Deuterium-substituted FP-CIT linear precursor and method for preparing d6-[18f] FP-CIT by using same

Abstract

In the present invention, a deuterium-substituted FP-CIT linear precursor is developed in order to increase the linear stability of a precursor. When the deuterium-substituted FP-CIT linear precursor according to the present invention is dissolved in an organic solvent and stored, linearity is maintained well even at room temperature, and the same effect as a conventional radiopharmaceutical product [18F]FP-CIT is exhibited. In addition, D6-[18F]FP-CIT can be prepared simply and in a high yield, and thus can be effectively used as a starting material for the synthesis of D6-[18F]FP-CIT. Furthermore, a novel radiopharmaceutical product D6-[18F]FP-CIT enables visualization of dopamine transporter (DAT) distribution to be performed through improved image contrast, and has particularly high accuracy in diagnosing Parkinson's disease and related degenerative brain diseases, and thus can be effectively used.

Description

Deuterium-substituted FP-CIT linear precursor and method for manufacturing D6-[18F]FP-CIT using the same

[0001] The present invention relates to a deuterium-substituted FP-CIT linear precursor and a D6-[ using the same 18 This relates to a method for manufacturing F]FP-CIT.

[0002] The present invention claims priority based on Korean Patent Application No. 10-2024-0139746 filed on October 14, 2024, and all contents disclosed in the specification and drawings of said application are incorporated by reference into the present application.

[0003] [ 18 F]Fluoride-labeled radiopharmaceuticals are diagnostic radiopharmaceuticals with a duration of 110 minutes [ 18 Due to the short half-life of F]fluoride, it is characterized by being manufactured and used on the same day of use. 18 The manufacturing steps of F]fluoride-labeled radiopharmaceuticals are [ 18 Production and activation steps of F]fluoride, radiopharmaceutical precursor [ 18 F]Fluoride labeling step, [ 18 The process proceeds to the purification and formulation stages of the [F]fluoride-labeled radiopharmaceutical. At this stage, the radiopharmaceutical precursor is typically [ 18 F]F fluoride has a leaving group at the labeled position and through nucleophilic substitution [ 18 F]fluoride is labeled.

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

[0005] The natural transformation into cyclic salts caused by the structural characteristics of compounds can not only affect the purity of radiopharmaceutical starting materials, but the coexistence of linear precursor structures and cyclic salt precursors also affects the manufacturing yield of the radiopharmaceutical.

[0006] Accordingly, the inventors conducted extensive research to find a method to maintain a stable linear structure by suppressing this natural change of the FP-CIT linear precursor, namely the conversion of the linear precursor into a cyclic salt. As a result, they developed a deuterium-substituted FP-CIT linear precursor and established a method to ensure long-term storage stability at room temperature. Furthermore, using this, they [provided] high yield D6-[ 18 The present invention was completed by manufacturing [F]FP-CIT.

[0007] As a result of diligent research to develop a new precursor capable of maintaining the linear precursor shape at room temperature, the inventors found that when the FP-CIT precursor is substituted with deuterium, not only is high purity maintained at room temperature, but D6-[ 18The present invention was completed by confirming that F]FP-CIT can be manufactured.

[0008] Accordingly, the object of the present invention is to provide a deuterium-substituted FP-CIT linear precursor represented by the following chemical formula 1:

[0009] [Chemical Formula 1]

[0010]

[0011] (In Chemical Formula 1 above, LG is a leaving group, which is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), or nitrobenzenesulfonyl (Nosyl).)

[0012] Another object of the present invention is to provide a method for producing a deuterium-substituted FP-CIT linear precursor of the present invention, comprising the following steps:

[0013] (S1) A step of preparing 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate by reacting propane-d6-1,3-diol with p-toluenesulfonic acid anhydride (Ts₂O) and NaOH at room temperature;

[0014] (S2) a step of mixing the 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate obtained in the above step with triethylamine (Et₃N) and heating to produce methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate; and

[0015] (S3) A step of reacting the methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate obtained in the above step with p-toluenesulfonic acid anhydride (Ts₂O) and diisopropylethylamine (DIPEA) at room temperature to obtain a deuterium-substituted FP-CIT linear precursor.

[0016] Another objective of the present invention is the deuterium-substituted FP-CIT linear precursor of the present invention and the activated [ 18 D6-[ comprising the step of reacting F]fluoride 18 The present invention provides a method for manufacturing F]FP-CIT.

[0017] Another objective of the present invention is D6-[ represented by the following chemical formula 2 18 It is to provide F]FP-CIT:

[0018] [Chemical Formula 2]

[0019] .

[0020] Another objective of the present invention is the D6-[ of the present invention 18 The purpose is to provide a radiopharmaceutical containing [F]FP-CIT as an active ingredient.

[0021]

[0022] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0023]

[0024] To achieve the above objective, the present invention provides a deuterium-substituted FP-CIT linear precursor represented by the following chemical formula 1:

[0025] [Chemical Formula 1]

[0026]

[0027] (In Chemical Formula 1 above, LG is a leaving group, which is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), or nitrobenzenesulfonyl (Nosyl).)

[0028] In one embodiment of the present invention, the LG is toluenesulfonyl (Tosyl), but is not limited thereto.

[0029] In another embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor may be N-(3'-methansulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane [N-(3'-methansulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane] or N-(3'-toluenesulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane [N-(3'-toluenesulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane]. However, it is not limited to this.

[0030] In another embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor may be stored dissolved in an organic solvent, but is not limited thereto.

[0031] In another 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.

[0032] In another embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor may be stored at a temperature of -20 to 50°C, but is not limited thereto.

[0033] In another embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor may be stored in an organic solvent at a concentration of 0.1 to 16 mg / mL, but is not limited thereto.

[0034] In another embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor may be maintained at 90 to 99%, 91 to 99%, 92 to 99%, 93 to 99%, 94 to 99%, 95 to 99%, 96 to 99%, 97 to 99%, or 98 to 99% compared to the amount of the initially stored FP-CIT linear precursor when stored for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 9 months, 10 months, 11 months, or 12 months, but is not limited thereto.

