LIQUID PRESERVATIVES, PRESERVATIVES FOR IMPROVING STORAGE STABILITY, STABILIZATION METHODS AND STORAGE KITS FOR STRAIGHT-CHAIN ​​FP-CIT PRECURSORS, PREPARATION METHODS AND PREPARATION KITS [18F]FP-CIT

Abstract

The invention relates to a method for stabilizing (preserving and pre-treating) a linear FP-CIT precursor with high purity, and a method for preparing [18F]FP-CIT using this precursor. If an organic solvent with the properties described in the invention is used to preserve the linear FP-CIT precursor, the conversion of the linear FP-CIT precursor to a cyclic salt or the decomposition of the linear FP-CIT precursor into various compounds is prevented, thereby allowing the maintenance of high purity of the linear FP-CIT precursor, and [18F]FP-CIT is a radiopharmaceutical that can be prepared with high yield using conventional [18F]FP-CIT binding conditions as currently in use, and thus the invention can be effectively used as a starting material for [18F]FPCIT. The invention relates to a liquid preparation for preserving the linear FP-CIT precursor, a preparation for improving the storage stability of the linear FP-CIT precursor, a preservation kit for the linear FP-CIT precursor, and a kit for preparing [18F]FP-CIT.

Description

High-purity stabilization method of FP-CIT linear precursor and method for manufacturing [18F]FP-CIT using the same

[0001] The present invention relates to a high-purity stabilization (storage, pretreatment) method of FP-CIT linear precursor and a method for producing [ 18 [F] It is about the manufacturing method of FP-CIT.

[0002] This invention claims the benefit of priority from Korean Patent Application No. 10-2023-0129820, filed September 26, 2023, and Korean Patent Application No. 10-2024-0037443, filed March 18, 2024, the entire contents of which are incorporated herein by reference.

[0003] [ 18 F] Fluoride-labeled radiopharmaceuticals are diagnostic radiopharmaceuticals with a radioactivity of 110 minutes. 18 [F] Due to the short half-life of fluoride, it has the characteristic of being manufactured and used on the same day of use. 18 F] The manufacturing steps of fluoride-labeled radiopharmaceuticals are [ 18 F] Production and activation steps of fluoride, a radiopharmaceutical precursor [ 18 F]Step of labeling fluoride, [ 18 [F] It proceeds to the purification and formulation stage of fluoride-labeled radiopharmaceuticals. At this time, the radiopharmaceutical precursor is usually [ 18 F]Fluoride has a leaving group at the position where it is labeled and through a nucleophilic substitution reaction [ 18 F]Fluoride is labeled.

[0004] [ 18As a precursor of F]FP-CIT, the FP-CIT linear precursor uses N-(3'-(methanesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane or N-(3'-toluenesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane. It has been reported that the compounds have a propyl group having a leaving group at the end in a tertiary amine, and in this case, a cyclic salt having a four-membered ring is formed through an intramolecular cyclization reaction.

[0005] In this way, the mixture of linear precursor structures and cyclic salt precursors due to the natural transformation into cyclic salts that occurs due to the structural characteristics of the compound can not only affect the purity of the starting material of the radiopharmaceutical, but also affect the manufacturing yield of the radiopharmaceutical.

[0006] Accordingly, the inventors of the present invention have conducted extensive research to find a method to stably maintain the linear structure by suppressing the natural change of the FP-CIT linear precursor, i.e., the conversion of the linear precursor into a cyclic salt, and as a result, not only have they established a stabilization method that can secure the long-term storage stability of the FP-CIT linear precursor, but also have used this to obtain a high labeling efficiency [ 18 The present invention was completed by manufacturing F]FP-CIT.

[0007] The present inventors [ 18As a result of extensive research to find a method to stably maintain the linear structure by suppressing the conversion of the FP-CIT linear precursor used in the production of F]FP-CIT to a cyclic salt precursor, not only was a stabilization method established to ensure long-term storage stability of the FP-CIT linear precursor, but also a high labeling efficiency was obtained by using this. 18 The present invention was completed by manufacturing F]FP-CIT.

[0008] An object of the present invention is to provide a liquid composition for storing an FP-CIT linear precursor comprising an organic solvent having the following characteristics:

[0009] (a) boiling point of 10 to 100°C;

[0010] (b) evaporation rate of 50 to 400 Torr; and

[0011] (c) Water solubility of 0.1 to 50%.

[0012] Another object of the present invention is to provide a composition for improving the storage stability of an FP-CIT linear precursor, comprising an organic solvent having the following characteristics:

[0013] (a) boiling point of 10 to 100°C;

[0014] (b) evaporation rate of 50 to 400 Torr; and

[0015] (c) Water solubility of 0.1 to 50%.

[0016] Another object of the present invention is to provide a method for stabilizing an FP-CIT linear precursor by storing the FP-CIT linear precursor in a composition according to the present invention.

[0017] Another object of the present invention is to provide a composition according to the present invention comprising a FP-CIT linear precursor as a starting material. 18 [F]To provide a method for manufacturing FP-CIT.

[0018] Another object of the present invention is to provide a method for preparing a FP-CIT linear precursor, comprising a FP-CIT linear precursor pretreatment step of dissolving the FP-CIT linear precursor in an organic solvent having the following characteristics: 18 [F]FP-CIT manufacturing method is provided:

[0019] (a) boiling point of 10 to 100°C;

[0020] (b) evaporation rate of 50 to 400 Torr; and

[0021] (c) Water solubility of 0.1 to 50%.

