) may be to leave the reaction vessel at a temperature of 50 to 150 ℃ for 1 to 60 seconds; or to heat at a temperature of 50 to 150 ℃ for 1 to 10 minutes, but is not limited thereto.

[0023] In another embodiment of the present invention, the SPE solution 2 may be, but is not limited to, 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.

[0024] In another embodiment of the present invention, the SPE cartridge 2 may be a reverse phase cartridge, but is not limited thereto.

[0025] In another embodiment of the present invention, the reverse phase cartridge may be selected from the group consisting of, but not limited to, 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.

[0026] In another embodiment of the present invention, step (f) may include, but is not limited to, the following steps:

[0027] (f-1) a step of capturing the hydrolysis mixture of step (e) above into SPE cartridge 2; and (f-2) a step of cleaning SPE cartridge 2 by pouring a cleaning solution into SPE cartridge 2.

[0028] In another embodiment of the present invention, the cleaning solution may be one or more selected from the group consisting of water, ethanol, and acetonitrile, but is not limited thereto.

[0029] In another embodiment of the present invention, the synthesis method may further include, but is not limited to, the following steps:

[0030] (g) a step of diluting the eluent obtained by passing the eluent 2 through the SPE cartridge 2 in a container containing SPE solution 3; and (h) a step of passing the diluted solution from step (g) through the SPE cartridge 3.

[0031] In another embodiment of the present invention, the eluent 2 may be 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), but is not limited thereto.

[0032] In another embodiment of the present invention, the SPE solution 3 may be 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), but is not limited thereto.

[0033] In another embodiment of the present invention, the SPE solution 3 may contain one or more stabilizers selected from the group consisting of ascorbic acid, sodium ascorbate, thiamine, and pyridoxine, but is not limited thereto.

[0034] In another embodiment of the present invention, the SPE cartridge 3 may be a normal cartridge, but is not limited thereto.

[0035] In another embodiment of the present invention, the normal cartridge may be selected from the group consisting of an alumina cartridge, a diol cartridge, and a silica cartridge, but is not limited thereto.

[0036] In another embodiment of the present invention, the diluent of step (g) may be an aqueous ethanol solution of 5 to 50%, but is not limited thereto.

[0037] In another embodiment of the present invention, the above 18 F-labeled radiopharmaceuticals are [ 18F]It may be FP-CIT, but is not limited thereto.

[0038] In another embodiment of the present invention, the synthesis method may be performed in an automated synthesis module, but is not limited thereto.

[0039] In another embodiment of the present invention, the automated synthesis module may be equipped with an integral manifold or an assembled manifold, but is not limited thereto.

[0040] In addition, the present invention comprises a first vial containing a precursor compound; radioactive fluoride [ 18 A second vial containing [F]; a third vial containing eluent 1; a fourth vial containing a reaction solvent; a fifth vial containing SPE solution 2; a sixth vial containing a washing solution; a reaction vessel; an SPE cartridge; and a manifold to which the vials, the reaction vessel, and the SPE cartridge are connected (coupled), utilizing solid phase extraction (SPE). 18 Provides a cassette for synthesizing F-labeled radiopharmaceuticals.

[0041] In one embodiment of the present invention, the eluent 1 may be a solution in which a cryptand is dissolved, but is not limited thereto.

[0042] In another embodiment of the present invention, the reaction solvent comprises a primary alcohol including methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, and n-octanol; and a secondary alcohol 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 one or more aprotic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), but not limited thereto.

[0043] In another embodiment of the present invention, the SPE solution 2 may be, but is not limited to, 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.

[0044] In another embodiment of the present invention, the cleaning solution may be one or more selected from the group consisting of water, ethanol, and acetonitrile, but is not limited thereto.

[0045] In another embodiment of the present invention, the reaction vessel may be made of glass or chemical-resistant plastic material, but is not limited thereto.

[0046] In another embodiment of the present invention, the bottom of the reaction vessel may be square or circular, flat, or have a shape in which the diameter decreases toward the bottom, but is not limited thereto.

[0047] In another embodiment of the present invention, the shape in which the diameter decreases toward the bottom may be hemispherical, conical, or square pyramidal, but is not limited thereto.

[0048] In another embodiment of the present invention, the reaction vessel may be connected to two or more manifold ports, but is not limited thereto.

[0049] In another embodiment of the present invention, the SPE cartridge may be one or more selected from the group consisting of an ion exchange cartridge, a reverse phase cartridge, and a normal phase cartridge, but is not limited thereto.

[0050] In another embodiment of the present invention, the cassette may further include a seventh vial containing eluent 2; and an eighth vial containing SPE solution 3, but is not limited thereto.

[0051] In another embodiment of the present invention, the eluent 2 may be 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), but is not limited thereto.

[0052] In another embodiment of the present invention, the SPE solution 3 may be 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), but is not limited thereto.

[0053] In another embodiment of the present invention, the SPE solution 3 may contain one or more stabilizers selected from the group consisting of ascorbic acid, sodium ascorbate, thiamine, and pyridoxine, but is not limited thereto.

[0054] According to the present invention 18 The synthesis method for F-labeled radiopharmaceuticals utilizes a solid-phase extraction (SPE) process, which improves reproducibility and reduces synthesis time compared to conventional HPLC processes, thereby enabling high purity and high yield. 18 F-labeled radiopharmaceuticals can be obtained, and conveniently using a cassette configured to perform the synthesis method according to the present invention in an automated synthesis module. 18 Since F-labeled radiopharmaceuticals can be synthesized, 18 It is expected to be usefully utilized in the production of F-labeled radiopharmaceuticals.

[0055] FIG. 1 is [of the present invention 18 This is a drawing showing the F]FP-CIT SPE integrated manifold cassette (automated synthesis module: FASTlab).

[0056] FIG. 2 is [of the present invention 18 This is a drawing showing the F]FP-CIT SPE assembled manifold cassette (automated composite module: All-In-One).

[0057] FIG. 3 is [of the present invention 18 This is a drawing showing an F]FP-CIT SPE assembled manifold cassette (automated composite module: PERFORM).

[0058] FIG. 4 shows the cassette of the present invention using 18 This is a flowchart illustrating the process of manufacturing F-labeled radiopharmaceuticals.

[0059] Figure 5 is a diagram showing a reaction vessel used in an automated synthesis module.

[0060] The inventors of the present invention utilize the SPE process 18 As a result of research conducted to synthesize F-labeled radiopharmaceuticals, 18 By adding a hydrolysis step to the synthesis of F-labeled radiopharmaceuticals, reproducibility is improved and synthesis time is shortened compared to the existing HPLC process, resulting in high purity and high yield. 18 Using an SPE process capable of obtaining F-labeled radiopharmaceuticals 18 The present invention was completed by developing a method for synthesizing F-labeled radiopharmaceuticals and a cassette configured to perform the synthesis method according to the present invention in an automated synthesis module.

[0061]

[0062] The present invention will be described in detail below.

[0063]

[0064] The present invention relates to (a) radioactive fluoride [ 18 Step of capturing F] in SPE cartridge 1;

[0065] (b) Elution solution 1 is poured into the SPE cartridge 1 to capture the radioactive fluoride [ 18 Step of eluting [F] into a reaction vessel;

[0066] (c) a step of adding a precursor compound to the reaction vessel;

[0067] (d) Add a reaction solvent to the above reaction vessel to obtain a precursor compound and radiofluoride [ 18 Step of reacting F];

[0068] (e) Add SPE solution 2 to the above reaction vessel to produce radioactive fluoride [ 18Step of hydrolyzing a [F] labeled precursor; and

[0069] (f) a step of SPE purifying the hydrolysis mixture of step (e) using SPE cartridge 2, using solid-phase extraction (SPE). 18 A method for synthesizing F-labeled radiopharmaceuticals is provided, wherein each step can be performed sequentially.