[0035] In another embodiment of the present invention, when the deuterium-substituted FP-CIT linear precursor is stored for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, 1% to 10%, 1% to 9%, 1% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 1% to 4%, 1% to 3%, or 1% to 2% of the amount of the initially stored FP-CIT linear precursor may be converted into an FP-CIT cyclic salt precursor, but is not limited thereto.

[0036] In another embodiment of the present invention, the deuterium substitution may inhibit the conversion of the FP-CIT linear precursor into a cyclic salt precursor, but is not limited thereto.

[0037] The present invention provides a method for producing the deuterium-substituted FP-CIT linear precursor comprising the following steps:

[0038] (S1) A step of preparing 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate by reacting propane-d6-1,3-diol with p-toluenesulfonic acid anhydride (Ts₂O) and NaOH at room temperature;

[0039] (S2) a step of mixing the 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate obtained in the above step with triethylamine (Et₃N) and heating to produce methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate; and

[0040] (S3) A step of reacting the methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate obtained in the above step with p-toluenesulfonic acid anhydride (Ts₂O) and diisopropylethylamine (DIPEA) at room temperature to obtain a deuterium-substituted FP-CIT linear precursor.

[0041] The present invention relates to the deuterium-substituted FP-CIT linear precursor of the present invention and an activated [ 18 D6-[ comprising the step of reacting F]fluoride 18 The present invention provides a method for manufacturing [F]FP-CIT. In addition, the present invention relates to the deuterium-substituted FP-CIT linear precursor of the present invention and an activated [ 18 D6-[ comprising the step of nucleophilically fluorinating F]fluoride 18 A method for manufacturing F]FP-CIT is provided.

[0042] In one embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor may be dissolved in a reaction solvent, but is not limited thereto.

[0043] In another embodiment of the present invention, the reaction solvent is one or more protic tertiary alcohols selected from the group consisting of t-butanol, t-amyl alcohol, and 1-methoxy-2-methyl-2-propanol; or

[0044] It 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.

[0045] In another embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor may be dissolved in a reaction solvent by heating at a temperature of 50 to 150 °C for 1 to 10 minutes, but is not limited thereto.

[0046] In another embodiment of the present invention, the D6-[ 18 The method for manufacturing F]FP-CIT involves a deuterium-substituted FP-CIT linear precursor and an activated [ 18 The step of heating after the reaction of [F]fluoride may be further included, but is not limited thereto.

[0047] In another embodiment of the present invention, the heating step may be performed at a temperature of 50 to 150 ℃, but is not limited thereto.

[0048] The present invention is represented by the following chemical formula 2, D6-[ 18 F]Provides FP-CIT:

[0049] [Chemical Formula 2]

[0050] .

[0051] The present invention is the D6-[ of the present invention 18 A radiopharmaceutical containing [F]FP-CIT as an active ingredient is provided.

[0052] In one embodiment of the present invention, the radioactive pharmaceutical may be a radioactive pharmaceutical for imaging diagnosis of degenerative brain diseases, but is not limited thereto.

[0053] In another embodiment of the present invention, the image diagnosis may be positron emission tomography (PET), but is not limited thereto.

[0054] In another embodiment of the present invention, the radiopharmaceutical may visualize the distribution of dopamine carriers (DAT), but is not limited thereto.

[0055] In another embodiment of the present invention, the degenerative brain disease may be Parkinson's disease, but is not limited thereto.

[0056] The present invention is D6-[ 18 A composition for diagnosing degenerative brain diseases is provided, comprising [F]FP-CIT as an active ingredient.

[0057]

[0058] In addition, D6-[ 18 The invention provides a drug containing [F]FP-CIT as an active ingredient for the diagnosis or prognosis prediction of degenerative brain diseases.

[0059] In addition, D6-[ 18 The invention provides a use for manufacturing a drug containing [F]FP-CIT as an active ingredient for the diagnosis or prognosis prediction of degenerative brain diseases.

[0060] In addition, a method for diagnosing or predicting the prognosis of a degenerative brain disease is provided, comprising one or more of the following steps:

[0061] (a) a step of treating a biological sample isolated from an individual with a pharmaceutical product containing D6-[18F]FP-CIT of the present invention as an active ingredient;

[0062] (b) a step of comparing the uptake rate in the sample with a control biological sample; and

[0063] (c) A step in which the uptake rate is lower than that of the control biological sample, and the patient is diagnosed with a degenerative brain disease or judged to have a poor prognosis.

[0064] In addition, a method for treating a degenerative brain disease is provided, comprising one or more of the following steps:

[0065] (a) a step of treating a biological sample isolated from an individual with a pharmaceutical product containing D6-[18F]FP-CIT of the present invention as an active ingredient;

[0066] (b) a step of comparing the uptake rate of the sample with a control biological sample;

[0067] (c) a step of diagnosing a degenerative brain disease or determining a poor prognosis when the uptake rate is lower than that of a control biological sample; and

[0068] (d) A stage of treating individuals diagnosed with degenerative brain disease or judged to have a poor prognosis.

[0069] The deuterium-substituted FP-CIT linear precursor of the present invention inhibits the conversion of the linear precursor stabilized by deuterium into a cyclic salt form, thereby maintaining a linear state even at room temperature, and furthermore, the existing radiopharmaceutical [ 18 D6-[ having the same effect as F]FP-CIT 18 Since F]FP-CIT can be manufactured simply and with high yield, it can be usefully applied in the field of radiopharmaceuticals. Furthermore, the existing radiopharmaceutical [ 18 F]FP-CIT had the disadvantage of rapid metabolite generation in the body, but the new radiopharmaceutical D6-[ 18 It was confirmed that [F]FP-CIT improves this and inhibits metabolite formation.

[0070] Figure 1 is a figure showing the results of confirming the purity of FP-CIT linear precursors and deuterium-substituted FP-CIT linear precursors stored in tetrahydrofuran (THF) or ethyl acetate (EA) at a storage concentration of 1 mg / mL at room temperature.

[0071] Figure 2 is a figure showing the results of confirming the purity of FP-CIT linear precursors and deuterium-substituted FP-CIT linear precursors stored in tetrahydrofuran (THF) or ethyl acetate (EA) at a storage concentration of 8 mg / mL at room temperature.