[0022] Another object of the present invention is to provide a kit for storing FP-CIT linear precursors.

[0023] Another object of the present invention is to [ 18 [F]FP-CIT manufacturing kit is provided.

[0024]

[0025] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

[0026] In order to achieve the above object, the present invention provides a liquid composition for storing an FP-CIT linear precursor comprising an organic solvent having the following characteristics:

[0027] (a) boiling point of 10 to 100°C;

[0028] (b) evaporation rate of 50 to 400 Torr; and

[0029] (c) Water solubility of 0.1 to 50%.

[0030] In addition, the present invention provides a composition for improving the storage stability of an FP-CIT linear precursor, comprising an organic solvent having the following characteristics:

[0031] (a) boiling point of 10 to 100°C;

[0032] (b) evaporation rate of 50 to 400 Torr; and

[0033] (c) Water solubility of 0.1 to 50%.

[0034] Additionally, the present invention provides a method for stabilizing an FP-CIT linear precursor by storing the FP-CIT linear precursor in a composition according to the present invention.

[0035] In one embodiment of the present invention, the organic solvent may be at least one selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM), but is not limited thereto.

[0036] In another 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:

[0037] [Chemical Formula 1]

[0038]

[0039] (In the above chemical formula 1,

[0040] R1 is sulfonyl or halogen,

[0041] R2 is C 1-5 It is alkyl,

[0042] X is a halogen.).

[0043] In another embodiment of the present invention, R1 is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), nitrobenzenesulfonyl (Nosyl), F, Cl, Br, or I,

[0044] The above R2 is methyl or ethyl,

[0045] The above X may be, but is not limited to, Cl, Br, or I.

[0046] In another embodiment of the present invention, the FP-CIT linear precursor may be, but is not limited to, N-(3'-(methanesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane, or N-(3'-toluenesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane.

[0047] In another embodiment of the present invention, the storage temperature of the FP-CIT linear precursor may be, but is not limited to, -50 to 0°C.

[0048] In another embodiment of the present invention, the FP-CIT linear precursor can be stored at a concentration of, but not limited to, 0.1 to 16 mg / mL.

[0049] In another embodiment of the present invention, the liquid composition can inhibit, but is not limited to, the conversion of an FP-CIT linear precursor to an FP-CIT cyclic salt precursor.

[0050] In another embodiment of the present invention, the FP-CIT linear precursor can be maintained at 50 to 99% of the initial stored amount of the FP-CIT linear precursor when stored for 12 months, but is not limited thereto.

[0051] In another embodiment of the present invention, the FP-CIT linear precursor can be converted to the FP-CIT cyclic salt precursor at a rate of, but not limited to, 1% to 50% of the initial stored amount of the FP-CIT linear precursor when stored for 12 months.

[0052] In another embodiment of the present invention, the FP-CIT linear precursor may have a ratio of (FP-CIT cyclic salt precursor) / (FP-CIT linear precursor) of 0.01 to 1 when stored for 12 months, but is not limited thereto.

[0053] In another embodiment of the present invention, the improvement in storage stability of the FP-CIT linear precursor may be, but is not limited to, inhibiting the conversion of the FP-CIT linear precursor into the FP-CIT cyclic salt precursor.

[0054] In addition, the present invention provides a composition according to the present invention comprising an FP-CIT linear precursor as a starting material, comprising the following steps: 18 Provides a method for preparing F]FP-CIT:

[0055] (a) a step of removing an organic solvent from a composition according to the present invention comprising an FP-CIT linear precursor to separate the FP-CIT linear precursor;

[0056] (b) a labeling reaction pre-step of preparing a mixture by dissolving the FP-CIT linear precursor separated in step (a) in a reaction solvent; and

[0057] (c) Activated [ 18 Add the mixture of step (b) to the reaction vessel containing F]fluoride ([ 18 [F]Fluoride) labeling reaction step.

[0058] In addition, the present invention provides a composition according to the present invention comprising an FP-CIT linear precursor as a starting material, comprising the following steps: 18 Provides a method for preparing F]FP-CIT:

[0059] (a) Activated [ 18 A step of preparing a mixture by adding a composition according to the present invention comprising an FP-CIT linear precursor to a reaction vessel containing F]fluoride;

[0060] (b) a pre-labeling reaction step of removing the organic solvent from the mixture of step (a);

[0061] (c) Add reaction solvent to the mixture from which the organic solvent has been removed ([ 18 [F]Fluoride) labeling reaction step.

[0062] In one embodiment of the present invention, the above [ 18 F]FP-CIT is a linear precursor of FP-CIT and an activated [ 18 F] It can be prepared through a nucleophilic fluorination reaction of fluoride, but is not limited thereto.

[0063] In another embodiment of the present invention, the reaction solvent may be, but is not limited to, a polar organic solvent.

[0064] In another embodiment of the present invention, the polar organic solvent may be one or more protic tertiary alcohols selected from the group consisting of t-butanol, t-amyl alcohol, and 1-methoxy-2methyl-2-propanol, but is not limited thereto.

[0065] In another 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 dimethyl formamide (DMF), but is not limited thereto.

[0066] In another embodiment of the present invention, the activated [ 18 [F]Fluoride can be activated with, but is not limited to, tetra-n-butylammonium or 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Cryptofix™ 222).