[0070] Including all claims below, the SPE cartridge 1 may be an ion exchange cartridge, and according to one embodiment of the present invention, the ion exchange cartridge may be a quaternary methylammonium (QMA) cartridge, but is not limited thereto.

[0071] Including the entire claims below, in the above specification, the radioactive fluoride [in step (a) 18 "Capturing" F] in SPE cartridge 1 means radioactive fluoride [ 18 F]( 18 F - This means that ) is retained in SPE cartridge 1.

[0072] Including all claims below, the eluent 1 may be a solution in which a cryptand is dissolved, and the cryptand is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan (Cryptopix 2.2.2, K 222 It may be, but is not limited to.

[0073] Including all claims below, the solution in which the cryptand is dissolved may be a solution dissolved in one or more solvents selected from the group consisting of an organic solvent and KOMs buffer, wherein the organic solvent may be 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), but is not limited thereto.

[0074] In the present specification, including all claims below, the KOMs buffer is a hydrogen ion concentration controlled eluent of Korean Registered Patent No. 10-1326000, prepared by reacting compounds of Formula 1 and Formula 2 in the manner of Reaction Scheme 1, and may be an eluent having a hydrogen ion concentration of 6 to 8.

[0075] [Chemical Formula 1]

[0076]

[0077] (In the above Chemical Formula 1, R1 is a C1-C10 primary or secondary alkyl group or an aryl group.)

[0078] [Chemical Formula 2]

[0079] MX

[0080] (In the above Chemical Formula 2, M is lithium, sodium, potassium, cesium, rubidium, or ammonium, and in the case of ammonium, is a quaternary ammonium represented by the following Chemical Formula 3. X is a hydroxide ion, carbonate ion, bicarbonate ion, phosphate ion, diphosphate ion, triphosphate ion, or t-butoxide.)

[0081] [Chemical Formula 3]

[0082]

[0083] (In the above Chemical Formula 3, R2 is hydrogen or a C1-C10 primary or secondary alkyl group.)

[0084] [Reaction Equation 1]

[0085]

[0086] Including all claims below, the KOMs buffer is prepared using methanesulfonic acid and potassium carbonate (K2CO3) with a hydrogen ion concentration of 6 to 8, 6.3 to 8, 6.5 to 8, 6.8 to 8, 7 to 8, 7.2 to 8, 7.4 to 8, 7.6 to 8, 7.8 to 8, 6.3 to 7.9, 6.5 to 7.9, 6.8 to 7.9, 7 to 7.9, 7.2 to 7.9, 7.4 to 7.9, 7.6 to 7.9, 7.7 to 7.9, 7.8 to 7.9, 6.5 to 7.8, 6.8 to 7.8, 7 to 7.8, 7.2 to 7.8, 7.4 to 7.8, The eluent may be of 7.6 to 7.8, 7.7 to 7.8, 7.7 to 7.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, or 7.8, and according to one embodiment of the present invention, the eluent may be of a hydrogen ion concentration of 7.8, but is not limited thereto.

[0087] Including all claims below, the present specification wherein the eluent 1 is Cryptofix (K 222) 1 to 50 mg, 1 to 40 mg, 1 to 30 mg, 1 to 25 mg, 5 to 40 mg, 5 to 30 mg, 5 to 25 mg, 10 to 30 mg, 10 to 25 mg, 15 to 25 mg, 20 to 25 mg, 20 to 24 mg, 20 to 23 mg, 20 to 22 mg, 21 to 24 mg, 21 to 23 mg, 21 to 22 mg, 22 to 23 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg is methanol 0.1 to 5 ml, 0.1 to 4 ml, 0.1 to 3 ml, 0.1 to 2 ml, 0.1 to 1 ml, 0.5 to 4 ml, It may be dissolved in 0.5 to 3 ml, 0.5 to 2 ml, 0.5 to 1 ml, 0.8 to 3 ml, 0.8 to 2 ml, 0.8 to 1.5 ml, 0.8 to 1.3 ml, 0.8 to 1 ml, 1 to 1.3 ml, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 ml and KOMs buffer 0.1 to 5 ml, 0.1 to 4 ml, 0.1 to 3 ml, 0.1 to 2 ml, or 0.1 to 1 ml, and according to one embodiment of the present invention, Cryptofix (K 222 ) 22 mg may be dissolved in methanol (1 mL) and KOMs buffer (0.1-1 mL).

[0088] Including the entire claims below, the above (a) radioactive fluoride [ 18 A step of capturing [F] in SPE cartridge 1 (capture); and (b) introducing eluent 1 into SPE cartridge 1 to capture the captured radioactive fluoride [ 18 The step of eluting [F] into the reaction vessel (elutation) is 18 In the synthesis process of F-labeled radiopharmaceuticals "[ 18 F] - In the "fluorination" stage, activated in the labeling stage [ 18 F] -The drying step may include reducing the reactivity of ions and minimizing the generation of hydroxylated byproducts. The drying step involves supplying nitrogen and vacuum to a reaction vessel and heating to 10 to 150°C, 50 to 150°C, 90 to 150°C, 90 to 130°C, 90 to 110°C, 90 to 100°C, 100 to 110°C, or 100°C for 100 to 200 seconds, 150 to 200 seconds, 180 to 200 seconds, 180 to 190 seconds, 190 to 200 seconds, or 190 seconds [ 18 F] - After drying the ions, they can be completely dried by adding 0.1 to 1 mL, 0.1 to 0.8 mL, 0.1 to 0.7 mL, 0.3 to 0.7 mL, 0.4 to 0.7 mL, 0.4 to 0.6 mL, 0.4 to 0.5 mL, 0.5 to 0.6 mL, or 0.5 mL of acetonitrile (drying solvent).

[0089] Including all claims below, the step of adding a precursor compound to the reaction vessel (c) above is 18 In the "precursor addition" step of the F-labeled radiopharmaceutical synthesis process, "[ 18 F] - After the reaction vessel, which has been dried in the "fluorination" step, is cooled naturally or to 60°C, the precursor compound can be added to the reaction vessel. Additionally, according to one embodiment of the present invention, since the precursor compound used is a linear precursor compound stored in a storage solvent as disclosed in Korean Patent Application No. 10-2024-0037443, the step of drying the storage solvent after adding the precursor compound to the reaction vessel can be additionally performed.

[0090] Including the entire claims below, the precursor compound may be N-(3'-(methanesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane, which is an FP-CIT linear precursor, or N-(3'-toluenesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane, and in the present invention, the 18 F-labeled radiopharmaceuticals are [ 18 F]It may be FP-CIT, but is not limited thereto, 18 F - If the radiopharmaceutical can be manufactured using a nucleophilic fluorination reaction of a reactor and the precursor compound does not contain a protecting group, then it can be manufactured by the synthesis method according to the present invention. 18 It can be included in all F-labeled radiopharmaceuticals.

[0091] Including all claims below, the present specification comprises adding a reaction solvent to the reaction vessel (d) to form a precursor compound and a radioactive fluoride [ 18 The step of reacting [F] 18In the synthesis process of an F-labeled radiopharmaceutical, the "precursor labeling" step comprises, wherein step (d) involves heating a reaction vessel to a temperature of 50 to 200°C, 50 to 180°C, 50 to 150°C, 50 to 130°C, 50 to 120°C, 50 to 110°C, 80 to 180°C, 80 to 150°C, 80 to 130°C, 80 to 120°C, 80 to 110°C, 100 to 150°C, 100 to 130°C, 100 to 120°C, 100 to 110°C, 110 to 120°C, 120 to 130°C, 100°C, 110°C, 120°C, or 130°C for 1 minute to 60 minutes, 1 minute to Radiofluoride to a precursor compound by heating for 50 minutes, 1 to 40 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 3 to 50 minutes, 3 to 40 minutes, 3 to 30 minutes, 3 to 20 minutes, 3 to 10 minutes, 5 to 40 minutes, 5 to 30 minutes, 5 to 25 minutes, 5 to 20 minutes, 5 to 10 minutes, 10 to 20 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes [ 18 [F] can be labeled, and according to one embodiment of the present invention, in an automated synthesis module using an integrated manifold, the precursor can be labeled by heating at 110°C for 20 minutes, and in an automated synthesis module using an assembled manifold, the precursor can be labeled by heating at 120°C for 10 minutes, but is not limited thereto. In addition, according to one embodiment of the present invention, a step of drying the reaction solvent after labeling the precursor by heating can be additionally performed.