[0072] Figures 3 and 4 are [ 18 F]FP-CIT and D6-[ 18 This is a diagram showing the results of comparing the uptake rates within the striatum, lumbar vertebrae, and femur, which are the major tissues of F]FP-CIT.

[0073] As a result of diligent research to develop a new precursor capable of maintaining the linear precursor shape at room temperature, the inventors found that when the FP-CIT precursor is substituted with deuterium, not only is high purity maintained at room temperature, but D6-[ 18 The present invention was completed by confirming that F]FP-CIT can be manufactured.

[0074] The present invention provides a deuterium-substituted FP-CIT linear precursor represented by the following chemical formula 1:

[0075] [Chemical Formula 1]

[0076]

[0077] (In Chemical Formula 1 above, LG is a leaving group, which is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), or nitrobenzenesulfonyl (Nosyl).)

[0078] In the entire specification including the following claims, in Formula 1, LG may be a leaving group toluenesulfonyl (Tosyl), but is not limited thereto.

[0079] The present invention provides a deuterium-substituted FP-CIT linear precursor represented by the following chemical formula 1:

[0080] [Chemical Formula 1]

[0081]

[0082] (In Chemical Formula 1 above, LG is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), or nitrobenzenesulfonyl (Nosyl).)

[0083] In this specification, including all claims below, "deuterium" is one of the isotopes of hydrogen. 2 It may be denoted as H or D (Deuterium), and in one embodiment of the present invention, deuterium may be denoted as D, but is not limited thereto.

[0084] Including all claims below, the “deuterium-substituted FP-CIT linear precursor” refers to one or more hydrogens (in an FP-CIT linear precursor compound) 1 This means that H) is substituted with deuterium (D). According to one embodiment of the present invention, a deuterium-substituted FP-CIT linear precursor refers to an FP-CIT linear precursor compound in which six hydrogen atoms at the N-1', 2', and 3' carbons of the N-3'-toluenesulfonyloxypropyl group are substituted with deuterium, such as the compound represented by Chemical Formula 1. The deuterium-substituted FP-CIT linear precursor has improved storage stability because the conversion of the FP-CIT linear precursor into a cyclic salt form due to deuterium is inhibited, allowing it to be stored for a long period (3 months, 6 months, 9 months, and 12 months) at room temperature.

[0085] In this specification, including all claims below, the leaving group (LG) is methanesulfonyl (Mesyl, ), toluenesulfonyl (toluenesulfonyl; Tosyl, , or nitrobenzenesulfonyl (nitrobenzenesulfonyl; Nosyl, ) may be, and according to one embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor is N-(3'-methansulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane [N-(3'-methansulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane], or N-(3'-toluenesulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane It may be [N-(3'-toluenesulfonyloxipropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane], but is not limited thereto.

[0086] Including all claims below, the deuterium-substituted FP-CIT linear precursor may be stored dissolved in an organic solvent, but is not limited thereto.

[0087] Including all claims below, 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.

[0088] Including all claims below, the deuterium-substituted FP-CIT linear precursor comprises -20 to 50 ℃, -20 to 45 ℃, -20 to 40 ℃, -20 to 35 ℃, -20 to 30 ℃, -20 to 25 ℃, -20 to 20 ℃, -15 to 50 ℃, -15 to 45 ℃, -15 to 40 ℃, -15 to 35 ℃, -15 to 30 ℃, -15 to 25 ℃, -15 to 20 ℃, -10 to 50 ℃, -10 to 45 ℃, -10 to 40 ℃, -10 to 35 ℃, -10 to 30 ℃, -10 to 25 ℃, -10 to 20 ℃, -5 to 50 ℃, -5 to 45 ℃, -5 to 40 ℃, -5 to 35 ℃, -5 to 30 ℃, -5 to 25 ℃, -5 to 20 ℃, 0 to 50 ℃, 0 to 45 ℃, 0 to 40 ℃, 0 to 35 ℃, 0 to 30 ℃, 0 to 25 ℃, 0 to 20 ℃, 1 to 50 ℃, 1 to 45 ℃, 1 to 40 ℃, 1 to 35 ℃, 1 to 30 ℃, 1 to 25 ℃, 1 to 20 ℃, 5 to 50 ℃, 5 to 45 ℃, 5 to 40 ℃, 5 to 35 ℃, 5 to 30 ℃, 5 to 25 ℃, 5 to 20 ℃, 10 to 50 It may be stored at a temperature of 10 to 45 ℃, 10 to 40 ℃, 10 to 35 ℃, 10 to 30 ℃, 10 to 25 ℃, 10 to 20 ℃, 15 to 50 ℃, 15 to 45 ℃, 15 to 40 ℃, 15 to 35 ℃, 15 to 30 ℃, 15 to 25 ℃, 15 to 20 ℃, 20 to 50 ℃, 20 to 45 ℃, 20 to 40 ℃, 20 to 35 ℃, 20 to 30 ℃, or 20 to 25 ℃, and according to one embodiment of the present invention, it may be stored at room temperature (1 to 35 ℃), but is not limited thereto.

[0089] Including all claims below, the deuterium-substituted FP-CIT linear precursor in an organic solvent is 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 It may be stored at a concentration of 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, 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, and according to one embodiment of the present invention, it may be stored at a concentration of 8 mg / mL, but is not limited thereto.

[0090] The present invention provides a method for producing a deuterium-substituted FP-CIT linear precursor of the present invention, comprising the following steps:

[0091] (S1) A step of preparing 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate by reacting propane-d6-1,3-diol with p-toluenesulfonic acid anhydride (Ts₂O) and NaOH at room temperature;

[0092] (S2) a step of mixing the 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate obtained in the above step with triethylamine (Et₃N) and heating to produce methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate; and

[0093] (S3) A step of reacting the methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate obtained in the above step with p-toluenesulfonic acid anhydride (Ts₂O) and diisopropylethylamine (DIPEA) at room temperature to obtain a deuterium-substituted FP-CIT linear precursor.