[0067] In addition, the present invention includes a FP-CIT linear precursor pretreatment step of dissolving the FP-CIT linear precursor in an organic solvent having the following characteristics: 18 Provides a method for manufacturing F]FP-CIT:

[0068] (a) boiling point of 10 to 100°C;

[0069] (b) evaporation rate of 50 to 400 Torr; and

[0070] (c) Water solubility of 0.1 to 50%.

[0071] In one embodiment of the present invention, the method may further include, but is not limited to, the following steps:

[0072] (a) a 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;

[0073] (b) a labeling reaction pre-step of preparing a mixture by dissolving the FP-CIT linear precursor separated in step (a) in a reaction solvent; and

[0074] (c) Activated [ 18 Add the mixture of step (b) to the reaction vessel containing F]fluoride ([ 18 [F]Fluoride) labeling reaction step.

[0075] In another embodiment of the present invention, the method may further include, but is not limited to, the following steps:

[0076] (a) Activated [ 18 A step of preparing a mixture by adding an organic solvent in which an FP-CIT linear precursor is dissolved to a reaction vessel containing F]fluoride;

[0077] (b) a pre-labeling reaction step of removing the organic solvent from the mixture of step (a);

[0078] (c) Add reaction solvent to the mixture from which the organic solvent has been removed ([ 18 [F]Fluoride) labeling reaction step.

[0079] The present invention also provides a kit for storing an FP-CIT linear precursor comprising a composition according to the present invention.

[0080] In addition, the present invention comprises a first kit, a second kit, and instructions [ 18 As a kit for manufacturing F]FP-CIT,

[0081] The first kit comprises a liquid composition for storing an FP-CIT linear precursor according to the present invention, which comprises an FP-CIT linear precursor,

[0082] The above second kit is activated [ 18 [F] characterized by containing fluoride and a reaction solvent, 18 Provides a kit for manufacturing F]FP-CIT.

[0083] When an organic solvent having the characteristics according to the present invention is used for the storage (preservation) of the FP-CIT linear precursor, the FP-CIT linear precursor can be maintained at a high purity by suppressing the conversion of the FP-CIT linear precursor into a cyclic salt form or decomposition into various compounds, and the existing [ 18 [F]FP-CIT labeling conditions were used to produce radiopharmaceuticals with high yields [ 18 Because F]FP-CIT can be synthesized [ 18 F]FP-CIT can be usefully used in manufacturing.

[0084] Figure 1 is a drawing showing a conventional FP-CIT linear precursor storage method.

[0085] Figure 2 is a drawing showing a method for storing an FP-CIT linear precursor according to the present invention.

[0086] Figure 3 is a drawing showing the results of checking the purity of FP-CIT linear precursor stored at a storage concentration of 1 mg / mL at room temperature according to the type of storage solvent.

[0087] Figure 4 is a drawing showing the results of checking the purity of FP-CIT linear precursor stored at a storage concentration of 1 mg / mL at -20°C according to the type of storage solvent.

[0088] Figure 5 is a drawing showing the results of confirming the purity of 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.

[0089] Figure 6 shows a method for producing a FP-CIT linear precursor stored according to the present invention. 18 This is a diagram showing a method for synthesizing F]FP-CIT.

[0090] Figure 7 shows a method for producing a FP-CIT linear precursor according to the present invention. 18 This is a diagram showing a method for synthesizing F]FP-CIT.

[0091] Radioactive pharmaceuticals [ 18 [F]FP-CIT linear precursor, which is the starting material for the production of FP-CIT, begins to convert into a cyclic salt precursor from the point at which synthesis is completed due to its structural characteristics, and its ratio gradually decreases. This was confirmed to be a problem that could not be solved even by storing it at low temperatures in a solid state.

[0092] Therefore, to solve these problems, a method for making linear salt precursors using tertiary amines with a leaving group and specific acids (e.g., methanesulfonic acid and p-toluenesulfonic acid) was developed, but while the linearity of the precursors was improved, the acid forming the salt [ 18 F]Changes in fluoride labeling conditions occur [ 18 Another problem that has arisen is the failure of manufacturing F]FP-CIT, which necessitates the development of a method for long-term storage of the FP-CIT linear precursor.

[0093] Accordingly, the inventors of the present invention conducted extensive research to find a method to suppress the conversion of the FP-CIT linear precursor into a cyclic salt precursor and stably maintain the linear structure. As a result, they confirmed that the FP-CIT linear precursor can be stably stored (stored) for a long period of time when stored in an organic solvent under specific conditions at a specific temperature, and thus established a method for stabilizing the FP-CIT linear precursor, and manufactured using the same. 18 F]FP-CIT is high [ 18 The present invention was completed by confirming that the F]fluoride labeling efficiency is exhibited.

[0094]

[0095] Hereinafter, the present invention will be described in detail.

[0096]

[0097] The present invention provides a liquid composition for storing an FP-CIT linear precursor or a composition for improving the storage stability of an FP-CIT linear precursor, comprising an organic solvent having the following characteristics.

[0098] (a) boiling point of 10 to 100 ℃;

[0099] (b) evaporation rate of 50 to 400 Torr; and

[0100] (c) Water solubility of 0.1 to 50%.

[0101] In addition, the present invention provides a liquid composition for storing an FP-CIT linear precursor or a composition for improving the storage stability of an FP-CIT linear precursor, comprising an organic solvent having the following characteristics:

[0102] (a) boiling point of 10 to 100 ℃;

[0103] (b) evaporation rate of 50 to 400 Torr; and

[0104] (c) Water solubility of 0.1 to 50%.