[0092] Including all claims below, the reaction solvent comprises: a primary alcohol comprising methanol, ethanol, n-propanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, and n-octanol; a secondary alcohol comprising 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

[0093] Including all claims below, the reaction solvent may be one or more aprotic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), and according to one embodiment of the present invention, the reaction solvent may be t-amyl alcohol or acetonitrile (CH3CN), but is not limited thereto.

[0094] Including all claims below, when t-amyl alcohol is used as the reaction solvent, due to the characteristic of t-amyl alcohol that does not mix with water, it is essential to dry the excess reaction solvent remaining after the reaction before entering the water-based SPE purification step after the labeling reaction.

[0095] In addition, as described in the entire claim below, if acetonitrile, which is known in the art not to be usable as a reaction solvent, is used, the reaction solvent drying and hydrolysis steps in the synthesis method according to the present invention can be reduced or eliminated, thereby enabling an improvement in yield through a reduction in the overall synthesis time. Furthermore, since there is a relatively low risk of degradation of the plastic formulation, it can be applied to other cassette-type automated synthesis modules that do not use chemical-resistant materials (e.g., GE Tracerlab, etc.). Additionally, due to the low boiling point of acetonitrile, the labeling temperature can be lowered, thereby shortening the heating and cooling times. Moreover, when t-amyl alcohol is used as a reaction solvent, the dried t-amyl alcohol may damage the inside of the equipment during the drying step after labeling, whereas using acetonitrile as a reaction solvent can reduce the risk of equipment damage.

[0096] Including all claims below, in this specification, SPE solution 2 is added to the reaction vessel (e) to produce radioactive fluoride [ 18 The step of hydrolyzing the F]-labeled precursor 18 In the F-labeled radiopharmaceutical synthesis process, the "hydrolysis" step, which occurs during the labeling step [ 18 It is characterized by being performed prior to the "SPE purification" step to facilitate solid-phase extraction (SPE) using an SPE cartridge, particularly SPE purification, by causing hydrolysis that breaks the intramolecular bonds of the reaction intermediate and unreacted precursor of the [F]FP-CIT labeled mixture.

[0097] Including all claims below, the step (e) is performed at a temperature of 50 to 150°C, 50 to 130°C, 50 to 120°C, 50 to 110°C, 60 to 130°C, 60 to 120°C, 60 to 110°C, 70 to 120°C, or 70 to 110°C for 1 to 60 seconds, 1 to 50 seconds, 1 to 40 seconds, 1 to 30 seconds, 5 to 50 seconds, 5 to 40 seconds, 5 to 30 seconds, 10 to 40 seconds, 20 to 40 seconds, 10 to 30 seconds, 20 to 30 seconds, 30 to 40 seconds, 25 to 35 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, or Leave for 60 seconds; or at a temperature of 50 to 150°C, 80 to 150°C, 100 to 150°C, 100 to 140°C, 100 to 130°C, 100 to 120°C, 110 to 140°C, 110 to 130°C, 110 to 120°C, 120 to 130°C, 100°C, 110°C, 120°C, 130°C, or 140°C for 1 to 10 minutes, 1 to 8 minutes, 1 to 5 minutes, 3 to 8 minutes, 3 to 6 minutes, 3 to 5 minutes, 4 to 6 minutes, 4 to 5 minutes, 5 to 6 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or Hydrolysis can be performed by heating for 10 minutes, and according to one embodiment of the present invention, in an automated synthesis module using an integrated manifold, hydrolysis can be performed by leaving it at a temperature of 70 to 110°C for 30 seconds without heating, and in an automated synthesis module using an assembled manifold, hydrolysis can be performed by heating at 120°C for 5 minutes, but is not limited thereto.

[0098] Including all claims below, the SPE solution 2 may be a hydrolysis solution in which one or more bases selected from the group consisting of sodium butoxide, sodium-t-butoxide, sodium n-butoxide, sodium sec-butoxide, sodium isobutoxide, sodium hydroxide, potassium hydroxide, sodium hydroxide, sodium methyl mercaptan, sodium thiomethoxide, sodium ethoxide, ammonia / ammonium hydroxide, and sodium methoxide are dissolved. The hydrolysis solution may be in the form of a pure aqueous solution in which one or more bases are dissolved in water, or in the form in which one or more bases are dissolved in a mixture of water and a miscible organic solvent such as acetonitrile. According to one embodiment of the present invention, the SPE solution 2 may be a hydrolysis solution capable of inducing a basic hydrolysis reaction in which sodium methoxide is dissolved in an aqueous solution of acetonitrile, but is not limited thereto. In addition, according to another embodiment of the present invention, the SPE solution 2 may be a hydrolysis solution capable of inducing a basic hydrolysis reaction, in which sodium-t-butoxide is dissolved in an aqueous acetonitrile solution, but is not limited thereto.

[0099] Including all claims below, the step of (f) SPE purifying the hydrolysis mixture of step (e) (the hydrolysis reaction mixture obtained as a result of step (e)) using SPE cartridge 2 18 In the "SPE purification" step of the F-labeled radiopharmaceutical synthesis process, specifically, radiofluoride [ 18 SPE purification can be achieved by capturing the hydrolysis mixture obtained as a result of the hydrolysis reaction of the labeled precursor compound in SPE cartridge 2, and then cleaning SPE cartridge 2 by pouring a cleaning solution into SPE cartridge 2 that is capturing the hydrolysis mixture.

[0100] Including the entire claims below, the step (f) comprises: (f-1) capturing the hydrolysis mixture of the step (e) in an SPE cartridge 2 (capturing); and

[0101] (f-2) A step of cleaning SPE cartridge 2 by pouring a cleaning solution into SPE cartridge 2 (which contains the hydrolysis mixture of step (e)) may be included (cleaning), but is not limited thereto.

[0102] According to one embodiment of the present invention, the hydrolysis mixture may be diluted with SPE solution 1 and water to increase the capture yield before capturing the hydrolysis mixture in SPE cartridge 2 in step (f-1) of the present specification, including the full claims below. The SPE solution 1 may be an aqueous solution containing acetonitrile with good solubility.

[0103] Including all claims below, the SPE cartridge 2 may be a reverse phase cartridge, and the reverse phase cartridge may be selected from the group consisting of, but not limited to, 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. According to one embodiment of the present invention, the SPE cartridge 2 may be a C18 cartridge.

[0104] Including all claims below, the cleaning solution may be one or more selected from the group consisting of water, ethanol, and acetonitrile, and the ethanol and acetonitrile also include aqueous solutions thereof. According to one embodiment of the present invention, water and ethanol (SPE solution 4) may be used as the cleaning solution, and preferably, SPE cartridge 2 may be cleaned with water and then cleaned with ethanol.

[0105] Including all claims below, the synthesis method comprises: (g) a step of diluting the eluent obtained by passing eluent 2 through the SPE cartridge 2 (SPE cartridge 2 after SPE purification is performed, i.e., SPE cartridge 2 in which the hydrolysis mixture captured after being washed with a washing solution in step (f-2) is contained) in a container containing SPE solution 3 (formulation step); and

[0106] (h) A step of passing the diluted solution of step (g) through the SPE cartridge 3 (transfer step) may be further included, but is not limited thereto.