[0094] In addition, the present invention relates to the above deuterium-substituted FP-CIT linear precursor and activated [ 18 D6-[ comprising the step of reacting F]fluoride 18 The present invention provides a method for manufacturing [F]FP-CIT, specifically, the deuterium-substituted FP-CIT linear precursor and an activated [ 18 D6-[ through the nucleophilic fluorination reaction of F]fluoride 18 F]FP-CIT can be manufactured.

[0095] In all claims below, the term “activated” means having nucleophilicity and becoming a stronger nucleophile to increase chemical reactivity with the deuterium-substituted FP-CIT linear precursor. In addition, it may also include being soluble in organic solvents. Various methods known in the art may be used for the activation and are not limited to the methods described in the embodiments of the present invention.

[0096] Including all claims below, the deuterium-substituted FP-CIT linear precursor may be dissolved in a reaction solvent, and according to one embodiment of the present invention, the deuterium-substituted FP-CIT linear precursor is 50 to 150 ℃, 50 to 145 ℃, 50 to 140 ℃, 50 to 135 ℃, 50 to 130 ℃, 50 to 125 ℃, 50 to 120 ℃, 50 to 115 ℃, 50 to 110 ℃, 50 to 105 ℃, 50 to 100 ℃, 50 to 95 ℃, 50 to 90 ℃, 50 to 85 ℃, 60 to 150 ℃, 60 to 145 ℃, 60 to 140 ℃, 60 to 135 ℃, 60 to 130 ℃, 60 to 125 ℃, 60 to 120 ℃, 60 to 115 ℃, 60 to 110 ℃, 60 to 105 ℃, 60 to 100 ℃, 60 to 95 ℃, 60 to 90 ℃, 60 to 85 ℃, 70 to 150 ℃, 70 to 145 ℃, 70 to 140 ℃, 70 to 135 ℃, 70 to 130 ℃, 70 to 125 ℃, 70 to 120 ℃, 70 to 115 ℃, 70 to 110 ℃, 70 to 105 ℃, 70 to 100 ℃, 70 to 95 ℃, 70 to 90 ℃, 70 to 85 ℃, 80 to 150 ℃, 80 to 145 ℃, 80 to 140 ℃, 80 to 135 ℃, 80 to 130 ℃, 80 to 125 ℃, 80 to 120 ℃, 80 to 115 ℃, 80 to 110 ℃, 80 to 105 ℃, 80 to 100 ℃, 80 to 95 ℃, 80 to 90 ℃, 80 to 85 ℃, 90 to 150 ℃, 90 to 145 ℃, 90 to 140 ℃, 90 to 135 ℃, 90 to 130 ℃, 90 to 125 ℃, 90 to 120 ℃, 90 to 115 ℃, 90 to 110 ℃, 90 to 105 ℃, 90 to 100 ℃, 90 to 95 ℃,Or at a temperature of 90 ℃ for 1 to 10 minutes, 1 to 9 minutes, 1 to 8 minutes, 1 to 7 minutes, 1 to 6 minutes, 1 to 5 minutes, 1 to 4 minutes, 1 to 3 minutes, 1 to 2 minutes, 2 to 10 minutes, 2 to 9 minutes, 2 to 8 minutes, 2 to 7 minutes, 2 to 6 minutes, 2 to 5 minutes, 2 to 4 minutes, 2 to 3 minutes, 3 to 10 minutes, 3 to 9 minutes, 3 to 8 minutes, 3 to 7 minutes, 3 to 6 minutes, 3 to 5 minutes, 3 to 4 minutes, 4 to 10 minutes, 4 to 9 minutes, 4 to 8 minutes, 4 to 7 minutes, 4 to 6 minutes, 4 to 5 minutes, 5 to 10 minutes, 5 to 9 minutes, 5 to 8 minutes, It may be dissolved in a reaction solvent by heating for 5 to 7 minutes, or 5 to 6 minutes, 1 minute or more, 2 minutes or more, 3 minutes or more, 4 minutes or more, or 5 minutes or more, but is not limited thereto. By heating and dissolving the above deuterium-substituted FP-CIT linear precursor in a reaction solvent, D6-[, 18 The manufacturing yield of F]FP-CIT can be improved.

[0097] Including all claims below, the reaction solvent is one or more protic tertiary alcohols selected from the group consisting of t-butanol, t-amyl alcohol, and 1-methoxy-2-methyl-2-propanol; or

[0098] It may be one or more aprotic organic solvents selected from the group consisting of acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), and according to one embodiment of the present invention, the reaction solvent may be t-amyl alcohol, but is not limited thereto.

[0099] Including the following full claims, in this specification, D6-[ 18 The method for manufacturing F]FP-CIT involves a deuterium-substituted FP-CIT linear precursor and an activated [ 18The method may further include a heating step after the reaction of the [F]fluoride, wherein the heating step comprises 50 to 150 ℃, 50 to 145 ℃, 50 to 140 ℃, 50 to 135 ℃, 50 to 130 ℃, 50 to 125 ℃, 50 to 120 ℃, 50 to 115 ℃, 50 to 110 ℃, 50 to 105 ℃, 50 to 100 ℃, 50 to 95 ℃, 50 to 90 ℃, 50 to 85 ℃, 60 to 150 ℃, 60 to 145 ℃, 60 to 140 ℃, 60 to 135 ℃, 60 to 130 ℃, 60 to 125 ℃, 60 to 120 ℃, 60 to 115 ℃, 60 to 110 ℃, 60 to 105 ℃, 60 to 100 ℃, 60 to 95 ℃, 60 to 90 ℃, 60 to 85 ℃, 70 to 150 ℃, 70 to 145 ℃, 70 to 140 ℃, 70 to 135 ℃, 70 to 130 ℃, 70 to 125 ℃, 70 to 120 ℃, 70 to 115 ℃, 70 to 110 ℃, 70 to 105 ℃, 70 to 100 ℃, 70 to 95 ℃, 70 to 90 ℃, 70 to 85 ℃, 80 to 150 ℃, 80 to 145 ℃, 80 to 140 ℃, 80 to 135 ℃, 80 to 130 ℃, 80 to 125 ℃, 80 to 120 ℃, 80 to 115 ℃, 80 to 110 ℃, 80 to 105 ℃, 80 to 100 ℃, 80 to 95 ℃, 80 to 90 ℃, 80 to 85 ℃, 90 to 150 ℃, 90 to 145 ℃, 90 to 140 ℃, 90 to 135 ℃, 90 to 130 ℃, 90 to 125 ℃, 90 to 120 ℃, 90 to 115 ℃, 90 to 110 ℃, 90 to 105 ℃, It may be performed at a temperature of 90 to 100 ℃, 90 to 95 ℃, or 90 ℃, but is not limited thereto.