[0105] Additionally, the present invention provides a method for stabilizing an FP-CIT linear precursor by storing the FP-CIT linear precursor in a composition according to the present invention.

[0106] In the present invention, the boiling point is 10 to 100 ℃, 10 to 90 ℃, 10 to 80 ℃, 10 to 70 ℃, 10 to 60 ℃, 10 to 50 ℃, 10 to 40 ℃, 10 to 30 ℃, 30 to 100 ℃, 30 to 90 ℃, 30 to 80 ℃, 30 to 70 ℃, 30 to 60 ℃, 60 to 100 ℃, 60 to 90 ℃, 60 to 80 ℃, 60 to 78 ℃, 63 to 78 ℃, 65 to 78 ℃, 66 to 78 ℃, 66 to 77.5 ℃, 66 to 77 ℃, 68 to 78 ℃, It may be, but is not limited to, 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.

[0107] In the present invention, the vapor pressure measured at 20° C. is 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 It may be, but is not limited to, 145 Torr, 70 to 144 Torr, 70 to 143 Torr, 70 to 142 Torr, 70 to 141 Torr, 70 to 140 Torr, 71 to 144 Torr, 71 to 143 Torr, 71 to 142 Torr, 71 to 141 Torr, 72 to 143 Torr, 72 to 142 Torr, 73 to 142 Torr, 73 Torr, or 142 Torr.

[0108] In the present invention, the water solubility at 20°C may be, but is not limited to, 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%. Doesn't.

[0109] In the present invention, the organic solvent may be at least one organic solvent selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM), preferably an anhydrous organic solvent, and according to one embodiment of the present invention, may be tetrahydrofuran (THF) or ethyl acetate (EA), but is not limited thereto.

[0110] The boiling points, evaporation rates, and water solubilities of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM) are shown in Table 1 below:

[0111]

[0112] In the present invention, the "FP-CIT linear precursor" is a radiopharmaceutical [ 18 [F]FP-CIT refers to a compound of the following chemical formula 1 as a starting material used in the synthesis of:

[0113] [Chemical Formula 1]

[0114]

[0115] (In the above chemical formula 1,

[0116] R1 is sulfonyl or halogen,

[0117] R2 is C 1-5 It is alkyl,

[0118] X is a halogen.).

[0119] In the present invention, R1 is methanesulfonyl (Mesyl, ), toluenesulfonyl (Tosyl, ), nitrobenzenesulfonyl (Nosyl, ), F, Cl, Br, or I,

[0120] The above R2 is methyl (Methyl, ), or ethyl (Ethyl, ) and,

[0121] The above X may be Cl, Br, or I, and according to one embodiment of the present invention, the FP-CIT linear precursor may be N-(3'-(methanesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane, or N-(3'-toluenesulfonyloxipropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane, but is not limited thereto.

[0122] In the present invention, the FP-CIT linear precursor, preferably the composition according to the present invention containing the FP-CIT linear precursor, can be stored (stored) at a temperature of -50 to 0°C, -40 to 0°C, -30 to 0°C, -20 to 0°C, -10 to 0°C, -50°C, -40°C, -30°C, -20°C, -10°C, or 0°C, and according to one embodiment of the present invention, the storage temperature of the FP-CIT linear precursor may be -20°C, but is not limited thereto.

[0123] In the present invention, the FP-CIT linear precursor is present in an amount 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 It may be stored at a concentration of, but is not limited 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, 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.

[0124] In the present invention, “FP-CIT linear precursor storage” means stabilizing an FP-CIT linear precursor having low chemical stability to prevent conversion into an FP-CIT cyclic salt precursor or decomposition into multiple compounds, thereby allowing the FP-CIT linear precursor to maintain its linearity (see Fig. 2).

[0125] In the present invention, “storage” may mean a state in which the FP-CIT linear precursor is dissolved in an organic solvent having the following characteristics.

[0126] (a) boiling point of 10 to 100 ℃;

[0127] (b) evaporation rate of 50 to 400 Torr; and

[0128] (c) Water solubility of 0.1 to 50%.

[0129] In the present invention, “FP-CIT linear precursor storage”, “FP-CIT linear precursor storage”, “FP-CIT linear precursor stabilization”, or “FP-CIT linear precursor storage stability improvement” may be used interchangeably.

[0130] Therefore, the liquid composition for storing an FP-CIT linear precursor or the composition for improving the storage stability of an FP-CIT linear precursor of the present invention is characterized in that it can suppress the conversion of an FP-CIT linear precursor into an FP-CIT cyclic salt precursor, thereby stably storing an FP-CIT linear precursor for a long period of time.

[0131] In addition, in the present invention, the improvement in storage stability of the FP-CIT linear precursor may mean stabilizing the FP-CIT linear precursor by suppressing the conversion of the FP-CIT linear precursor into the FP-CIT cyclic salt precursor, thereby maintaining the linearity of the FP-CIT linear precursor for a long period of time.

[0132] According to one embodiment of the present invention, the FP-CIT linear precursor may be maintained at, but not limited to, 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 stored FP-CIT linear precursor amount when stored for 12 months.

[0133] According to one embodiment of the present invention, the FP-CIT linear precursor may be converted to the FP-CIT cyclic salt precursor at a rate of, but not limited to, 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%, 9.3%, or 10% of the initially stored amount of the FP-CIT linear precursor when stored for 12 months.