[0107] Including all claims below, the eluent 2 may be 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); and according to one embodiment of the present invention, the eluent 2 may be ethanol, but is not limited thereto.

[0108] Including all claims below, the SPE solution 3 may be 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), and may have one or more stabilizers selected from the group consisting of ascorbic acid, sodium ascorbate, thiamine, and pyridoxine dissolved therein. According to one embodiment of the present invention, the SPE solution 3 may be a physiological saline solution in which ascorbic acid, a stabilizer, is dissolved, but is not limited thereto.

[0109] In all claims below, the term "stabilizer" in this specification refers to an agent for preventing radiolysis, and in the present invention, unreacted radiofluoride after the labeling step [ 18 [F] in the mixture state until it is removed through SPE purification [ 18 It was used to prevent the degradation of F]FP-CIT, and not only SPE solution 3 but also after the labeling step [ 18 It can be added to any material that can come into contact with F]FP-CIT (e.g., SPE solution 1, SPE solution 2, SPE solution 4, water bag, etc. in the present invention).

[0110] In the present specification, including the entire claims below, a vitamin C compound or a vitamin B compound (Korean Registered Patent No. 10-2207372) may be used as the stabilizer, and for example, ascorbic acid (vitamin C), sodium ascorbate (vitamin C inorganic salt), thiamine (vitamin B1), and pyridoxine (vitamin B6), etc. may be used as the stabilizer.

[0111] Including all claims below, in this specification, the mixture of eluent 2 and SPE solution 3 after step (g), wherein eluent 2 is passed through SPE cartridge 2 to produce [ 18 The F]FP-CIT eluent, i.e., the diluted solution of step (g), may be in the form of an aqueous ethanol solution of 5 to 50%, 5 to 40%, 5 to 30%, 5 to 20%, 5 to 15%, 5 to 10%, 10 to 40%, 10 to 30%, 10 to 20%, 10 to 15%, 5%, 10%, or 15%, and according to one embodiment of the present invention, may be in the form of a 10% aqueous ethanol solution.

[0112] Including the entire claims below, the SPE cartridge 3 is a normal cartridge, and the normal cartridge may be selected from the group consisting of an alumina cartridge, a diol cartridge, and a silica cartridge, and according to one embodiment of the present invention, the normal cartridge may be an alumina cartridge.

[0113] According to one embodiment of the present invention, in the entirety of the following claims, step (h) may involve passing the diluted solution of step (g) through an SPE cartridge 3 and a sterile filter (25 mm PTFE filter).

[0114] Including all claims below, the synthesis method may be performed in an automated synthesis module (automated synthesis equipment), and the automated synthesis module may be equipped with an integrated manifold or an assembled manifold.

[0115] In this specification, including all claims below, "manifold" refers to one of the components of a cassette mounted on a radiopharmaceutical automated synthesis module (automated synthesis equipment), and means a cassette component that is mounted on the automated synthesis module to enable valve operation and serves as a framework to which all components of the cassette, such as tubing and cartridges, are connected. The manifold is formed with a plurality of ports to which reagent vials, syringes, cartridges, and tubing can be connected, and valves capable of opening, closing, and adjusting the direction of each port. Both ends of the manifold are connected directly or indirectly via tubing to the automated synthesis module so that nitrogen, air, and vacuum can be supplied. The number of ports and valves can be appropriately adjusted according to the configuration of the cassette containing the manifold.

[0116] In addition, as per the entire claim below, the manifold may be manufactured from a chemical-resistant plastic material such as polypropylene, and one or more manifolds may be mounted in a form connected in series or in parallel in this specification. If composed of one manifold, it is referred to as an "integrated manifold," and if composed of two or more manifolds, it is referred to as an "assembly manifold." An assembly manifold may be mounted in a single stage (series) or two stages (parallel) in an automated synthesis module. Representative automated synthesis modules using an integrated manifold include GE’s FASTLab, representative automated synthesis modules using an assembly manifold mounted in a single stage include GE’s TRACERlab, and representative automated synthesis modules using an assembly manifold mounted in two stages include Trasis’s All-In-One and Neptis’s PERFORM. The manifold may be composed of an appropriate number and size of manifolds depending on the type of automated synthesis module to be mounted.

[0117] In all claims below, the term "chemical-resistant plastic" in this specification means a plastic material that withstands chemical substances or chemical treatments such as organic solvents, acids, and bases, and includes, for example, polypropylene, polyamide (nylon), high-density polyethylene (HDPE), etc.

[0118] Additionally, as per the entire claim below, the present invention utilizes solid-phase extraction (SPE) comprising the following steps. 18 A method for synthesizing an F-labeled radiopharmaceutical is provided, and the following steps can be performed sequentially:

[0119] (a) radioactive fluoride [ 18 Step of capturing F] in SPE cartridge 1;

[0120] (b) Elution solution 1 is poured into the SPE cartridge 1 to capture the radioactive fluoride [ 18Step of eluting [F] into a reaction vessel;

[0121] (c) a step of adding a precursor compound to the reaction vessel;

[0122] (d) Add a reaction solvent to the above reaction vessel to obtain a precursor compound and radiofluoride [ 18 Step of reacting F];

[0123] (e) Add SPE solution 2 to the above reaction vessel to produce radioactive fluoride [ 18 Step of hydrolyzing the F] labeled precursor;

[0124] (f-1) A step of capturing the hydrolysis mixture of step (e) above in SPE cartridge 2;

[0125] (f-2) A step of cleaning SPE cartridge 2 by pouring a cleaning solution into the SPE cartridge 2;

[0126] (g) a step of diluting the eluent obtained by passing eluent 2 through the SPE cartridge 2 cleaned in step (f-2) above in a container containing SPE solution 3; and

[0127] (h) A step of passing the diluted solution of step (g) through SPE cartridge 3.

[0128]

[0129] Additionally, as per the entire claim below, the present invention comprises a first vial containing a precursor compound;

[0130] Radioactive fluoride [ 18 A second vial containing [F];

[0131] A third vial containing eluent 1;

[0132] A fourth vial containing a reaction solvent;

[0133] A fifth vial containing SPE solution 2;

[0134] A sixth vial containing a cleaning solution;

[0135] Reaction vessel;

[0136] SPE cartridge; and

[0137] A method for using solid phase extraction (SPE) comprising a manifold to which the above-mentioned vial, reaction vessel, and SPE cartridge are connected (coupled) 18 The present invention provides a cassette for synthesizing F-labeled radiopharmaceuticals. The cassette is according to the present invention 18 The synthesis method for F-labeled radiopharmaceuticals is enabled to be performed in an automated synthesis module.

[0138] Including all claims below, the cassette may further include a seventh vial containing eluent 2; and an eighth vial containing SPE solution 3, and may also include all components necessary for the synthesis of a radiopharmaceutical, such as a syringe, tubing, a filter, a drying solvent, and SPE solution 1.

[0139] In the present specification, including all claims below, "cassette" refers to a disposable unit in which radiochemistry is performed, and is composed of a manifold kit and a reagent kit, and may include all components necessary for the synthesis of radiopharmaceuticals so as to be mounted on an automated synthesis module to easily synthesize radiopharmaceuticals.

[0140] Including all claims below, the sixth vial containing the cleaning solution may preferably be a vial containing SPE solution 4, and water may be provided through a separate water source. The water source may be a container such as a water bag or vial containing HPLC-grade water or water for injection, connected to a manifold to supply water.

