Methods of stabilizing high purity linear precursors and methods of preparing [fluorine 18]fp-cit using linear precursors

Abstract

The present invention relates to a method of stabilizing (storing and pre-treating) a high-purity FP-CIT linear precursor and a method of preparing [F]FP-CIT using the FP-CIT linear precursor. 18 If the FP-CIT linear precursor is stored using the organic solvent having the characteristics according to the present invention, the FP-CIT linear precursor is inhibited from being converted into a cyclic salt form or degraded into various compounds, so that a high-purity FP-CIT linear precursor can be maintained, and a radiopharmaceutical can be prepared by using the existing [F]FP-CIT labeling conditions as they are [F]FP-CIT, 18 Therefore, the present invention can be effectively used as a starting material for [F]FP-CIT. 18 18 ​​

Description

Technical Field

[0001] This invention relates to a method for stabilizing (storing, pretreating) a high-purity FP-CIT linear precursor and the preparation of [using the linear precursor]. 18 The F]FP-CIT method.

[0002] This application claims priority and benefits to Korean Patent Application No. 10-2023-0129820, filed on September 26, 2023, and Korean Patent Application No. 10-2024-0037443, filed on March 18, 2024, the disclosures of which are incorporated herein by reference in their entirety. Background Technology

[0003] [ 18 F] Fluoride-labeled radiopharmaceuticals are diagnostic radiopharmaceuticals, characterized by [ 18 F] Fluorides have a short half-life of 110 minutes, which allows them to be prepared and utilized on the same day they are used. 18 The preparation steps of fluoride-labeled radiopharmaceuticals include the following steps: generation and activation. 18 F] fluoride, with [ 18 F] Fluoride is used to label radiopharmaceutical precursors, and for purification and formulation [ 18 F] Fluoride-labeled radiopharmaceuticals. In this case, the radiopharmaceutical precursor is usually labeled [ 18 The F] fluoride has a leaving group at the position and is labeled by a nucleophilic substitution reaction. 18 F] Fluorides.

[0004] As [ 18 The precursors of FP-CIT, N-(3'-methanesulfonyloxypropyl)-2-β-methoxycarbonyl-3-β-(4'-iodophenyl)torane or N-(3'-toluenesulfonyloxypropyl)-2-β-methoxycarbonyl-3-β-(4'-iodophenyl)torane, are used as linear precursors of FP-CIT. The corresponding compounds are in the form of propyl groups with leaving groups at the end in tertiary amines, in which case it is reported that cyclic salts with square rings are formed by intramolecular cyclization reactions.

[0005] As mentioned above, the mixing of linear precursor structures with cyclic salt precursors—caused by the spontaneous transformation of compounds into cyclic salts due to their structural properties—affects not only the purity of radiopharmaceutical starting materials but also the yield of radiopharmaceutical preparations.

[0006] Therefore, due to extensive research aimed at developing a method to stably maintain the linear structure by suppressing the natural changes (i.e., conversion to cyclic salts) of the FP-CIT linear precursor, the inventors have not only successfully developed a stable method that ensures the long-term storage stability of the FP-CIT linear precursor, but also used this method to prepare […]. 18 F]FP-CIT, thus completing the present invention. Summary of the Invention

[0007] [Technical Issues] Because of the efforts to develop a method that inhibits the conversion of the linear FP-CIT precursor into a cyclic salt precursor (for the preparation of […]), 18 Extensive research has been conducted on methods to stably maintain the linear structure of FP-CIT. The inventors have not only successfully developed a stable method that ensures the long-term storage stability of FP-CIT linear precursors, but have also used this method to prepare […]. 18 F]FP-CIT, thus completing the present invention.

[0008] This invention aims to provide a liquid composition for storing linear precursors of FP-CIT, said liquid composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0009] The present invention also aims to provide a composition for improving the storage stability of FP-CIT linear precursors, said composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0010] The present invention also aims to provide a method for stabilizing FP-CIT linear precursors by storing FP-CIT linear precursors in a composition according to the present invention.

[0011] The present invention also aims to provide a method for preparing [using the composition according to the invention]. 18 The method of F]FP-CIT, wherein the composition comprises an FP-CIT linear precursor as a starting material.

[0012] The present invention also aims to provide a method for preparing [ 18F] A method for FP-CIT, comprising a pretreatment step of dissolving a linear FP-CIT precursor in an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0013] The present invention also aims to provide a kit for storing linear precursors of FP-CIT.

[0014] The present invention also aims to provide a method for preparing [ 18 F]FP-CIT kit.

[0015] However, the technical problems to be solved by the present invention are not limited to those described above, and those skilled in the art will clearly understand other technical problems not mentioned from the following description.

[0016] [Technical Solution] According to one aspect of the present invention, a liquid composition for storing FP-CIT linear precursors is provided, said liquid composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0017] According to another aspect of the present invention, a composition for improving the storage stability of FP-CIT linear precursors is provided, the composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0018] According to another aspect of the invention, a method is provided for stabilizing FP-CIT linear precursors by storing FP-CIT linear precursors in a composition according to the invention.

[0019] As an exemplary embodiment of the present invention, the organic solvent may be one or more selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3) and dichloromethane (DCM), but is not limited thereto.

[0020] As another exemplary embodiment of the present invention, the FP-CIT linear precursor may be a compound represented by the following chemical formula 1, but is not limited thereto: [Chemical Formula 1] (In chemical formula 1, R1 is a sulfonyl group or a halogen. R2 is C 1-5 Alkyl, and X represents a halogen.