[0100] The present invention is represented by the following chemical formula 2, D6-[ 18 F]Provides FP-CIT:

[0101] [Chemical Formula 2]

[0102] .

[0103]

[0104] The present invention is the D6-[ of the present invention 18 A radiopharmaceutical containing [F]FP-CIT as an active ingredient is provided.

[0105] Including all claims below, the radiopharmaceutical of the present invention may be a radiopharmaceutical for imaging diagnosis of degenerative brain diseases, but is not limited thereto.

[0106] Including all claims below, the imaging diagnosis of the present invention may be positron emission tomography (PET), but is not limited thereto.

[0107] Including all claims below, the radiopharmaceutical of the present invention may visualize the distribution of dopamine transporters (DAT), but is not limited thereto.

[0108] Including all claims below, the degenerative brain disease of the present invention may be one or more selected from the group consisting of Alzheimer's disease, mild cognitive impairment, stroke or vascular dementia, frontotemporal dementia, Lewy body dementia, Creutzfeldt-Jakob disease, traumatic head injury, syphilis, acquired immunodeficiency syndrome or other viral infection, brain abscess, brain tumor, multiple sclerosis, dementia due to metabolic disease, hypoxia, Parkinson's disease, progressive supernucleus palsy, amyotrophic lateral sclerosis (ALS), Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, ischemia, stroke, attention deficit hyperactivity disorder, schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, spinal cord injury, and myelitis. In one embodiment of the present invention, the degenerative brain disease of the present invention may be Parkinson's disease, but is not limited thereto.

[0109] Including all claims below, as provided in this specification, the radiopharmaceutical of the present invention has targeted uptake and in vivo stability [ 18 It may be superior to radiopharmaceuticals containing [F]FP-CIT as an active ingredient, but is not limited thereto.

[0110] Including all claims below, the evaluation of target uptake may be performed by measuring radioactive ligand uptake in a site where a dopamine transporter (DAT) is present, e.g., in the striatum, but is not limited thereto. Additionally, in the present invention, the target location (region of interest) may be the striatum, but is not limited thereto.

[0111] Including all claims below, in this specification, the in vivo safety assessment is performed on the free [ metabolites formed during the metabolic process 18The uptake site of [F]Fluoride can be evaluated as an indicator, and this can be performed, for example, by measuring radioactive ligand uptake in the femur or lumbar spine, but is not limited thereto. Additionally, in the present invention, the non-target location may be the cerebellum, femur, or lumbar spine, but is not limited thereto.

[0112] In all claims below, the “Dopamine Transporter (DAT)” is a transmembrane protein encoded by the human SLC6A3 gene (also referred to as DAT1) that performs the role of reabsorbing the neurotransmitter dopamine from the synaptic cleft into the cytoplasm. In the present invention, the dopamine transporter may be NCBI (National Center for Biotechnology Information) Gene ID: 6531, but is not limited thereto.

[0113] Including the full claims below, the radiopharmaceutical of the present invention can visualize the distribution of dopamine transporters (DATs), but is not limited thereto. Specifically, dopamine secreted from the terminals of presynaptic cells passes through synapses, binds to receptors on the next neuron to transmit signals, dissociates from the receptors, and is reabsorbed through dopamine transporters at the terminals of presynaptic cells. Dopamine receptors and dopamine transporters are located in the substantia nigra-striatal pathway of the midbrain and are distributed at high density, particularly in the striatum. Since the expression of dopamine transporters is significantly reduced in patients with Parkinson's disease compared to healthy individuals, the radiopharmaceutical of the present invention, which visualizes the distribution of dopamine transporters, can be usefully utilized in the diagnosis of Parkinson's disease and related degenerative brain diseases.

[0114] The present invention is the D6-[ of the present invention 18A pharmaceutical composition for diagnosing degenerative brain diseases is provided, comprising F]FP-CIT as an active ingredient.

[0115] The present invention is the D6-[ of the present invention 18 The present invention provides a radiopharmaceutical comprising [F]FP-CIT. The above-described radiopharmaceutical may be applied without limitation to the radiopharmaceutical of the present invention and to pharmaceutical compositions for diagnosing degenerative brain diseases.

[0116] In all claims below, the term “pharmaceuticalally acceptable” means a compound or composition that is suitable for use in contact with tissues of a subject (e.g., human) and is within the scope of sound medical judgment, having a reasonable benefit / risk ratio without excessive toxicity, irritation, allergic reaction, or other problems or complications.

[0117] Including all claims below, the (radioactive) medicine or pharmaceutical composition may be formulated and used in the form of an injectable, perfusion solution, or sterile injectable solution, etc., according to conventional methods, but is not limited thereto.

[0118] Including all claims below, the injectable formulation comprises solvents such as distilled water for injection, 0.9% sodium chloride injection solution, Ringer's injection solution, dextrose injection solution, dextrose + sodium chloride injection solution, PEG, lactated Ringer's injection solution, ethanol, propylene glycol, non-volatile oils—sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tween, nijungtinamide, hexamine, and dimethylacetamide; and buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums. It may include isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid; sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid, and sodium bisulfite acetone; non-inflammatory agents such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium CMC, sodium alginate, Tween 80, and aluminum monostearate.

[0119] Including all claims below, the degenerative brain disease of the present invention may be Parkinson's disease, but is not limited thereto.

[0120] Including all claims below, the term “administration” in this specification means providing a predetermined composition of the present invention to an individual by any suitable method and may be used interchangeably with treatment.

[0121] Including all claims below, the pharmaceutical may include a radiopharmaceutical, and the pharmaceutical and the radiopharmaceutical may be used interchangeably, but are not limited thereto.