[0134] According to one embodiment of the present invention, the FP-CIT linear precursor may have a ratio of (FP-CIT cyclic salt precursor) / (FP-CIT linear precursor) of, but not limited to, 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 when stored for 12 months.

[0135]

[0136] In addition, the present invention provides a composition according to the present invention comprising an FP-CIT linear precursor as a starting material, comprising the following steps: 18 Provides a method for preparing F]FP-CIT (see FIGS. 6 and 7):

[0137] (a) a step of removing an organic solvent from a composition according to the present invention comprising an FP-CIT linear precursor to separate the FP-CIT linear precursor;

[0138] (b) a labeling reaction pre-step of preparing a mixture by dissolving the FP-CIT linear precursor separated in step (a) in a reaction solvent; and

[0139] (c) Activated [ 18 Add the mixture of step (b) to the reaction vessel containing F]fluoride ([18 [F]Fluoride) labeling reaction step.

[0140] In addition, the present invention provides a composition according to the present invention comprising an FP-CIT linear precursor as a starting material, comprising the following steps: 18 Provides a method for preparing F]FP-CIT (see FIGS. 6 and 7):

[0141] (a) Activated [ 18 A step of preparing a mixture by adding a composition according to the present invention comprising an FP-CIT linear precursor to a reaction vessel containing F]fluoride;

[0142] (b) a pre-labeling reaction step of removing the organic solvent from the mixture of step (a); and

[0143] (c) Add reaction solvent to the mixture from which the organic solvent has been removed ([ 18 [F]Fluoride) labeling reaction step.

[0144] In the present invention, the above [ 18 F]FP-CIT is a linear precursor of FP-CIT and an activated [ 18 [F] It is characterized by being manufactured through a nucleophilic fluorination reaction of fluoride.

[0145] In the present invention, the reaction solvent is a polar organic solvent, and the polar organic solvent is at least one protic tertiary alcohol selected from the group consisting of t-butanol, t-amyl alcohol, and 1-methoxy-2methyl-2-propanol; or

[0146] It may be one or more aprotic organic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethyl formamide (DMF), but is not limited thereto.

[0147] In the present invention, "activated [ 18[F]Fluoride" is produced in a cyclotron, eluted with an anion exchange column and a phase transfer catalyst, and dried to obtain an anhydrous [ 18 F] means fluoride ion, and according to one embodiment of the present invention, the activated [ 18 [F]Fluoride may be activated with, but is not limited to, the phase transfer catalyst tetra-n-butylammonium or 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Cryptofix™ 222).

[0148] In addition, the present invention includes a FP-CIT linear precursor pretreatment step of dissolving the FP-CIT linear precursor in an organic solvent having the following characteristics: 18 Provides a method for manufacturing F]FP-CIT:

[0149] (a) boiling point of 10 to 100 ℃;

[0150] (b) evaporation rate of 50 to 400 Torr; and

[0151] (c) Water solubility of 0.1 to 50%.

[0152] In the present invention, the method may further include, but is not limited to, the following steps:

[0153] (a) a 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;

[0154] (b) a labeling reaction pre-step of preparing a mixture by dissolving the FP-CIT linear precursor separated in step (a) in a reaction solvent; and

[0155] (c) Activated [ 18 [F] A labeling reaction step of adding the mixture of step (b) to a reaction vessel containing fluoride.

[0156] In the present invention, the method may further include, but is not limited to, the following steps:

[0157] (a) Activated [ 18 A step of preparing a mixture by adding an organic solvent in which an FP-CIT linear precursor is dissolved to a reaction vessel containing F]fluoride;

[0158] (b) a pre-labeling reaction step of removing the organic solvent from the mixture of step (a);

[0159] (c) A labeling reaction step in which a reaction solvent is added to a mixture from which the organic solvent has been removed.

[0160]

[0161] The present invention also provides a kit for storing an FP-CIT linear precursor comprising a composition according to the present invention.

[0162] In the present invention, the kit may additionally include instructions describing specific details (storage temperature, storage concentration, storage container, etc.) regarding the composition according to the present invention.

[0163] In addition, the present invention comprises a first kit, a second kit, and instructions [ 18 As a kit for manufacturing F]FP-CIT,

[0164] The first kit comprises a composition according to the present invention comprising an FP-CIT linear precursor;

[0165] The above second kit is activated [ 18 F] May include, but is not limited to, fluoride and reaction solvents.

[0166] In the present invention, the instructions are [ 18 [F] A detailed description of the method for manufacturing FP-CIT may be provided.

[0167] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples.

[0168]

[0169] [Example]

[0170] Example 1. Confirmation of the purity of FP-CIT linear precursor according to storage solvent.

[0171] 1-1. Tetrahydrofurane (THF)

[0172] N-(3'-(methanesulfonyloxypropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane, a high-purity FP-CIT linear precursor, was stored at room temperature in THF (Tetrahydrofurane) as a storage solvent at a concentration of 1 mg / mL and its purity was confirmed for 12 months using HPLC analysis. HPLC analysis was performed under the following conditions: column (Luna C18 2504.6 mm), mobile phase (A:B = 0.1% trifluoroacetic acid:acetonitrile), analysis program (0 min; 100:0, 0-15 min; 30:70, 15-16 min; 100:0, 16-30 min; 100:0), flow rate (1 mL / min), UV wavelength (254 nm).