[0021] As another exemplary embodiment of the present invention, R1 is methanesulfonyl, tosyl, nosyl, F, Cl, Br, or I. R2 is methyl or ethyl, and X can be Cl, Br, or I, but is not limited to these.

[0022] As another exemplary embodiment of the present invention, the FP-CIT linear precursor may be N-(3'-methanesulfonyloxypropyl)-2-β-methoxycarbonyl-3-β-(4'-iodophenyl)torane or N-(3'-toluenesulfonyloxypropyl)-2-β-methoxycarbonyl-3-β-(4'-iodophenyl)torane, but is not limited thereto.

[0023] As another exemplary embodiment of the present invention, the storage temperature of the FP-CIT linear precursor can be from -50°C to 0°C, but is not limited thereto.

[0024] As another exemplary embodiment of the present invention, the FP-CIT linear precursor can be stored at a concentration of 0.1 mg / mL to 16 mg / mL, but the concentration is not limited thereto.

[0025] As another exemplary embodiment of the present invention, the liquid composition can inhibit the conversion of FP-CIT linear precursors into FP-CIT cyclic salt precursors, but is not limited thereto.

[0026] As another exemplary embodiment of the present invention, when stored for 12 months, the FP-CIT linear precursor can maintain 50% to 99% of the initial storage amount of the FP-CIT linear precursor, but is not limited thereto.

[0027] As another exemplary embodiment of the present invention, when the FP-CIT linear precursor is stored for 12 months, 1% to 50% of the initial storage amount of the FP-CIT linear precursor can be converted into the FP-CIT cyclic salt precursor, but is not limited thereto.

[0028] As another exemplary embodiment of the present invention, when stored for 12 months, the FP-CIT linear precursor may have a (FP-CIT cyclic salt precursor) / (FP-CIT linear precursor) ratio of 0.01 to 1, but is not limited thereto.

[0029] As another exemplary embodiment of the present invention, the improvement of storage stability of the FP-CIT linear precursor can inhibit the conversion of the FP-CIT linear precursor into the FP-CIT cyclic salt precursor, but is not limited thereto.

[0030] According to another aspect of the invention, a method for preparing [using the composition according to the invention] is provided. 18 The method for FP-CIT, wherein the composition comprises an FP-CIT linear precursor as a starting material, the method comprising: (a) The step of separating the FP-CIT linear precursor by removing the organic solvent from the composition containing the FP-CIT linear precursor according to the invention; (b) Pre-labeling reaction step: A mixture is prepared by dissolving the FP-CIT linear precursor isolated in step (a) in a reaction solvent; and (c) Labeling reaction step: by labeling with […] containing activated […] 18 The mixture described in step (b) is added to the reaction vessel containing the fluoride (F) while (using [ 18 The fluoride (F) is labeled.

[0031] According to another aspect of the invention, there is a method for preparing [using the composition according to the invention]. 18 The method for FP-CIT, wherein the composition comprises an FP-CIT linear precursor as a starting material, the method comprising: (a) By directing the activated [ 18 The step of preparing a mixture by adding a composition containing an FP-CIT linear precursor according to the present invention to a reaction vessel for fluorides; (b) Pre-labeling reaction step: removal of the organic solvent from the mixture described in step (a); and (c) Labeling reaction step: by adding a reaction solvent to the mixture from which the organic solvent has been removed (using […]). 18 The fluoride (F) is labeled.

[0032] As an exemplary embodiment of the present invention, the FP-CIT linear precursor can be used with activated […]. 18 The nucleophilic fluorination reaction of F] fluorides is used to prepare [ 18 F]FP-CIT, but not limited to this.

[0033] As another exemplary embodiment of the present invention, the reaction solvent may be a polar organic solvent, but is not limited thereto.

[0034] As another exemplary embodiment of the present invention, the polar organic solvent may be one or more protic tertiary alcohols selected from the group consisting of tert-butanol, tert-amyl alcohol and 1-methoxy-2-methyl-2-propanol, but is not limited thereto.

[0035] As another exemplary embodiment of the present invention, the polar organic solvent may be one or more aprotic organic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), but is not limited thereto.

[0036] As another exemplary embodiment of the present invention, the activated [ 18 F] Fluorides can be activated with tetra-n-butylammonium or 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix™ 222), but are not limited thereto.

[0037] According to another aspect of the present invention, a method for preparing [ 18 F] A method for FP-CIT, the method comprising: a pretreatment step of dissolving an FP-CIT linear precursor in an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0038] As an exemplary embodiment of the present invention, the method may further include the following steps, but is not limited thereto: (a) The step of separating the FP-CIT linear precursor by removing the organic solvent from the organic solvent in which the FP-CIT linear precursor is dissolved; (b) Pre-labeling reaction step: A mixture is prepared by dissolving the FP-CIT linear precursor isolated in step (a) in a reaction solvent; and (c) Labeling reaction step: by labeling with […] containing activated […] 18 The mixture described in step (b) is added to the reaction vessel for the fluoride to (use [F] fluoride) 18 The fluoride (F) is labeled.

[0039] As another exemplary embodiment of the present invention, the method may further include the following steps, but is not limited thereto: (a) By directing the activated [ 18 To prepare a mixture, an organic solvent containing a linear precursor of FP-CIT is added to the reaction vessel of the F] fluoride; (b) a pre-labeling reaction step by removing the organic solvent from the mixture in step (a); and (c) Labeling reaction step: by adding a reaction solvent to the mixture from which the organic solvent has been removed (using […]). 18 The fluoride (F) is labeled.