[0141] Including all claims below, the SPE cartridge may be one or more selected from the group consisting of an ion exchange cartridge, a reverse phase cartridge, and a normal cartridge, and according to one embodiment of the present invention, the SPE cartridge may include all of the ion exchange cartridge, the reverse phase cartridge, and the normal cartridge.

[0142] In all claims below, the "reaction vessel" in this specification is one of the components of a cassette in which reactants (precursor compounds, radioisotopes, etc.) and reagents required for the synthesis of a radiopharmaceutical are supplied and product(s) are discharged in an appropriate order. The vessel has an internal volume (1-10 mL) suitable for holding reactants and reagents and is manufactured from glass or chemical-resistant plastic materials that are radiation-resistant and pharmaceutical-grade. In the present invention, the bottom of the reaction vessel may be square or circular, and the bottom surface may be flat or have a shape in which the diameter decreases toward the bottom (e.g., the bottom of the reaction vessel may be hemispherical, conical, or square pyramidal), but is not limited thereto, and a reaction vessel of an appropriate shape may be used depending on the automated synthesis module used for synthesis.

[0143] Including all claims below, the reaction vessel may be connected to two or more manifold ports. For example, AIO, an automated synthesis module using an assembled manifold, may use a reaction vessel with a flat bottom surface connected to two manifold ports, or a reaction vessel with a hemispherical shape with a bottom surface that decreases in diameter toward the bottom connected to three manifold ports; PERFORM, an automated synthesis module using an assembled manifold, may use a reaction vessel with a flat bottom surface connected to two manifold ports; and FASTlab, an automated synthesis module using an integral manifold, may use a reaction vessel with a conical shape with a bottom surface that decreases in diameter toward the bottom connected to three manifold ports. According to one embodiment of the present invention, the reaction vessel may be connected to two to three manifold ports, but is not limited thereto, and may be connected to an appropriate number of ports depending on the automated synthesis module used.

[0144] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the invention, and the scope of the invention is not limited by the following embodiments.

[0145]

[0146] The inventors [utilize solid-phase extraction to [ 18 A method for manufacturing F]FP-CIT and a novel cassette package capable of applying this to an automated synthesis module were developed.

[0147]

[0148] [[ 18 F]FP-CIT Manufacturing Cassette Package]

[0149] 1. Manifold kit

[0150] A manifold kit refers to the entire composition of a molded product, generally used for single-use, which is mounted in an automated synthesis module (radiopharmaceutical automated synthesis equipment) and in which synthesis, purification, and formulation are performed. In the present invention, GE’s FASTLab and Trasis’s All-In-One were used as automated synthesis modules.

[0151]

[0152] The manifold kit configuration is as follows:

[0153] 1-1. Manifold (Fig. 1: Port 1-25, Fig. 2: Port 1-24, Fig. 3: Port 1-20)

[0154] The manifold is equipped with ports to which reagent vials, syringes, cartridges, and tubing can be connected, and valves to control the opening, closing, and direction of each port. Both ends of the manifold are connected directly or indirectly via tubing to an automated synthesis module to supply nitrogen, air, and vacuum.

[0155]

[0156] 1-2. SPE Cartridge

[0157] Also referred to as an SPE column, it consists of a solid particle adsorbent packed inside a cartridge-shaped plastic device. Depending on the properties of the packed adsorbent, substances of interest can be concentrated or purified through ion exchange or polar / non-polar separation. The cartridge is typically connected to one or more manifold ports and can be connected directly or indirectly using tubing. In this invention, an ion exchange cartridge, a reverse-phase cartridge, and a normal-phase cartridge were used as SPE cartridges:

[0158] The ion exchange SPE cartridge (SPE cartridge 1) utilizes the electrostatic attraction of charged functional groups on a compound to the charged groups on the surface of an adsorbent, and is used to obtain an eluent containing desired ions by selectively capturing molecules having opposite charges on the surface of the adsorbent. In the present invention, a QMA cartridge having a positively charged quaternary ammonium group is used [ 18 In the F]-fluorination step, [ 18 F] - Ions (activated fluoride ions) were captured and eluted, and conditioned with KOMs buffer (Korean Patent No. 10-1326000) and water before use.

[0159] The reverse phase SPE cartridge (SPE cartridge 2) operates on the principle of capturing compounds through the interaction between a non-polar adsorbent (generally silica with connected hydrocarbon chains) and a polar eluent, and separating them using a polar eluent. The separation ability based on hydrophobicity varies depending on the hydrocarbon length on the silica surface and the adsorbent composition. In the present invention, the C18 cartridge, which has the strongest hydrophobicity, was used in the SPE purification step and conditioned with ethanol and water before use.

[0160] The standard SPE cartridge (SPE Cartridge 3) separates compounds using chemical properties such as hydrogen bonding, pi-pi interactions, dipole-dipole interactions, and dipole-induced dipole interactions, utilizing polar adsorbents such as silica gel, diatomaceous earth, alumina, and magnesium silicate. In the present invention, [after synthesis and formulation] 18 The [F]FP-CIT injection solution was purified using an alumina cartridge. The alumina cartridge was conditioned with water prior to use.

[0161]

[0162] 1-3. Reaction vessel

[0163] The reaction vessel used was a glass or chemical-resistant plastic vessel with a volume of 1–10 mL. The reaction vessel was connected to one or more ports to elute F-18([ 18 F] - The movement of ions), reagents, and solvents is made possible. The reaction vessel may have a square or circular bottom, a flat bottom surface, or a shape in which the diameter decreases toward the bottom (e.g., the bottom of the reaction vessel is hemispherical, conical, or square pyramidal). In the present invention, a cylindrical reaction vessel with a flat bottom (Fig. 2) and a reaction vessel with a conical bottom (Fig. 1) were used.

[0164]

[0165] 1-4. Syringe

[0166] The syringe was made of chemical-resistant plastic material commonly used for medical purposes, and a luer-lock type was used for direct connection to the manifold. The syringe was connected to one or more manifold ports to enable the movement of reagents, solvents, and air, and volumes of 1-30 mL were used depending on the purpose and configuration of the automated synthesis module.

[0167]

[0168] 1-5. Tubing

[0169] The tubing used was made of commonly used silicone or chemical-resistant plastic material and consisted of male / female luer-lock connectors that can be connected to ports at both ends of the manifold or to an automated synthesis module. The length of the tubing may vary depending on the connection target, the distance between ports, and the distance between ports and the automated synthesis module, and typically, tubing with a length of 1 to 50 cm is used.

[0170]

[0171] 1-6. Filter

[0172] Three main types of filters were used; specifically, a 13 mm PTFE filter mounted on the nitrogen outlet of the automatic synthesis module, [ 18 A 25 mm PTFE filter was used to sterilize the F]FP-CIT injection solution, and a vent filter was used to block the inflow of external air and prevent positive pressure inside the vial.

[0173]

[0174] 2. Reagent kit

[0175] The reagent kit includes precursors, eluents, and SPE solutions, etc. [ 18 It contains all the reagents required for the synthesis of [F]FP-CIT, and the amount of each reagent included in the kit is equal to or slightly greater than the amount required for the reaction. The reagents were placed in vials made of glass or chemical-resistant plastic suitable for their chemical properties and sealed with rubber stoppers and aluminum seals. Water was supplied by connecting a water bag containing HPLC-grade water or sterile water for injection to the manifold.

[0176]

[0177] 2-1. Precursor

[0178] In the present invention, the FP-CIT linear precursor disclosed in Korean Patent Application No. 10-2024-0037443 was used. The linear precursor was stored in anhydrous ethyl acetate (EA) at a concentration of 6-8 mg / mL and, in principle, kept frozen until immediately before use.