[0173] HPLC analysis results showed that when the purity at the start of storage was considered 100%, the purity was maintained at over 90% after 1 month of storage and over 85% after 5 months, but gradually decreased to approximately 20% purity after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 3 and Table 2 below.

[0174]

[0175] 1-2. Ethyl acetate (EA)

[0176] Except that the storage solvent was EA (Ethyl acetate), the same experimental method and analysis conditions as 1-1 were used. HPLC analysis results showed that when the purity at the start of storage was considered 100%, the purity was maintained at over 90% after 1 month of storage and over 80% after 5 months, but gradually decreased to approximately 22% purity after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 3 and Table 2 below.

[0177]

[0178] 1-3. Chloroform (CHCl3)

[0179] Except that the storage solvent was chloroform (CHCl3), the same experimental method and analysis conditions as 1-1 above were used. HPLC analysis results showed that when the purity at the start of storage was considered 100%, the purity was maintained at 70% or more after 1 month of storage, but gradually decreased to 20% after 5 months and approximately 1% or less after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 3 and Table 2 below.

[0180]

[0181] 1-4. Dichloromethane (DCM)

[0182] Except for using dichloromethane (DCM) as the storage solvent, the same experimental method and analysis conditions as 1-1 were used. HPLC analysis results showed that when the purity at the start of storage was considered 100%, the purity was maintained at more than 50% after 1 month of storage, but gradually decreased to 34% after 5 months and approximately 9% after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 3 and Table 2 below.

[0183]

[0184]

[0185] Example 2. Confirmation of the purity of FP-CIT linear precursor according to storage temperature.

[0186] 2-1. Tetrahydrofurane (THF)

[0187] Except for the storage temperature being -20°C, the same experimental method and analysis conditions as Example 1-1 were used. HPLC analysis results showed that, when the purity at the start of storage was considered 100%, the purity was maintained at 95% or higher after 5 months of storage, and at 90% or higher after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 4 and Table 3 below.

[0188]

[0189] 2-2. Ethyl acetate (EA)

[0190] Except for the storage temperature being -20°C, the same experimental method and analysis conditions as in Example 1-2 were used. HPLC analysis results showed that, when the purity at the start of storage was considered 100%, the purity was maintained at over 95% even after 12 months of storage. The purity of the FP-CIT linear precursor over time is summarized in Figure 4 and Table 3 below.

[0191]

[0192] 2-3. Chloroform (CHCl3)

[0193] Except for the storage temperature being -20°C, the same experimental method and analysis conditions as in Examples 1-3 were used. HPLC analysis results showed that when the purity at the start of storage was considered 100%, the purity was maintained at over 85% after 1 month of storage, but gradually decreased to 65% after 5 months and approximately 51% after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 4 and Table 3 below.

[0194]

[0195] 2-4. Dichloromethane (DCM)

[0196] Except for the storage temperature being -20°C, the same experimental method and analysis conditions as in Example 1-4 were used. As a result of HPLC analysis, when the purity at the start of storage was considered 100%, the purity was maintained at over 95% after 1 month of storage, and over 80% after 5 months, but it gradually decreased to about 70% purity after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 4 and Table 3 below.

[0197]

[0198]

[0199] Example 3. Confirmation of the purity of FP-CIT linear precursor according to storage solvent, its concentration, and storage temperature.

[0200] 3-1. Tetrahydrofurane (THF) and room temperature

[0201] Except that the storage concentration was 8 mg / mL, the same experimental method and analysis conditions as in Example 1-1 were used and performed in the same manner as in Example 1-1. As a result of HPLC analysis, when the purity at the start of storage was considered 100%, the purity was maintained at more than 90% after 1 month of storage, but gradually decreased to 30% after 5 months and approximately 5% after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 5 and Table 4 below.

[0202]

[0203] 3-2. Ethyl acetate (EA) and room temperature

[0204] Except that the storage concentration was 8 mg / mL, the same experimental method and analysis conditions as in Example 1-2 were performed. As a result of HPLC analysis, when the purity at the start of storage was considered 100%, the purity was maintained at more than 70% after 1 month of storage, but gradually decreased to 43% after 5 months and approximately 8% after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 5 and Table 4 below.

[0205]

[0206] 3-3. Tetrahydrofurane (THF) and -20℃

[0207] Except for the storage temperature being -20°C, the same experimental method and analysis conditions as Example 3-1 were used. HPLC analysis results showed that, when the purity at the start of storage was considered 100%, the purity was maintained at over 95% after 5 months of storage and 89% after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 5 and Table 4 below.

[0208]

[0209] 3-4. Ethyl acetate (EA) and -20℃

[0210] Except for the storage temperature being -20°C, the same experimental method and analysis conditions as Example 3-2 were used. HPLC analysis results showed that, when the purity at the start of storage was considered 100%, the purity was maintained at over 98% after 5 months of storage and at over 90% after 12 months. The purity of the FP-CIT linear precursor over time is summarized in Fig. 5 and Table 4 below.

[0211]

[0212]

[0213] Example 4. Using FP-CIT linear precursor [ 18F ]FP-CIT synthesis

[0214] 4-1. Treatment of reaction solvent t-amyl alcohol during storage solvent treatment process

[0215] 8 mg of FP-CIT linear precursor stored in EA and t-amyl alcohol as a reaction solvent were used [ 18 [F]FP-CIT was synthesized (Figure 6). The specific storage solvent treatment method and synthesis conditions are as follows:

[0216] The FP-CIT linear precursor stored in EA was heated to over 50°C while blowing nitrogen gas to dry the storage solvent, and t-amyl alcohol, a reaction solvent, was added to prepare the FP-CIT linear precursor dissolved in the reaction solvent.