[0122] In all claims below, the dosage (throughput) of a drug or composition is determined by the type of active ingredient drug, along with various relevant factors such as the disease to be diagnosed, the route of administration, the patient's age, gender, weight, and the severity of the disease. Specifically, the effective dose of a drug or composition according to the present invention may vary depending on the patient's age, gender, and weight, and generally, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, may be administered daily or every other day, or divided into 1 to 3 doses per day. However, since the dosage may be increased or decreased depending on the route of administration, the severity of the disease, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0123] In this specification, including the entire set of claims below, “diagnosis” means confirming the existence or characteristics of a pathological condition. For the purposes of the present invention, diagnosis includes confirming the existence, onset, or likelihood of onset (inventive risk) of a degenerative brain disease, but is not limited thereto, and also includes confirming the severity of a degenerative brain disease. More specifically, the term “diagnosis” as used in the present invention includes determining the susceptibility of an object to a specific disease or condition, determining whether an object currently has a specific disease or condition, determining the prognosis of an object afflicted with a specific disease or condition, or therametrics (e.g., monitoring the condition of an object to provide information on therapeutic efficacy).

[0124] In this specification, including all claims below, “prognosis prediction” may mean predicting the degree of progression of a degenerative brain disease. It may mean predicting the probability of progression, deterioration, recurrence, maintenance, etc., of the disease stage of a degenerative brain disease through the increase or decrease in the level of the biomarker of the present invention.

[0125] In the entire specification including the following claims, “biological sample” may be included without limitation as long as it is taken from a subject for whom a degenerative brain disease is to be diagnosed or a prognosis is to be predicted, but specifically may be a tissue or cell with a lesion. In the present invention, said tissue or cell may be a tissue or cell separated from the striatum, lumbar vertebrae, or femur, but is not limited thereto.

[0126] In one embodiment of the present invention, the control biological sample may be a biological sample isolated from a normal animal model or a normal individual, but is not limited thereto. Additionally, in the present invention, the isolated biological sample may be isolated from a normal animal model or individual by conventional technical methods and may be a commercially available cell, but is not limited thereto.

[0127] In all claims below, the term “individual” in the present invention refers to an object requiring disease risk prediction, diagnosis, prognosis prediction, or treatment, and more specifically, may refer to mammals such as human or non-human primates, mice, rats, dogs, cats, horses, and cattle, but is not limited thereto. In the present invention, the individual may be used interchangeably with animal models, but is not limited thereto.

[0128] Including all claims below, in the method for treating a degenerative brain disease according to the present invention, the step of treating an individual may be a step of treating the individual with one or more selected from the group consisting of levodopa, carbidopa, entacapone, and rasagiline mesylate, but is not limited thereto.

[0129] In this specification, including all claims below, “intake rate” refers to SUV mean Value or SUV ratio (SUV mean It may be calculated using the Ratio value, but is not limited to this.

[0130] In all claims below, the “low intake rate” means that the detected substance is not detected, or that the amount detected is relatively small. For example, “decreased” means that the level of the experimental group is at least 1%, 2%, 3%, 4%, 5%, 10% or more, e.g., 5%, 10%, 20%, 30%, 40%, or 50%, 60%, 70%, 80%, 90% or more lower than that of the control group, and / or 0.5 times, 1.1 times, 1.2 times, 1.4 times, 1.6 times, 1.8 times or more lower. Specifically, it may mean a decrease of 1 to 1.5 times, 1.5 to 2 times, 2 to 2.5 times, 2.5 to 3 times, 3 to 3.5 times, 3.5 to 4 times, 4 to 4.5 times, 4.5 to 5 times, 5 to 5.5 times, 5.5 to 6 times, 6 to 6.5 times, 6.5 to 7 times, 7 to 7.5 times, 7.5 to 8 times, 8 to 8.5 times, 8.5 to 9 times, 9 to 9.5 times, 9.5 to 10 times, or 10 times or more compared to that of the control group, but is not limited thereto. A person skilled in the art can understand that the meaning of the opposite term is to have the opposite meaning in accordance with the above definition.

[0131] In all claims below, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0132] In all claims below, the terms of degree, such as “about,” “approximately,” “substantially,” “average,” “generally,” etc., are used in the sense of being at or close to the value when inherent manufacturing and material tolerances are presented in the sense mentioned, and are used to prevent unscrupulous infringers from unfairly exploiting the disclosure regarding the precise or absolute value mentioned to aid in understanding the present invention. For example, the terms “about,” “approximately,” “substantially,” “average,” “generally,” etc., may refer to amounts within 10%, within 5%, within 3%, within 1%, within 0.1%, and within 0.01% of the mentioned amount.

[0133] Including all claims below, "%" used to indicate the concentration of a particular substance may be (w / w) %, (w / v) %, (v / v) %, or mol % unless otherwise noted, but is not limited thereto.

[0134] In the entirety of the following claims, "step of" or "step of" does not mean "step for".

[0135] In all claims below, the term “group consisting of” or “combination thereof” included in a Markush-type expression means one or more mixtures or combinations selected from a group consisting of components described in a Markush-type expression, and means including one or more selected from the group consisting of said components.

[0136] In the entirety of the following claims, the term "active ingredient" refers to any substance used interchangeably with active drugs, active ingredients, active formulations, drugs, and therapeutic formulations, and used to prevent, alleviate, improve, or treat a target disease.

[0137]

[0138] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the invention, and the scope of the invention is not limited by the following embodiments.

[0139]

[0140] [Example]

[0141] Example 1. Verification of the purity of the existing FP-CIT linear precursor

[0142]

[0143] 1-1. Verification of the purity of the existing FP-CIT linear precursor when the storage solvent is tetrahydrofuran

[0144] N-(3'-methanesulfonyloxypropyl)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane (Korean Patent Application Publication No. 10-2025-0046134), a high-purity FP-CIT linear precursor, was added to the storage solvent tetrahydrofuran (THF) at a concentration of 1 mg / mL and stored at room temperature, and stability was evaluated for 12 months using HPLC analysis. HPLC analysis was performed under the following conditions: column (Luna C18 250*4.6 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).

[0145] As a result of HPLC analysis, when the purity at the start of storage was considered to be 100%, a purity of 95% or less was observed after 1 month of storage and 90% or less after 3 months of storage. The purity of the FP-CIT linear precursor according to the above time is summarized in Figure 1 and Table 1 below.