[0179]

[0180] 2-2. Eluent 1

[0181] Eluent 1 is [captured in SPE Cartridge 1, an ion exchange cartridge] 18 F] - It is intended for eluting ions (activated fluoride ions), generally large soft metal ions such as rubidium and cesium, Kryptofix™ (K222 A solution is used in which cationic counterions, such as potassium or tetraalkylammonium salts that form complexes with cryptands such as ), are dissolved in an organic solvent. In the present invention, K 222 The dissolved methanol was mixed with an eluent having a hydrogen ion concentration of 7.8 prepared using methanesulfonic acid and potassium carbonate (K2CO3) (Korean Registered Patent No. 10-1326000, hereinafter referred to as KOMs buffer) and used as eluent 1.

[0182]

[0183] 2-3. Eluent 2

[0184] Eluent 2 is [captured in SPE cartridge 2] 18 As a reagent for eluting the [F]FP-CIT injection solution, organic solvents commonly used for SPE elution (e.g., 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)) may be used, and may be provided as organic solvents alone or in the form of aqueous solutions. In the present invention, 100% ethanol was used.

[0185]

[0186] 2-4. Drying Solvent

[0187] [Eluted from SPE cartridge 1 18 F] - The presence of water in ion-containing eluent 1 is activated in the subsequent labeling step [ 18 F] -Since it can reduce the reactivity of ions and generate hydroxylated byproducts, we sought to completely remove water before reacting with the precursor to minimize these phenomena. In the present invention, an anhydrous organic solvent was added and heated to remove water through an azeotropic distillation process, and acetonitrile anhydrous was used as the anhydrous organic solvent (drying solvent).

[0188]

[0189] 2-5. Reaction Solvent

[0190] The reaction solvent is [in the labeling step] 18 F] - An organic solvent capable of maintaining the activity of the ions and the solubility of the precursor was used. The organic solvent may be a protic tertiary alcohol such as t-butanol, t-amyl alcohol, and 1-methoxy-2-methyl-2-propanol, an aprotic organic solvent such as acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), and in the present invention, t-amyl alcohol and acetonitrile (CH3CN) were used as reaction solvents.

[0191]

[0192] 2-6. SPE Solution 1

[0193] SPE Solution 1 is the [remaining in the reaction vessel after hydrolysis] 18 It refers to the solution used to draw the [F]FP-CIT mixture into a syringe by diluting it with water before transferring it to SPE Cartridge 2. The purpose of using SPE Solution 1 is for [in the reaction vessel] 18 The purpose is to reduce the remaining amount of F]FP-CIT and to increase the capture yield of SPE cartridge 2. In the present invention, [ 18 An aqueous solution containing acetonitrile, which has good solubility for the [F]FP-CIT mixture, was used.

[0194]

[0195] 2-7. SPE Solution 2

[0196] SPE Solution 2 occurs during the labeling step [ 18 By inducing hydrolysis that breaks the intramolecular bonds of the reaction intermediate and unreacted precursor of the [F]FP-CIT labeled mixture, using an SPE cartridge [ 18 It serves to facilitate the purification of [F]FP-CIT. Generally known hydrolysis methods include salt hydrolysis, acid hydrolysis, and basic hydrolysis, and basic hydrolysis was performed in the present invention. Basic hydrolysis uses strong bases such as alkali metal alkoxides, alkali metal hydroxides, and thiooxide bases, and strong bases that may be used include sodium hydroxide, potassium hydroxide, sodium hydride, sodium methyl mercaptan, sodium thiomethoxide, sodium ethoxide, sodium butoxide, ammonia / ammonium hydroxide, and sodium methoxide. In the present invention, sodium methoxide (CAS number: 124-41-4) or sodium tert-butoxide (CAS number: 865-48-5) dissolved in an aqueous acetonitrile solution was used as the basic solution to induce the basic hydrolysis reaction.

[0197]

[0198] 2-8. SPE Solution 3

[0199] [Separated from SPE Cartridge 2 using Eluent 2 18 The F]FP-CIT eluent is transferred to a vial containing SPE Solution 3 before being discharged into the final product collection vial. By mixing Eluent 2 and SPE Solution 3, [ 18The [F]FP-CIT eluent is diluted to finally become a 10% ethanol aqueous solution. For SPE Solution 3, water for injection, physiological saline, and buffer solutions may be used, and stabilizers such as ascorbic acid, sodium ascorbate, and vitamin B compounds (thiamine (vitamin B1), pyridoxine (vitamin B6)) may be added to prevent radiolysis. In the present invention, physiological saline containing ascorbic acid was used as SPE Solution 3.

[0200]

[0201] 2-9. Cleaning Solution

[0202] The cleaning solution transferred to SPE cartridge 2 using SPE solution 1 [ 18 In the F]FP-CIT hydrolysis mixture [ 18 This is intended to remove by-products excluding [F]FP-CIT, and the cleaning solution may include ethanol, acetonitrile and aqueous solutions thereof, water, etc. In the present invention, an aqueous solution containing ethanol (SPE solution 4) and water were used as the cleaning solution.

[0203]

[0204] [Example]

[0205] Example 1. Using an automated synthesis module utilizing an integrated manifold [ 18 F]Manufacturing of FP-CIT

[0206]

[0207] FASTlab from GE Healthcare Ltd (GE) was used as an automated synthesis module using an integrated manifold.

[0208]

[0209] 1-1. Cassette package (Fig. 1)

[0210] Applicable to automated synthesis modules using an integrated manifold [ 18 F] By manufacturing FP-CIT cassette packages, [ 18F]FP-CIT was manufactured. As shown in Fig. 1, the cassette package consists of a reaction vessel, three SPE cartridges, and three syringes connected to a manifold having a total of 25 valves, two types of eluent, four types of SPE solutions, a precursor, a drying solvent, and a water bag, and the final product collection vial is connected to an external vial.

[0211]

[0212] 1-2. Automated Synthesis Process

[0213] Step 1: [ 18 [F]-fluoride

[0214] Radiofluoride generated in a cyclotron [ 18 Capture F] in SPE cartridge 1, and K 222 Eluent 1, in which 22 mg is dissolved in methanol (1 mL) and KOMs buffer (0.1-1 mL), is injected into SPE cartridge 1 using syringe 1 and into the reaction vessel [ 18 F] - Ions were eluted. Nitrogen and vacuum were supplied to the reaction vessel, and it was heated to 100°C for 190 seconds [ 18 F] - After drying the ions, 0.5 mL of acetonitrile (drying solvent) was added to dry them completely.

[0215]

[0216] Step 2: Add precursor

[0217] [ 18 F] - After the reaction vessel is naturally cooled after ion drying is complete, [from the precursor vial using vacuum pressure 18 F] - The precursor solution was transferred to the reaction vessel after ion drying was completed. To dry the precursor storage solvent, nitrogen and vacuum were supplied, and the solution was heated to 70°C and then naturally cooled to 60°C.

[0218]

[0219] Step 3: Precursor Labeling

[0220] The reaction solvent was transferred to the reaction vessel using vacuum pressure, heated at 110°C for 20 minutes to label the precursor, and the remaining reaction solvent was dried by supplying nitrogen and vacuum.

[0221]

[0222] Step 4: Hydrolysis

[0223] SPE solution 2 was transferred to a reaction vessel using vacuum pressure and hydrolyzed by leaving it at approximately 70-110°C for 30 seconds.

[0224]

[0225] Step 5: SPE Purification

[0226] capture

[0227] Draw up SPE solution 1 using syringe 2 and transfer it to the reaction vessel [ 18 The [F]FP-CIT hydrolysis mixture was diluted. Water was transferred from the water bag to the reaction vessel using the same method. After drawing water up from the water bag again using syringe 2, the [remaining in the reaction vessel 18 The entire [F]FP-CIT hydrolysis mixture was drawn into the syringe and sufficiently diluted within the syringe. After passing the diluted solution in syringe 2 through SPE cartridge 2, the same procedure was repeated two more times [ 18 The F]FP-CIT hydrolysis mixture was all captured in SPE cartridge 2.