[0040] According to another aspect of the present invention, a kit for storing FP-CIT linear precursors is provided, the kit comprising a composition according to the present invention.

[0041] According to another aspect of the present invention, a method for preparing [ 18 The F]FP-CIT kit comprises a first kit, a second kit, and instructions. The first kit contains a liquid composition according to the invention for storing a linear precursor of FP-CIT, comprising the linear precursor of FP-CIT, and The second kit contains activated [ 18 F] Fluorides and reaction solvents.

[0042] [Beneficial Effects] When an organic solvent having the characteristics according to the invention is used to store (preserve) the FP-CIT linear precursor, the organic solvent can be effectively used to prepare […]. 18 F]FP-CIT, because it can maintain high purity of FP-CIT linear precursors not only by inhibiting the conversion of FP-CIT linear precursors to cyclic salt forms or degradation into various compounds, but also by using existing […]. 18 F]FP-CIT labeling conditions for high-yield synthesis of radiopharmaceuticals[ 18 F]FP-CIT. Attached Figure Description

[0043] Figure 1 This illustrates a method for storing existing FP-CIT linear precursors; Figure 2 A method for storing FP-CIT linear precursors according to the present invention is shown; Figure 3 The results show the confirmation of the purity of the FP-CIT linear precursor stored at a storage concentration of 1 mg / mL at room temperature, depending on the type of storage solvent. Figure 4 The results show the confirmation of the purity of the FP-CIT linear precursor stored at a storage concentration of 1 mg / mL at -20°C, depending on the type of storage solvent. Figure 5The results confirm the purity of the FP-CIT linear precursor stored at a storage concentration of 8 mg / mL in tetrahydrofuran (THF) or ethyl acetate (EA) at room temperature or -20 °C. Figure 6 The method of synthesizing [using the FP-CIT linear precursor stored according to the present invention] is illustrated. 18 F]FP-CIT method; Figure 7 The method of synthesizing [using the FP-CIT linear precursor stored according to the present invention] is illustrated. 18 The F]FP-CIT method. Detailed Implementation

[0044] FP-CIT linear precursor as a preparation of radiopharmaceuticals 18 The starting material of F]FP-CIT begins to transform into a cyclic salt precursor due to its structural characteristics upon completion of synthesis, which leads to a gradual decrease in the proportion of the precursor. This problem persists even when the precursor is stored in a solid state at low temperatures.

[0045] Therefore, to address these issues, a method has been developed to prepare linear salt precursors using tertiary amines with a leaving group (propyl group) and specific acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, etc.); while this improves the linearity of the precursor, it introduces another problem: the acid forming the salt changes […]. 18 F] Fluoride labeling conditions, which lead to [ 18 There are difficulties with FP-CIT, therefore, there is a need to develop a method for long-term storage of FP-CIT linear precursors.

[0046] Therefore, due to extensive research aimed at developing a method to suppress the conversion of linear FP-CIT precursors into cyclic salt precursors and stably maintain a linear structure, the inventors have not only established a method for stabilizing linear FP-CIT precursors, demonstrating that linear FP-CIT precursors can be stably stored (preserved) for a long period when stored in an organic solvent under specific conditions and at specific temperatures, but also demonstrated that […]. 18 F]FP-CIT shows high [ 18 The invention was completed by improving the efficiency of fluoride labeling (F).

[0047] The invention will be described in detail below.

[0048] This invention provides a liquid composition for storing FP-CIT linear precursors or a composition for improving the storage stability of FP-CIT linear precursors, said composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0049] Additionally, the present invention provides a liquid composition for storing FP-CIT linear precursors or a composition for improving the storage stability of FP-CIT linear precursors, said composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0050] In addition, the present invention provides a method for stabilizing FP-CIT linear precursors by storing FP-CIT linear precursors in a composition according to the present invention.

[0051] In this invention, the boiling point can be 10 to 100°C, 10 to 90°C, 10 to 80°C, 10 to 70°C, 10 to 60°C, 10 to 50°C, 10 to 40°C, 10 to 30°C, 30 to 100°C, 30 to 90°C, 30 to 80°C, 30 to 70°C, 30 to 60°C, 60 to 100°C, 60 to 90°C, 60 to 80°C, 60 to 78°C, 63 to 78°C, or 65 to 78°C. 66 to 78°C, 66 to 77.5°C, 66 to 77°C, 68 to 78°C, 70 to 78°C, 73 to 78°C, 75 to 78°C, 65 to 75°C, 65 to 73°C, 65 to 70°C, 65 to 67°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, or 77.1°C, but not limited to these.

[0052] In this invention, the evaporation rate (vapor pressure) measured at 20°C can be 50 to 400 Torr (mmHg), 50 to 380 Torr, 50 to 350 Torr, 50 to 330 Torr, 50 to 300 Torr, 50 to 200 Torr, 50 to 180 Torr, 50 to 160 Torr, 50 to 150 Torr, 60 to 350 Torr, 60 to 300 Torr, 60 to 200 Torr, 60 to 180 Torr, 60 to 160 Torr, 60 to 150 Torr, 70 to 200 Torr, 70 to 180 Torr, 70 to 160 Torr, 70 to 150 Torr, 70 to 145 Torr, 70 to 144 Torr, 70 to 143 Torr, 70 to 142 Torr, 70 to 141 Torr. 70 to 140 tonnage, 71 to 144 tonnage, 71 to 143 tonnage, 71 to 142 tonnage, 71 to 141 tonnage, 72 to 143 tonnage, 72 to 142 tonnage, 73 to 142 tonnage, 73 to 142 tonnage, or 142 tonnage, but not limited to these.