[0217] Activated [ 18 F]fluoride mixture ([ 18 F]FK 222 ) is added to the reaction vessel containing FP-CIT linear precursor dissolved in t-amyl alcohol (dissolved in the reaction solvent) and heated to 50°C or higher to [ 18 F]FP-CIT was synthesized.

[0218] The reaction mixture was diluted with water and unreacted [ 18 F]Fluoride and [ 18 F]FP-CIT is separated from [ 18 The synthesis yield of F]FP-CIT was confirmed. 18 The synthetic yield of F]FP-CIT was 35%.

[0219]

[0220] 4-2. [ 18 Treatment of t-amyl alcohol as a reaction solvent during the F]FP-CIT synthesis process

[0221] 8 mg of FP-CIT linear precursor stored in EA and t-amyl alcohol were used as a reaction solvent. 18 [F]FP-CIT was synthesized (Figure 7). The specific storage solvent treatment method and synthesis conditions are as follows:

[0222] Activated [18 F]fluoride mixture ([ 18 F]FK 222 ) was added to the reaction vessel containing 8 mg of FP-CIT linear precursor stored in EA, and the vessel was heated to above 50°C while blowing nitrogen gas to dry the storage solvent.

[0223] The reaction solvent t-amyl alcohol is activated [ 18 F] After adding to the reaction vessel containing fluoride and FP-CIT linear precursor, heat to 50℃ or higher and [ 18 F]FP-CIT was synthesized. After purifying the reaction mixture, [ 18 The synthesis yield of F]FP-CIT was 35.4%.

[0224]

[0225] 4-3. [ 18 Treatment of acetonitrile as a reaction solvent during the F]FP-CIT synthesis process

[0226] 8 mg of FP-CIT linear precursor stored in EA and acetonitrile as a reaction solvent were used [ 18 F]FP-CIT was synthesized, and the storage solvent handling method and synthesis conditions were the same as in Example 4-2, except for the reaction solvent. As a result, after purifying the reaction mixture, [ 18 The synthetic yield of F]FP-CIT was 17.2%.

[0227]

[0228] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0229] When an organic solvent having the characteristics according to the present invention is used for the storage (preservation) of the FP-CIT linear precursor, the FP-CIT linear precursor can be maintained at a high purity by suppressing the conversion of the FP-CIT linear precursor into a cyclic salt form or decomposition into various compounds, and the existing [ 18 [F]FP-CIT labeling conditions were used to produce radiopharmaceuticals with high yields [ 18 [F]FP-CIT can be synthesized [ 18 It has industrial applicability as it can be usefully used in the manufacturing of F]FP-CIT.

Claims

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

2. In paragraph 1, A liquid composition for storing an FP-CIT linear precursor, characterized in that the organic solvent is at least one selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM).

3. In any one of paragraphs 1 and 2, A liquid composition for storing an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor is a compound represented by the following chemical formula 1: [Chemical Formula 1] (In the above chemical formula 1, R1 is sulfonyl or halogen, R2 is C 1-5 It is alkyl, X is a halogen.).

4. In paragraph 3, wherein R1 is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), nitrobenzenesulfonyl (Nosyl), F, Cl, Br, or I, The above R2 is methyl or ethyl, A liquid composition for storing an FP-CIT linear precursor, characterized in that the above X is Cl, Br, or I.

5. In any one of paragraphs 1 to 4, A liquid composition for storing an FP-CIT linear precursor, characterized in that the storage temperature of the FP-CIT linear precursor is -50 to 0 ℃.

6. In any one of paragraphs 1 to 5, A liquid composition for storing an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor is stored at a concentration of 0.1 to 16 mg / mL.

7. In any one of paragraphs 1 to 6, A liquid composition for storing an FP-CIT linear precursor, wherein the liquid composition inhibits the conversion of an FP-CIT linear precursor into an FP-CIT cyclic salt precursor.

8. In any one of paragraphs 1 to 7, A liquid composition for storing an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor retains 50 to 99% of the initially stored amount of the FP-CIT linear precursor when stored for 12 months.

9. In any one of paragraphs 1 to 8, A liquid composition for storing an FP-CIT linear precursor, characterized in that 1% to 50% of the initially stored amount of the FP-CIT linear precursor is converted into an FP-CIT cyclic salt precursor when stored for 12 months.

10. In any one of paragraphs 1 to 9, A liquid composition for storing an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor has a ratio of (FP-CIT cyclic salt precursor) / (FP-CIT linear precursor) of 0.01 to 1 when stored for 12 months.

11. A composition for improving the storage stability of an FP-CIT linear precursor comprising an organic solvent having the following characteristics: (a) boiling point of 10 to 100 ℃; (b) evaporation rate of 50 to 400 Torr; and (c) Water solubility of 0.1 to 50%.

12. In paragraph 11, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that the organic solvent is at least one selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM).

13. In any one of paragraphs 11 to 12, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor is a compound represented by the following chemical formula 1: [Chemical Formula 1] (In the above chemical formula 1, R1 is sulfonyl or halogen, R2 is C 1-5 It is alkyl, X is a halogen.).