[0228]

[0229] sejung

[0230] Using syringe 2, 5 mL of water was drawn up from the water bag and passed through SPE cartridge 2, and the same procedure was repeated 3 more times to clean SPE cartridge 2 with a total of 20 mL of water 4 times.

[0231] After the above water washing, SPE solution 4 was passed through SPE cartridge 2 using the same syringe 2, and the same procedure was repeated 3 more times to wash SPE cartridge 2 with a total of 20 mL of SPE solution 4.

[0232]

[0233] Step 6: Formulation

[0234] After drawing up eluent 2 using syringe 3 and passing it through SPE cartridge 2, the resulting [ 18 The [F]FP-CIT eluent was transferred to a vial containing SPE Solution 3. The mixture of Eluent 2 and SPE Solution 3 passed through SPE Cartridge 2, and the resulting [ 18 The F]FP-CIT eluent is in the state of a 10% ethanol aqueous solution [ 18 It becomes a diluted F]FP-CIT solution. Nitrogen is supplied to SPE cartridge 2 to recover all remaining eluent while ensuring sufficient mixing.

[0235]

[0236] Step 7: Transfer

[0237] [in the state of a 10% aqueous ethanol solution 18 The F]FP-CIT diluted solution was passed through SPE cartridge 3 and a sterile filter, and then transferred to a final product collection vial.

[0238]

[0239] 1-3. Synthesis Results

[0240] The total synthesis time was 68 minutes, which is more than 20% shorter than automated synthesis using HPLC purification (approx. 85 minutes). The starting radioactivity (based on QMA captured radioactivity) of the automated synthesis using t-amyl alcohol as the reaction solvent was 917 mCi, the non-attenuation-corrected yield was 33.2%, and the radiochemical purity was 91.8%.

[0241] The starting radioactivity (based on QMA captured radioactivity) of the automated synthesis using acetonitrile (CH3CN) as the reaction solvent was 1030 mCi, the non-attenuation corrected yield was 9.3%, and the radiochemical purity was 92.3%.

[0242]

[0243] Example 2. Using an automated synthesis module utilizing an assembled manifold [ 18 F]Manufacturing of FP-CIT

[0244]

[0245] As a representative automated composite module using an assembled manifold, we used the All-In-One from Trasis SA, in which the manifolds are connected in two parallel stages.

[0246]

[0247] 2-1. Cassette package (Fig. 2)

[0248] Applicable to automated synthesis modules using modular manifolds [ 18 F] By manufacturing FP-CIT cassette packages, [ 18 F]FP-CIT was manufactured. As shown in Fig. 2, the cassette package is connected in a two-stage parallel configuration and consists of a reaction vessel, three SPE cartridges, and three syringes connected to a manifold having a total of 24 valves, two types of eluent, four types of SPE solutions, a precursor, a drying solvent, and a water bag, and the final product collection vial is connected to an external vial.

[0249]

[0250] 2-2. Automated Synthesis Process

[0251] Step 1: [ 18 [F]-fluoride

[0252] Radiofluoride generated in a cyclotron [ 18 Capture F] in SPE cartridge 1, and K 222Eluent 1, in which 22 mg is dissolved in methanol (1 mL) and KOMs buffer (0.1-1 mL), is injected into SPE cartridge 1 using syringe 1 and into the reaction vessel [ 18 F] - Ions were eluted. Nitrogen and vacuum were supplied to the reaction vessel, and it was heated to 100°C for 190 seconds [ 18 F] - After drying the ions, 0.5 mL of acetonitrile (drying solvent) was added and completely dried at the same temperature.

[0253]

[0254] Step 2: Add precursor

[0255] [ 18 F] - After cooling the reaction vessel with completed ion drying to 60°C, using vacuum pressure from the precursor vial [ 18 F] - The precursor solution was transferred to the reaction vessel where ion drying was completed. The precursor storage solvent was dried at the same temperature while supplying nitrogen and vacuum.

[0256]

[0257] Step 3: Precursor Labeling

[0258] The reaction solvent was transferred to the reaction vessel using vacuum pressure, heated at 120°C for 10 minutes to label the precursor, and the remaining reaction solvent was dried by supplying nitrogen and vacuum.

[0259]

[0260] Step 4: Hydrolysis

[0261] The basic hydrolysis solution was transferred to a reaction vessel using vacuum pressure and hydrolyzed at 120°C for 5 minutes.

[0262]

[0263] Step 5: SPE Purification

[0264] capture

[0265] Transfer SPE solution 1 to the reaction vessel using syringe 2, and [18 The [F]FP-CIT hydrolysis mixture was diluted. Water was transferred from the water bag to the reaction vessel using the same method. After drawing water from the water bag again using syringe 2, the [remaining in the reaction vessel 18 The entire [F]FP-CIT hydrolysis mixture was drawn into the syringe and sufficiently diluted within the syringe. After passing the diluted solution in syringe 2 through SPE cartridge 2, the same procedure was repeated one more time to [ 18 The F]FP-CIT hydrolysis mixture was all captured in SPE cartridge 2.

[0266]

[0267] sejung

[0268] Using syringe 3, 10 mL of water was drawn up from the water bag and passed through SPE cartridge 2, and the same procedure was repeated one more time to clean SPE cartridge 2 with a total of 20 mL of water.

[0269] After the above water washing, SPE solution 4 was passed through SPE cartridge 2 using the same syringe 3, and the same procedure was repeated one more time to wash SPE cartridge 2 with a total of 20 mL of SPE solution 4.

[0270]

[0271] Step 6: Formulation

[0272] After drawing up eluent 2 using syringe 3 and passing it through SPE cartridge 2, the resulting [ 18 The [F]FP-CIT eluent was transferred to a vial containing SPE Solution 3. The mixture of Eluent 2 and SPE Solution 3 passed through SPE Cartridge 2, and the resulting [ 18 The F]FP-CIT eluent is in the state of a 10% ethanol aqueous solution [ 18 It becomes a diluted F]FP-CIT solution. Nitrogen is supplied to SPE cartridge 2 to recover all remaining eluent while ensuring sufficient mixing.

[0273]

[0274] Step 7: Transfer

[0275] [in the state of a 10% aqueous ethanol solution 18 The [F]FP-CIT diluted solution was passed through SPE cartridge 3 and a sterile filter, then transferred to a final product collection vial.

[0276]

[0277] 2-3. Synthesis Results

[0278] The total synthesis time was 57 minutes, which is more than 30% shorter than automated synthesis using an AIO instrument with HPLC purification (approx. 85 minutes). The average starting radioactivity (based on QMA captured radioactivity) of the automated synthesis using t-amyl alcohol as the reaction solvent was 1292 mCi, the non-attenuation-corrected yield was 41.7%, and the radiochemical purity was 90.2%.

[0279] The starting radioactivity (based on QMA captured radioactivity) of the automated synthesis using acetonitrile (CH3CN) as the reaction solvent was 905 mCi, the non-attenuation corrected yield was 7.8%, and the radiochemical purity was 90.7%.

[0280] According to the present invention 18 The synthesis method for F-labeled radiopharmaceuticals utilizes a solid-phase extraction (SPE) process, which improves reproducibility and reduces synthesis time compared to conventional HPLC processes, thereby enabling high purity and high yield. 18 F-labeled radiopharmaceuticals can be obtained, and conveniently using a cassette configured to perform the synthesis method according to the present invention in an automated synthesis module. 18 Since F-labeled radiopharmaceuticals can be synthesized, 18 It is expected to be usefully utilized in the production of F-labeled radiopharmaceuticals, thus having potential for industrial application.