[0053] In this invention, the water solubility at 20°C can be 0.1 to 50%, 0.1 to 40%, 0.1 to 30%, 0.5 to 50%, 0.5 to 40%, 0.5 to 30%, 0.8 to 50%, 0.8 to 40%, 0.8 to 30%, 1 to 50%, 1 to 40%, 1 to 30%, 1.5 to 50%, 1.5 to 40%, 1.5 to 30%, 2 to 30%, 3 to 30%, 5 to 30%, 8 to 30%, 10 to 30%, 20 to 30%, 8 to 20%, 8 to 10%, 8.3%, or 30%, but is not limited thereto.

[0054] In this invention, the organic solvent may be one or more organic solvents selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3) and dichloromethane (DCM), preferably an anhydrous organic solvent, and may be tetrahydrofuran (THF) or ethyl acetate (EA), but is not limited thereto.

[0055] The boiling points, evaporation rates, and water solubility of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM) are shown in Table 1 below.

[0056] [Table 1] The term "FP-CIT linear precursor" as used in this article refers to a precursor represented by the following chemical formula 1, used in the synthesis of radiopharmaceuticals. 18 F]FP-CIT starting material compounds: [Chemical Formula 1] (In chemical formula 1, R1 is a sulfonyl group or a halogen. R2 is C 1-5 Alkyl, and X represents a halogen.

[0057] In this invention, X can be Cl, Br or I, and according to an exemplary embodiment of the present invention, the FP-CIT linear precursor can be N-(3-methanesulfonyloxypropyl)-2-β-methoxycarbonyl-3-β-(4-iodophenyl)torane or N-(3-toluenesulfonyloxypropyl)-2-β-methoxycarbonyl-3-β-(4-iodophenyl)torane, but is not limited thereto.

[0058] In this invention, the FP-CIT linear precursor, preferably the composition containing the FP-CIT linear precursor according to the invention, can preferably be stored (preserved) at a temperature of -50°C to 0°C, -40°C to 0°C, -30°C to 0°C, -20°C to 0°C, -10°C to 0°C, -50°C, -40°C, -30°C, -20°C, -10°C or 0°C, and according to an exemplary embodiment of the invention, the storage temperature of the FP-CIT linear precursor can be -20°C, but is not limited thereto.

[0059] In this invention, the linear precursor of FP-CIT can be present in concentrations of 0.1 to 16 mg / mL, 0.1 to 15 mg / mL, 0.1 to 13 mg / mL, 0.1 to 10 mg / mL, 0.1 to 8 mg / mL, 0.1 to 5 mg / mL, 0.1 to 3 mg / mL, 0.1 to 2 mg / mL, 0.1 to 1 mg / mL, 0.5 to 16 mg / mL, 0.5 to 15 mg / mL, 0.5 to 13 mg / mL, 0.5 to 10 mg / mL, 0.5 to 8 mg / mL, 0.5 to 5 mg / mL, 0.5 to 3 mg / mL, 0.5 to 2 mg / mL, 0.5 to 1 mg / mL, 1 to 16 mg / mL, 1 to 15 mg / mL, 1 to 13 mg / mL, 1 to 10 mg / mL, 1 to 8 mg / mL, 1 to 5 mg / mL, 1 to 3 mg / mL, 1 to 2 mg / mL, 0.1 mg / mL, etc. It may be stored at concentrations of 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL or 8 mg / mL, but the concentrations are not limited thereto.

[0060] The term "storing (preserving) FP-CIT linear precursors" as used in this article refers to stabilizing FP-CIT linear precursors with low chemical stability to inhibit their conversion into FP-CIT cyclic salt precursors or their degradation into various compounds, thereby allowing the FP-CIT linear precursors to maintain their linearity (see [link to article]). Figure 2 ).

[0061] The term "storage" as used herein may refer to the state in which the FP-CIT linear precursor is dissolved in an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0062] The terms “storing FP-CIT linear precursors”, “preserving FP-CIT linear precursors”, “stabilizing FP-CIT linear precursors”, or “improving the storage stability of FP-CIT linear precursors” used in this article are interchangeable.

[0063] Therefore, the liquid composition for storing FP-CIT linear precursors or the composition for improving the storage stability of FP-CIT linear precursors of the present invention is characterized by its ability to inhibit the conversion of FP-CIT linear precursors into FP-CIT cyclic salt precursors and to stably store FP-CIT linear precursors for a long period of time.

[0064] In addition, the improved storage stability of the FP-CIT linear precursor in this invention can be understood as maintaining the linearity of the FP-CIT linear precursor for a long period of time by inhibiting the conversion of the FP-CIT linear precursor into the FP-CIT cyclic salt precursor, thereby stabilizing the FP-CIT linear precursor.

[0065] According to an exemplary embodiment of the present invention, the FP-CIT linear precursor can be maintained at 50 to 99%, 60 to 99%, 70 to 99%, 80 to 99%, 90 to 99%, 90 to 98%, 90 to 97%, 90 to 96%, 90%, 90.7%, 91%, 92%, 93%, 94%, 95%, 95.5%, or 96% of the initial storage amount of the FP-CIT linear precursor after 12 months of storage, but the percentages are not limited thereto.