14. In paragraph 13, wherein R1 is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), nitrobenzenesulfonyl (Nosyl), F, Cl, Br, or I, The above R2 is methyl or ethyl, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that the above X is Cl, Br, or I.

15. In any one of paragraphs 11 to 14, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that the storage temperature of the FP-CIT linear precursor is -50 to 0 ℃.

16. In any one of paragraphs 11 to 15, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor is stored at a concentration of 0.1 to 16 mg / mL.

17. In any one of paragraphs 11 to 16, A composition for improving the storage stability of an FP-CIT linear precursor, wherein the improved storage stability of the FP-CIT linear precursor is achieved by inhibiting the conversion of the FP-CIT linear precursor into an FP-CIT cyclic salt precursor.

18. In any one of paragraphs 11 to 17, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor is maintained at 50 to 99% of the initially stored amount of the FP-CIT linear precursor when stored for 12 months.

19. In any one of paragraphs 11 to 18, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that 1% to 50% of the initially stored amount of the FP-CIT linear precursor is converted into an FP-CIT cyclic salt precursor when the FP-CIT linear precursor is stored for 12 months.

20. In any one of paragraphs 11 to 19, A composition for improving the storage stability of an FP-CIT linear precursor, characterized in that the FP-CIT linear precursor has a ratio of (FP-CIT cyclic salt precursor) / (FP-CIT linear precursor) of 0.01 to 1 when stored for 12 months.

21. A method for stabilizing an FP-CIT linear precursor, wherein the FP-CIT linear precursor is stored in a composition according to any one of claims 1 to 10.

22. A composition according to any one of claims 1 to 10, comprising an FP-CIT linear precursor, as a starting material, comprising the following steps: 18 Method for preparing F]FP-CIT: (a) a step of removing an organic solvent from the composition of any one of claims 1 to 10 containing an FP-CIT linear precursor to separate the FP-CIT linear precursor; (b) a labeling reaction pre-step of preparing a mixture by dissolving the FP-CIT linear precursor separated in step (a) in a reaction solvent; and (c) Activated [ 18 [F] A labeling reaction step of adding the mixture of step (b) to a reaction vessel containing fluoride.

23. A composition according to any one of claims 1 to 10, comprising an FP-CIT linear precursor, as a starting material, comprising the following steps: 18 Method for preparing F]FP-CIT: (a) Activated [ 18 A step of preparing a mixture by adding a composition of any one of claims 1 to 10 comprising an FP-CIT linear precursor to a reaction vessel containing F]fluoride; (b) a pre-labeling reaction step of removing the organic solvent from the mixture of step (a); and (c) A labeling reaction step in which a reaction solvent is added to a mixture from which the organic solvent has been removed.

24. In paragraph 22 or 23, Above [ 18 F]FP-CIT is a linear precursor of FP-CIT and an activated [ 18 [F] characterized in that it is prepared through a nucleophilic fluorination reaction of fluoride, 18 F]FP-CIT manufacturing method.

25. In any one of paragraphs 22 to 24, The above reaction solvent is characterized in that it is a polar organic solvent, [ 18 F]FP-CIT manufacturing method.

26. In paragraph 25, The polar organic solvent is characterized in that it is at least one protic tertiary alcohol selected from the group consisting of t-butanol, t-amyl alcohol, and 1-methoxy-2methyl-2-propanol. 18 F]FP-CIT manufacturing method.

27. In any one of paragraphs 25 to 26, The polar organic solvent is characterized in that it is at least one aprotic organic solvent selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethyl formamide (DMF). 18 F]FP-CIT manufacturing method.

28. In any one of paragraphs 22 to 27, The above activated [ 18 F]fluoride is characterized by being activated with tetra-n-butylammonium or 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Cryptofix™ 222), [ 18 F]FP-CIT manufacturing method.

29. A method for preparing an FP-CIT linear precursor, comprising: a pretreatment step of dissolving an FP-CIT linear precursor in an organic solvent having the following characteristics; 18 F]FP-CIT Manufacturing Method: (a) boiling point of 10 to 100 ℃; (b) evaporation rate of 50 to 400 Torr; and (c) Water solubility of 0.1 to 50%.

30. In paragraph 29, The method is characterized in that it further comprises the following steps: (a) a 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) a labeling reaction pre-step of preparing a mixture by dissolving the FP-CIT linear precursor separated in step (a) in a reaction solvent; and (c) Activated [ 18 [F] A labeling reaction step of adding the mixture of step (b) to a reaction vessel containing fluoride.

31. In any one of paragraphs 29 to 30, The method is characterized in that it further comprises the following steps: (a) Activated [ 18 A step of preparing a mixture by adding an organic solvent in which an FP-CIT linear precursor is dissolved to a reaction vessel containing F]fluoride; (b) a pre-labeling reaction step of removing the organic solvent from the mixture of step (a); (c) A labeling reaction step in which a reaction solvent is added to a mixture from which the organic solvent has been removed.

32. A FP-CIT linear precursor storage kit comprising a liquid composition for storing the FP-CIT linear precursor of any one of claims 1 to 10.

33. [Including Kit 1, Kit 2, and Instructions] 18 As a kit for manufacturing F]FP-CIT, The first kit comprises a liquid composition for storing an FP-CIT linear precursor according to any one of claims 1 to 10, wherein the liquid composition comprises an FP-CIT linear precursor, The above second kit is activated [ 18 [F] characterized by containing fluoride and a reaction solvent, 18 F]FP-CIT manufacturing kit.

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