Claims

1. (a) Radioactive fluoride [ 18 Step of capturing F] in SPE cartridge 1; (b) Elution solution 1 is poured into the SPE cartridge 1 to capture the radioactive fluoride [ 18 Step of eluting [F] into a reaction vessel; (c) a step of adding a precursor compound to the reaction vessel; (d) Add a reaction solvent to the above reaction vessel to obtain a precursor compound and radiofluoride [ 18 Step of reacting F]; (e) Add SPE solution 2 to the above reaction vessel to produce radioactive fluoride [ 18 A step of hydrolyzing a [F] labeled precursor compound; and (f) a step of SPE purifying the hydrolysis mixture of step (e) using SPE cartridge 2, using solid phase extraction (SPE). 18 Synthesis method of F-labeled radiopharmaceuticals.

2. In Paragraph 1, The above SPE cartridge 1 is characterized as being an ion exchange cartridge, 18 Synthesis method of F-labeled radiopharmaceuticals.

3. In Paragraph 2, The above ion exchange cartridge is characterized as being a quaternary methylammonium (QMA) cartridge, 18 Synthesis method of F-labeled radiopharmaceuticals.

4. In Paragraph 1, The above eluent 1 is characterized as being a solution in which a cryptand is dissolved. 18 Synthesis method of F-labeled radiopharmaceuticals.

5. In Paragraph 4, The above cryptand is characterized as being 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan (Cryptopix 2.2.2), 18 Synthesis method of F-labeled radiopharmaceuticals.

6. In Paragraph 4, The solution in which the above-mentioned cryptand is dissolved is characterized as being a solution dissolved in one or more solvents selected from the group consisting of organic solvents and KOMs buffers. 18 Synthesis method of F-labeled radiopharmaceuticals.

7. In Paragraph 6, The above organic solvent is characterized by being 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). 18 Synthesis method of F-labeled radiopharmaceuticals.

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 Characterized by being one or more aprotic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF). 18 Synthesis method of F-labeled radiopharmaceuticals.

9. In Paragraph 1, The above step (d) is characterized by heating the reaction vessel to a temperature of 50 to 200°C for 1 to 60 minutes. 18 Synthesis method of F-labeled radiopharmaceuticals.

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 Characterized by heating at a temperature of 50 to 150 ℃ for 1 to 10 minutes, 18 Synthesis method of F-labeled radiopharmaceuticals.

11. In Paragraph 1, The above SPE solution 2 is characterized as being 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. 18 Synthesis method of F-labeled radiopharmaceuticals.

12. In Paragraph 1, The above SPE cartridge 2 is characterized as being a reverse phase cartridge, 18 Synthesis method of F-labeled radiopharmaceuticals.

13. In Paragraph 12, The above reverse phase cartridge is characterized by being 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. 18 Synthesis method of F-labeled radiopharmaceuticals.

14. In Paragraph 1, The above (f) step is characterized by including the following steps, 18 Synthesis method of F-labeled radiopharmaceuticals: (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, The above cleaning solution is characterized by being one or more selected from the group consisting of water, ethanol, and acetonitrile. 18 Synthesis method of F-labeled radiopharmaceuticals.

16. In Paragraph 1, The above synthesis method is characterized by further including the following steps, 18 Synthesis method of F-labeled radiopharmaceuticals: (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, The above eluent 2 is characterized by being 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 Synthesis method of F-labeled radiopharmaceuticals.

18. In Paragraph 16, The above SPE solution 3 is characterized by being 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 Solution), and GBSS (Gey's Balanced Salt Solution). 18 Synthesis method of F-labeled radiopharmaceuticals.

19. In Paragraph 18, The above SPE solution 3 is characterized by having one or more stabilizers selected from the group consisting of ascorbic acid, sodium ascorbate, thiamine, and pyridoxine dissolved therein. 18 Synthesis method of F-labeled radiopharmaceuticals.

20. In Paragraph 16, The above SPE cartridge 3 is characterized as being a normal cartridge, 18 Synthesis method of F-labeled radiopharmaceuticals.

21. In Paragraph 20, The above normal cartridge is characterized by being selected from the group consisting of an alumina cartridge, a diol cartridge, and a silica cartridge. 18 Synthesis method of F-labeled radiopharmaceuticals.

22. In Paragraph 16, The diluent of step (g) above is characterized as being a 5 to 50% aqueous ethanol solution. 18 Synthesis method of F-labeled radiopharmaceuticals.

23. In Paragraph 1, The above 18 F-labeled radiopharmaceuticals are [ 18 Characterized by being F]FP-CIT, 18 Synthesis method of F-labeled radiopharmaceuticals 24. In Paragraph 1, The above synthesis method is characterized by being performed in an automated synthesis module. 18 Synthesis method of F-labeled radiopharmaceuticals.

25. In Paragraph 24, The above-mentioned automated synthesis module is characterized by being equipped with an integrated manifold or an assembled manifold. 18 Synthesis method of F-labeled radiopharmaceuticals.

26. A first vial containing a precursor compound; Radioactive fluoride [ 18 A second vial containing [F]; A third vial containing eluent 1; A fourth vial containing a reaction solvent; A fifth vial containing SPE solution 2; A sixth vial containing a cleaning solution; Reaction vessel; SPE cartridge; and A method for using Solid Phase Extraction (SPE), comprising a vial, a reaction vessel, and a manifold to which an SPE cartridge is connected. 18 F-labeled radiopharmaceutical synthesis cassette.

27. In Paragraph 26, The above eluent 1 is characterized as being a solution in which a cryptand is dissolved. 18 F-labeled radiopharmaceutical synthesis cassette.

28. In Paragraph 26, 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 Characterized by being one or more aprotic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF). 18 F-labeled radiopharmaceutical synthesis cassette.

29. In Paragraph 26, The above SPE solution 2 is characterized as being 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. 18 F-labeled radiopharmaceutical synthesis cassette.

30. In Paragraph 26, The above cleaning solution is characterized by being one or more selected from the group consisting of water, ethanol, and acetonitrile. 18 F-labeled radiopharmaceutical synthesis cassette.

31. In Paragraph 26, The above reaction vessel is characterized by being made of glass or chemical-resistant plastic material. 18 F-labeled radiopharmaceutical synthesis cassette.

32. In Paragraph 26, The bottom of the reaction vessel is characterized by being square or circular, flat, or having a shape in which the diameter decreases toward the bottom. 18 F-labeled radiopharmaceutical synthesis cassette.

33. In Paragraph 32, The shape in which the diameter decreases toward the bottom is characterized by being hemispherical, conical, or square pyramidal. 18 F-labeled radiopharmaceutical synthesis cassette.

34. In Paragraph 26, The above reaction vessel is characterized by being connected to two or more manifold ports, 18 F-labeled radiopharmaceutical synthesis cassette.

35. In Paragraph 26, The above SPE cartridge is characterized by being one or more selected from the group consisting of an ion exchange cartridge, a reverse phase cartridge, and a normal phase cartridge. 18 F-labeled radiopharmaceutical synthesis cassette.

36. In Paragraph 26, The above cassette is characterized by further comprising a seventh vial containing eluent 2; and an eighth vial containing SPE solution 3. 18 F-labeled radiopharmaceutical synthesis cassette.

37. In Paragraph 36, The above eluent 2 is characterized by being 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 F-labeled radiopharmaceutical synthesis cassette.

38. In Paragraph 36, The above SPE solution 3 is characterized by being 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 Solution), and GBSS (Gey's Balanced Salt Solution). 18 F-labeled radiopharmaceutical synthesis cassette.

39. In Paragraph 38, The above SPE solution 3 is characterized by having one or more stabilizers selected from the group consisting of ascorbic acid, sodium ascorbate, thiamine, and pyridoxine dissolved therein. 18 F-labeled radiopharmaceutical synthesis cassette.

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