[0146]

[0147] 1-2. Verification of the purity of the existing FP-CIT linear precursor when the storage solvent is ethyl acetate

[0148] The procedure was performed using the same method and analysis conditions as in 1-1 above, except that the storage solvent was ethyl acetate (EA). As a result of HPLC analysis, when the purity at the start of storage was considered 100%, a purity of 95% or less was observed after 1 month and 3 months of storage. The purity of the FP-CIT linear precursor over the above time is summarized in Figure 1 and Table 1 below.

[0149]

[0150] Example 2. Synthesis of Deuterium-Substituted FP-CIT Linear Precursor and Verification of Its Purity

[0151]

[0152] 2-1. Synthesis of Deuterium-Substituted FP-CIT Linear Precursor

[0153]

[0154] 2-1-1. Synthesis of 3-hydroxypropyl-1,1,2,2,3,3-d6 4-methylbenzenesulfonate

[0155] 60% sodium hydroxide (450 mg, 10.50 mmol, 1.5 equiv.) was added to tetrahydrofuran (0.25 M, 30.0 mL) cooled to 0°C and stirred for 15 minutes, then propane-d6-1,3-diol (600 mg, 7.00 mmol, 1.0 equiv.) was added to the mixture and stirred for 1 hour. While maintaining the temperature, p-toluenesulfonic acid anhydride (2.0 g, 7.00 mmol, 1.0 equiv.) was slowly added to the mixture, the temperature was raised to room temperature, and the mixture was stirred for 20 hours. When the reaction was complete, the mixture was extracted with water (250 mL) and ethyl acetate (250 mL x 2), and the organic layer was dried with anhydrous sodium sulfate. The solvent was removed from the filtrate obtained by vacuum filtration, and the residue was separated by medium-pressure chromatography (0–100% ethyl acetate / hexane) to obtain 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate (600 mg, 2.54 mmol, 40%). 1H NMR (400 MHz, CHLOROFORM-D) δ 7.80–7.76 (m, 2H), 7.37–7.30 (m, 2H), 2.43 (s, 3H).

[0156]

[0157] 2-1-2. Synthesis of Methyl (2S,3S)-8-(3-hydroxypropyl-1,1,2,2,3,3-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate

[0158] 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate (580 mg, 2.54 mmol, 1.0 equiv.) and methyl (2S,3S)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (nor-ß-CIT, 1.09 g, 2.94 mmol, 1.2 equiv.) were dissolved in toluene (24.0 mL, 0.1 M), then triethylamine (1.71 mL, 12.7 mmol, 5.0 equiv.) was added, and the mixture was stirred at 110°C for 15 hours. When the reaction was complete, all solvent was removed under reduced pressure, the residue was extracted with water (100 mL) and dichloromethane (150 mL x 2), and the organic layer was dried with anhydrous sodium sulfate. The solvent was removed from the filtrate obtained by vacuum filtration, and the residue was separated by medium pressure chromatography (5% triethylamine / diethyl ether) to obtain methyl (2S,3S)-8-(3-hydroxypropyl-1,1,2,2,3,3-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (920 mg, 2.11 mmol, 86%). 1H NMR (400 MHz, CHLOROFORM-D) δ 7.63 - 7.52 (m, 2H), 6.99 - 6.93 (m, 2H), 3.58 (d, J = 37.7 Hz, 1H), 3.48 (s, 3H), 2.89 (m, 2H), 2.13 (m, 2H), 1.72 (m, 4H), 1.38 - 1.02 (m, 1H).

[0159]

[0160] 2-1-3. Synthesis of N-(3'-Toluenesulfonyloxypropyl-1,1,2,2,3,3-d6)-2-β-Carbomethoxy-3-β-(4'-Iodophenyl)tropane

[0161] Methyl (2S,3S)-8-(3-hydroxypropyl-1,1,2,2,3,3-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (100 mg, 0.23 mmol, 1.0 equiv.) was dissolved in dichloromethane (2.3 mL, 0.1 M) and cooled to 0°C. p-toluenesulfonic acid anhydride (165 mg, 0.5 mmol, 2.2 equiv.) and diisopropylethylamine (0.12 mL, 0.68 mmol, 3.0 equiv.) were added to the mixture and stirred at room temperature for 2 hours. When the reaction was complete, the mixture was extracted with an aqueous sodium carbonate solution (100 mL) and dichloromethane (100 mL x 2), and the organic layer was dried with anhydrous sodium sulfate. The solvent was removed from the filtrate obtained by vacuum filtration, and N-(3'-toluenesulfonyloxypropyl-1,1,2,2,3,3-d6)-2-β-carbomethoxy-3-β-(4'-iodophenyl)tropane (70 mg, 0.12 mmol, 52%) was obtained by medium pressure chromatography (0-10% methanol / dichloromethane). 1H NMR (400 MHz, CHLOROFORM-D) δ 7.83 - 7.77 (m, 2H), 7.66 - 7.61 (m, 2H), 7.40 - 7.33 (m, 2H), 6.93 - 6.85 (m, 2H), 4.29 (ddd, J = 30.3, 5.7, 1.4 Hz, 2H), 3.37 (m, 4H), 3.08 - 2.99 (m, 1H), 2.89 - 2.74 (m, 1H), 2.62 - 2.47 (m, 1H), 2.44 (s, 3H), 2.37 (dd, J = 16.9, 9.1 Hz, 1H), 2.25 - 2.07 (m, 2H), 1.95 (dt, J = 14.9, 4.5 Hz, 1H); 13C NMR (101 MHz, CHLOROFORM-D) δ 174.01, 160.81, 160.45, 145.85, 138.07, 137.34, 132.02, 130.28, 129.32, 128.12, 117.68, 93.57, 63.70, 62.82, 52.78, 49.15, 34.31, 31.97, 24.56, 23.74, 21.77; LCMS: calculated for C25H24D6INO5S 589.5181 found [M+H, N+Na]+ 590.10, 612.10.