[0066] According to an exemplary embodiment of the present invention, when the FP-CIT linear precursor is stored for 12 months, 1 to 50%, 1 to 40%, 1 to 30%, 1 to 20%, 1 to 10%, 1 to 8%, 1 to 5%, 3 to 5%, 4 to 10%, 4.5 to 9.3%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9.3%, or 10% of the initial stored amount of the FP-CIT linear precursor can be converted into the FP-CIT cyclic salt precursor, but the percentages are not limited thereto.

[0067] According to an exemplary embodiment of the present invention, when the FP-CIT linear precursor is stored for 12 months, the ratio of (FP-CIT cyclic salt precursor) to (FP-CIT linear precursor) may be 0.01 to 1, 0.01 to 0.8, 0.01 to 0.5, 0.01 to 0.3, 0.01 to 0.2, 0.01 to 0.1, 0.05 to 1, 0.05 to 0.8, 0.05 to 0.5, 0.05 to 0.3, 0.05 to 0.2, or 0.05 to 0.1, but is not limited thereto.

[0068] Furthermore, the present invention provides a method for preparing [using the composition according to the present invention] 18 The method for FP-CIT, wherein the composition comprises an FP-CIT linear precursor as a starting material, the method comprising (see [link to relevant documentation]). Figure 6 and Figure 7 ): (a) The step of separating the FP-CIT linear precursor by removing the organic solvent from the composition containing the FP-CIT linear precursor according to the invention; (b) Pre-labeling reaction step: A mixture is prepared by dissolving the FP-CIT linear precursor isolated in step (a) in a reaction solvent; and (c) Labeling reaction step: by labeling with […] containing activated […] 18 The mixture from step (b) is added to the reaction vessel containing the fluoride (F) while (using [ 18 The fluoride (F) is labeled.

[0069] Furthermore, the present invention provides a method for preparing [using the composition according to the present invention]. 18 The method for FP-CIT, wherein the composition comprises an FP-CIT linear precursor as a starting material, the method comprising (see [link to relevant documentation]). Figure 6 and Figure 7 ): (a) By directing the activated [ 18 The step of preparing a mixture by adding a composition containing an FP-CIT linear precursor according to the present invention to a reaction vessel for fluorides; (b) Pre-labeling reaction step: removal of the organic solvent from the mixture described in step (a); and (c) Labeling reaction step: by adding a reaction solvent to the mixture from which the organic solvent has been removed (using […]). 18 The fluoride (F) is labeled.

[0070] In this invention, [ 18 The characteristic of F]FP-CIT lies in the interaction between the FP-CIT linear precursor and activated [ 18 It is prepared by the nucleophilic fluorination reaction of F fluoride.

[0071] In this invention, the reaction solvent is a polar organic solvent, and the polar organic solvent may be one or more protic tertiary alcohols selected from the group consisting of tert-butanol, tert-amyl alcohol, and 1-methoxy-2-methyl-2-propanol; or The solvent is selected from one or more aprotic organic solvents in the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), but is not limited thereto.

[0072] The term "activated" as used in this article 18 "F] Fluoride" refers to anhydrous [ 18 F] fluoride ions, which are generated in a cyclotron, are then eluted and dried using an anion exchange column and an eluent containing a phase change catalyst, and are suitable for isotope labeling. Furthermore, according to an exemplary embodiment of the invention, activated [ 18 F] Fluorides can be activated using tetra-n-butylammonium or 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix™222) as phase change catalysts, but the phase change catalysts are not limited to these.

[0073] In addition, the present invention provides a method for preparing [ 18 F] A method for FP-CIT, the method comprising: pretreating the FP-CIT linear precursor by dissolving the FP-CIT linear precursor in an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

[0074] In this invention, the method may further include the following steps, but is not limited thereto: (a) The step of separating the FP-CIT linear precursor by removing the organic solvent from the organic solvent in which the FP-CIT linear precursor is dissolved; (b) Pre-labeling reaction step: A mixture is prepared by dissolving the FP-CIT linear precursor isolated in step (a) in a reaction solvent; and (c) Labeling reaction step: by labeling with […] containing activated […] 18 The mixture described in step (b) is added to the reaction vessel for the fluoride F for labeling.

[0075] In this invention, the method may further include the following steps, but is not limited thereto: (a) By directing the activated [ 18 To prepare a mixture, an organic solvent containing a linear precursor of FP-CIT is added to the reaction vessel of the F] fluoride; (b) Pre-labeling reaction step: removal of the organic solvent from the mixture described in step (a); and (c) Labeling reaction step: Labeling is performed by adding a reaction solvent to the mixture from which the organic solvent has been removed.

[0076] Furthermore, the present invention provides a kit for storing linear precursors of FP-CIT, the kit comprising a composition according to the present invention.

[0077] In this invention, the kit may additionally include an instruction manual containing specific descriptions of the compositions according to the invention (storage temperature, storage concentration, storage container, etc.).

[0078] Furthermore, the present invention provides a method for preparing [ 18 The F]FP-CIT kit comprises a first kit, a second kit, and instructions. The first kit contains the composition according to the invention, comprising a linear precursor of FP-CIT, and The second kit may contain activated [ 18 F] Fluorides and reaction solvents, but not limited to these.

[0079] In this invention, the specification may include descriptions of the preparation according to the invention. 18 The instruction manual providing detailed instructions on the F]FP-CIT method.

[0080] [Invention] Preferred embodiments will be presented below to aid in understanding the invention. However, these embodiments are provided merely to facilitate a clearer understanding of the invention, and the scope of the invention is not limited to these embodiments.

[0081] Example Example 1. Confirmation of the purity of the FP-CIT linear precursor based on the storage solvent. 1-1. Tetrahydrofuran (THF) The high-purity FP-CIT linear precursor N-(3'-methanesulfonyloxypropyl)-2-β-methoxycarbonyl-3-β-(4'-iodophenyl)tropane was stored at a concentration of 1 mg / mL in the storage solvent tetrahydrofuran (THF) at room temperature, and its purity was confirmed by HPLC analysis after 12 months. HPLC analysis was performed under the following conditions: column (Luna C18 250 4.6 mm), mobile phase (A:B = 0.1% trifluoroacetic acid:acetonitrile), analytical program (0 min; 100:0, 0 to 15 min; 30:70, 15 to 16 min; 100:0, 16 to 30 min; 100:0), flow rate (1 mL / min), and UV wavelength (254 nm).

[0082] HPLC analysis showed that, assuming an initial purity of 100%, purity remained at 90% or higher after one month of storage, and at 85% or higher after five months, but gradually decreased, with approximately 20% purity observed after 12 months. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 3 And in Table 2 below.

[0083] 1-2. Ethyl acetate (EA) Except for the storage solvent being ethyl acetate (EA), HPLC analysis was performed using the same experimental methods and analytical conditions as described in 1-1. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 90% or higher after one month of storage, and at 80% or higher after five months, but gradually decreased, with approximately 22% purity observed after 12 months. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 3 And in Table 2 below.

[0084] 1-3. Chloroform (CHCl3) Except for the storage solvent being chloroform (CHCl3), HPLC analysis was performed using the same experimental methods and analytical conditions as described in 1-1. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 70% or higher after one month of storage, but gradually decreased, with approximately 22% purity observed after 5 months and approximately 1% or less purity observed after 12 months. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 3 And in Table 2 below.

[0085] 1-4. Dichloromethane (DCM) Except for the storage solvent being dichloromethane (DCM), HPLC analysis was performed using the same experimental methods and analytical conditions as described in 1-1. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 50% or higher after one month of storage, but gradually decreased, with purities of 34% and approximately 9% observed after 5 and 12 months, respectively. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 3 And in Table 2 below.

[0086] [Table 2] Example 2. Confirmation of the purity of the FP-CIT linear precursor based on storage temperature 2-1. Tetrahydrofuran (THF) Except for the storage temperature of -20°C, HPLC analysis was performed using the same experimental methods and analytical conditions as in Examples 1-1. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 95% or higher after five months of storage, and even after 12 months of storage, the purity remained at 90% or higher. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 4 And in Table 3 below.

[0087] 2-2. Ethyl acetate (EA) Except for the storage temperature of -20°C, HPLC analysis was performed using the same experimental methods and analytical conditions as in Examples 1-2. The results of the HPLC analysis showed that, assuming an initial purity of 100%, the purity remained at 95% or higher even after twelve months of storage. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 4 And in Table 3 below.

[0088] 2-3. Chloroform (CHCl3) Except for the storage temperature of -20°C, HPLC analysis was performed using the same experimental methods and analytical conditions as in Examples 1-3. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 85% or higher after one month of storage, but gradually decreased, with 65% purity and approximately 51% purity observed after 5 and 12 months, respectively. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 4 And in Table 3 below.

[0089] 2-4. Dichloromethane (DCM) Except for the storage temperature of -20°C, HPLC analysis was performed using the same experimental methods and analytical conditions as in Examples 1-4. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 95% or higher after one month of storage, and at 80% or higher after five months of storage, but gradually decreased, with approximately 70% purity observed after 12 months. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 4 And in Table 3 below.

[0090] [Table 3] Example 3. Confirmation of the purity of the FP-CIT linear precursor based on the storage solvent, its concentration, and storage temperature. 3-1. Tetrahydrofuran (THF) and room temperature Except for the storage concentration of 8 mg / mL, HPLC analysis was performed using the same experimental methods and analytical conditions as in Examples 1-1. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 90% or higher after one month of storage, but gradually decreased, with 30% purity and approximately 5% purity observed after 5 and 12 months, respectively. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 5 And in Table 4 below.

[0091] 3-2. Ethyl acetate (EA) and room temperature Except for the storage concentration of 8 mg / mL, HPLC analysis was performed using the same experimental methods and analytical conditions as in Examples 1-2. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 70% or higher after one month of storage, but gradually decreased, with 43% purity and approximately 8% purity observed after 5 and 12 months, respectively. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 5 And in Table 4 below.

[0092] 3-3. Tetrahydrofuran (THF) and -20℃ Except for the storage temperature of -20°C, HPLC analysis was performed using the same experimental methods and analytical conditions as in Example 3-1. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 95% or higher after 5 months of storage, and even after 12 months, it remained at 89%. The change in purity of the FP-CIT linear precursor over time is summarized in... Figure 5 And in Table 4 below.

[0093] 3-4. Ethyl acetate (EA) and -20℃ Except for the storage temperature of -20°C, HPLC analysis was performed using the same experimental methods and analytical conditions as in Examples 3-2. The HPLC results showed that, assuming an initial purity of 100%, the purity remained at 98% or higher after 5 months of storage, and even after 12 months of storage, it remained at 90% or higher. The changes in the purity of the FP-CIT linear precursor over time are summarized in... Figure 5 And in Table 4 below.

[0094] [Table 4] Example 4. Synthesis of linear precursors using FP-CIT [ 18 F]FP-CIT 4-1. Treatment of tert-amyl alcohol as a reaction solvent during storage solvent processing The [product / process] was synthesized using 8 mg of FP-CIT linear precursor stored in EA and tert-amyl alcohol as the reaction solvent. 18 F]FP-CIT( Figure 6 The specific storage solvent treatment methods and synthesis conditions are as follows: The storage solvent was dried by heating the FP-CIT linear precursor stored in EA at 50°C or higher while blowing nitrogen into the FP-CIT linear precursor, and the FP-CIT linear precursor dissolved in the reaction solvent was prepared by adding the reaction solvent tert-amyl alcohol.

[0095] By including the activated [ 18 F] Fluoride mixture ([ 18 F]FK 222 The linear precursor of FP-CIT, dissolved in tert-amyl alcohol (dissolved in the reaction solvent), was added to the reaction vessel, and the resulting mixture was heated at 50°C or higher to synthesize […]. 18 F]FP-CIT.

[0096] The reaction mixture was diluted with water, and unreacted [products] were separated using C18 Sep-Pak. 18 F] fluorides and [ 18 F]FP-CIT, to confirm [ 18 The synthesis yield of F]FP-CIT. 18 The synthesis yield of F]FP-CIT was 35%.

[0097] 4-2. [ 18 Treatment of tert-amyl alcohol as a reaction solvent during the synthesis of F]FP-CIT The [product / method] was synthesized using 8 mg of FP-CIT linear precursor stored in EA and tert-amyl alcohol as the reaction solvent. 18 F]FP-CIT( Figure 7 The specific storage solvent treatment methods and synthesis conditions are as follows: By including the activated [ 18 F] Fluoride mixture ([ 18 F]FK 222 8 mg of FP-CIT linear precursor stored in EA was added to the reaction vessel, and the resulting mixture was heated at 50 °C or higher while the storage solvent was dried by blowing nitrogen into the reaction vessel.

[0098] By including the activated [ 18 The reaction solvent tert-amyl alcohol was added to the reaction vessel of the [F] fluoride and the linear precursor of FP-CIT, and then the resulting mixture was heated at 50°C or higher to synthesize [F]. 18 F]FP-CIT. After purification of the reaction mixture, [ 18 The synthesis yield of F]FP-CIT was 35.4%.

[0099] 4-3. [ 18 Treatment of acetonitrile as a reaction solvent during the synthesis of F]FP-CIT The linear precursor of FP-CIT stored in EA and acetonitrile as the reaction solvent were synthesized. 18 F]FP-CIT, and except for the reaction solvent, the storage solvent treatment method and synthesis conditions are the same as in Examples 4-2. As a result, after purifying the reaction mixture, [ 18 The synthesis yield of F]FP-CIT was 17.2%.

[0100] The above description of the invention has been provided for illustrative purposes, and those skilled in the art will understand that the invention can be readily modified into other specific forms without changing its technical spirit or essential characteristics. Therefore, it should be understood that the above embodiments are exemplary in all respects and not restrictive.

[0101] Industrial applicability When storing (preserving) the FP-CIT linear precursor using an organic solvent having the characteristics of the present invention, not only can the high purity of the FP-CIT linear precursor be maintained by inhibiting its conversion to cyclic salt form or degradation into various compounds, but it can also be used in its original state with existing […]. 18 High-yield synthesis of radiopharmaceuticals under F]FP-CIT labeling conditions 18F]FP-CIT, therefore, the present invention can be effectively used for [ 18 The preparation of F]FP-CIT is industrially applicable.

Claims

1. A liquid composition for storing a linear precursor of FP-CIT, said liquid composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

2. The liquid composition of claim 1, wherein the organic solvent is one or more selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM).

3. The liquid composition of claim 1 or 2, wherein the FP-CIT linear precursor is a compound represented by the following chemical formula 1: [Chemical Formula 1] In chemical formula 1, R1 is a sulfonyl group or a halogen, and R2 is... C1-5 Alkyl group, and X is a halogen.

4. The liquid composition of claim 3, wherein R1 is mesylate, tosyl, nosyl, F, Cl, Br, or I. R2 is methyl or ethyl, and X is Cl, Br, or I.

5. The liquid composition according to any one of claims 1 to 4, wherein the FP-CIT linear precursor is stored at a temperature of -50°C to 0°C.

6. The liquid composition according to any one of claims 1 to 5, wherein the FP-CIT linear precursor is stored at a concentration of 0.1 mg / mL to 16 mg / mL.

7. The liquid composition of any one of claims 1 to 6, wherein the liquid composition inhibits the conversion of the FP-CIT linear precursor to the FP-CIT cyclic salt precursor.

8. The liquid composition according to any one of claims 1 to 7, wherein when stored for 12 months, the FP-CIT linear precursor maintains 50% to 99% of the initial storage amount of the FP-CIT linear precursor.

9. The liquid composition according to any one of claims 1 to 8, wherein when the FP-CIT linear precursor is stored for 12 months, 1% to 50% of the initial stored amount of the FP-CIT linear precursor is converted into the FP-CIT cyclic salt precursor.

10. The liquid composition of any one of claims 1 to 9, wherein the FP-CIT linear precursor has a (FP-CIT cyclic salt precursor) / (FP-CIT linear precursor) ratio of 0.01 to 1 when stored for 12 months.

11. A composition for improving the storage stability of FP-CIT linear precursors, said composition comprising an organic solvent having the following characteristics: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

12. The composition of claim 11, wherein the organic solvent is one or more selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM).

13. The composition of claim 11 or 12, wherein the FP-CIT linear precursor is a compound represented by the following chemical formula 1: [Chemical Formula 1] In chemical formula 1, R1 is a sulfonyl group or a halogen, and R2 is a C group. 1-5 Alkyl group, and X is a halogen.

14. The composition of claim 13, wherein R1 is mesylate, tosyl, nosyl, F, Cl, Br, or I. R2 is methyl or ethyl, and X is Cl, Br, or I.

15. The composition of any one of claims 11 to 14, wherein the FP-CIT linear precursor is stored at a temperature of -50°C to 0°C.

16. The composition of any one of claims 11 to 15, wherein the FP-CIT linear precursor is stored at a concentration of 0.1 mg / mL to 16 mg / mL.

17. The composition of any one of claims 11 to 16, wherein the improvement in storage stability of the FP-CIT linear precursor inhibits the conversion of the FP-CIT linear precursor to the FP-CIT cyclic salt precursor.

18. The composition of any one of claims 11 to 17, wherein the FP-CIT linear precursor maintains 50% to 99% of the initial storage amount of the FP-CIT linear precursor when stored for 12 months.

19. The composition of any one of claims 11 to 18, wherein when the FP-CIT linear precursor is stored for 12 months, 1% to 50% of the initial stored amount of the FP-CIT linear precursor is converted to the FP-CIT cyclic salt precursor.

20. The composition of any one of claims 11 to 19, wherein the FP-CIT linear precursor has a (FP-CIT cyclic salt precursor) / (FP-CIT linear precursor) ratio of 0.01 to 1 after 12 months of storage.

21. A method for stabilizing an FP-CIT linear precursor by storing the FP-CIT linear precursor in a composition as described in any one of claims 1 to 10.

22. A method for preparing [using the composition as described in any one of claims 1 to 10] 18 The method for FP-CIT, wherein the composition comprises an FP-CIT linear precursor as a starting material, the method comprising: (a) The step of separating the FP-CIT linear precursor from the composition comprising the FP-CIT linear precursor as described in any one of claims 1 to 10; (b) Pre-labeling reaction step: A mixture is prepared by dissolving the FP-CIT linear precursor isolated in step (a) in a reaction solvent; and (c) Labeling reaction step: by labeling with […] containing activated […] 18 The mixture described in step (b) is added to the reaction vessel for the fluoride F for labeling.

23. A method for preparing [using the composition as described in any one of claims 1 to 10] 18 The method for FP-CIT, wherein the composition comprises an FP-CIT linear precursor as a starting material, the method comprising: (a) By directing the activated [ 18 The step of preparing a mixture by adding the composition containing the FP-CIT linear precursor as described in any one of claims 1 to 10 to a fluoride reaction vessel; (b) Pre-labeling reaction step: removal of the organic solvent from the mixture described in step (a); and (c) Labeling reaction step: Labeling is performed by adding a reaction solvent to the mixture from which the organic solvent has been removed.

24. The method of claim 22 or 23, wherein the [ 18 F]FP-CIT via FP-CIT linear precursor and activated [ 18 It is prepared by the nucleophilic fluorination reaction of F fluoride.

25. The method of any one of claims 22 to 24, wherein the reaction solvent is a polar organic solvent.

26. The method of claim 25, wherein the polar organic solvent is one or more protic tertiary alcohols selected from the group consisting of tert-butanol, tert-amyl alcohol, and 1-methoxy-2-methyl-2-propanol.

27. The method of claim 25 or 26, wherein the polar organic solvent is one or more aprotic organic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO) and dimethylformamide (DMF).

28. The method of any one of claims 22 to 27, wherein the activated [ 18 F] fluoride is activated with tetrabutylammonium or 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix™ 222).

29. A method for preparing [ 18 The F]FP-CIT method, the method comprising: The FP-CIT linear precursor is dissolved in an organic solvent with the following characteristics: FP-CIT linear precursor pretreatment steps: (a) Boiling point is 10°C to 100°C; (b) Evaporation rate of 50 to 400 Torr; and (c) Water solubility is 0.1% to 50%.

30. The method of claim 29, further comprising the following steps: (a) The step of separating the FP-CIT linear precursor by removing the organic solvent from the organic solvent in which the FP-CIT linear precursor is dissolved; (b) Pre-labeling reaction step: A mixture is prepared by dissolving the FP-CIT linear precursor isolated in step (a) in a reaction solvent; and (c) Labeling reaction step: by labeling with […] containing activated […] 18 The mixture described in step (b) is added to the reaction vessel for the fluoride F for labeling.

31. The method of claim 29 or 30, further comprising the following steps: (a) By directing the activated [ 18 To prepare a mixture, an organic solvent containing a linear precursor of FP-CIT is added to the reaction vessel of the F] fluoride; (b) Pre-labeling reaction step: removal of the organic solvent from the mixture described in step (a); and (c) Labeling reaction step: Labeling is performed by adding a reaction solvent to the mixture from which the organic solvent has been removed.

32. A kit for storing FP-CIT linear precursors, comprising a liquid composition for storing the FP-CIT linear precursors as described in any one of claims 1 to 10.

33. A method for preparing [ 18 The F]FP-CIT kit includes a first kit, a second kit, and instructions. The first kit comprises a liquid composition for storing the FP-CIT linear precursor as described in any one of claims 1 to 10, comprising the FP-CIT linear precursor, and The second kit contains activated [ 18 F] Fluorides and reaction solvents.

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