[0162]

[0163] 2-2. Verification of Purity of Deuterium-Substituted FP-CIT Linear Precursor When the Storage Solvent is Tetrahydrofuran

[0164] The procedure was performed using the same method and analysis conditions as in 1-1 above, except that the precursor was a deuterium-substituted FP-CIT linear precursor. As a result of HPLC analysis, when the purity at the start of storage was considered 100%, a purity of over 99% was observed after 1 month of storage and over 98% after 3 months. The purity of the deuterium-substituted FP-CIT linear precursor over the above time is summarized in Figure 1 and Table 1 below.

[0165]

[0166] 2-3. Verification of Purity of Deuterium-Substituted FP-CIT Linear Precursor When Ethyl Acetate is the Storage Solvent

[0167] The procedure was performed using the same method and analysis conditions as in 1-2 above, except that the precursor was a deuterium-substituted FP-CIT linear precursor. As a result of HPLC analysis, when the purity at the start of storage was considered 100%, a purity of over 98% was observed after 1 month of storage and over 97% after 3 months. The purity of the deuterium-substituted FP-CIT linear precursor over the above time is summarized in Figure 1 and Table 1 below.

[0168] [Table 1]

[0169]

[0170]

[0171] Example 3. Verification of purity according to the concentration of the existing FP-CIT linear precursor

[0172]

[0173] 3-1. Verification of the purity of the existing FP-CIT linear precursor when the storage solvent is tetrahydrofuran at room temperature

[0174] The procedure was performed using the same method and analysis conditions as in Example 1-1, except that the storage concentration was 8 mg / mL. As a result of HPLC analysis, when the purity at the start of storage was considered as 100%, it gradually decreased, and a purity of 95% or less was observed after 1 month and 3 months of storage, and a purity of approximately 73% was observed after 3 months of storage. The purity of the FP-CIT linear precursor over the above time is summarized in Figure 2 and Table 2 below.

[0175]

[0176] 3-2. Verification of the purity of the existing FP-CIT linear precursor when the storage solvent is ethyl acetate at room temperature

[0177] The procedure was performed using the same method and analysis conditions as in Examples 1-2, except that the storage concentration was 8 mg / mL. As a result of HPLC analysis, when the purity at the start of storage was considered 100%, the purity decreased to approximately 75% after 1 month of storage and approximately 64% after 3 months. The purity of the FP-CIT linear precursor over the above time is summarized in Figure 2 and Table 2 below.

[0178]

[0179] Example 4. Verification of purity according to concentration of deuterium-substituted FP-CIT linear precursor

[0180] 4-1. Verification of the purity of deuterium-substituted FP-CIT linear precursor when the storage solvent is tetrahydrofuran at room temperature

[0181] The procedure was performed using the same method and analysis conditions as in Example 2-2, except that the storage concentration was 8 mg / mL. As a result of HPLC analysis, it was observed that, when the purity at the start of storage was considered 100%, the purity was maintained at approximately 99% and 98% for 1 month and 3 months of storage, respectively. The purity of the FP-CIT linear precursor over the above time is summarized in Figure 2 and Table 2 below.

[0182]

[0183] 4-2. Verification of the purity of deuterium-substituted FP-CIT linear precursor when the storage solvent is ethyl acetate at room temperature

[0184] The procedure was performed using the same method and analysis conditions as in Examples 2-3, except that the storage concentration was 8 mg / mL. As a result of HPLC analysis, it was observed that, when the purity at the start of storage was considered 100%, the purity was maintained at approximately 99% and 98% up to 1 month and 3 months of storage, respectively. The purity of the FP-CIT linear precursor over the above time is summarized in Figure 2 and Table 2 below.

[0185] [Table 2]

[0186]

[0187]

[0188] Example 5. Synthesis of deuterium-substituted D6-[18F]FP-CIT using a deuterium-substituted FP-CIT linear precursor

[0189]

[0190] 5-1. Use of Non-heated Deuterium-Substituted FP-CIT Linear Precursors

[0191] Activated [ 18 F]fluoride mixture([ 18 F]FK 222 8 mg of deuterium-substituted FP-CIT linear precursor is added to a reaction vessel containing ) along with t-amyl alcohol as the reaction solvent and heated at 90°C or higher to D6-[ 18F]FP-CIT was synthesized. After purifying the reaction mixture, D6-[ 18 The synthetic yield of [F]FP-CIT was 1.64%.

[0192]

[0193] 5-2. Use of Heated Deuterium-Substituted FP-CIT Linear Precursors

[0194] After heating 8 mg of deuterium-substituted FP-CIT linear precursor and the reaction solvent t-amyl alcohol at a temperature of 90°C or higher for at least 5 minutes, the activated [ 18 F]fluoride mixture([ 18 F]FK 222 Add to a reaction vessel containing ) and heat at 90°C or higher to D6-[ 18 F]FP-CIT was synthesized. After purifying the reaction mixture, D6-[ 18 The synthetic yield of [F]FP-CIT was 31.14%.

[0195]

[0196] Example 6. MicroPET imaging evaluation of deuterium-substituted D6-[18F]FP-CIT

[0197]

[0198] 6-1. MicroPET Imaging Evaluation Method for Deuterium-Substituted D6-[18F]FP-CIT

[0199] [ 18 F]FP-CIT and deuterium-substituted D6-[ 18 [F]FP-CIT was synthesized from each precursor under the same radiolabeling conditions. Deuterium-substituted D6-[ 18 F]FP-CIT was synthesized by the method described in Example 5-2, and [ 18 F]FP-CIT was synthesized by the method described in Example 4 of Korean Patent Application Publication No. 10-2025-0046134.

[0200] Normal C57BL / 6 female rodents (body weight 22-25 g, n = 10) were divided into two groups, and [ 18F]FP-CIT (0.335 ± 0.021 mCi, n = 5) or deuterium-substituted D6-[ 18 [F]FP-CIT (0.325 ± 0.036 mCi, n = 5) was administered via the tail vein. Static PET / MR images were acquired at intervals of 45–75 minutes after administration. Imaging was performed using a nanoScan®PET / MRI system (Mediso, Hungary), and MR images were acquired using a mouse whole-body coil (coil 35). The MR imaging parameters were set to FOV 64 mm, slice thickness 1 mm, repetition time (TR) 25 ms, echo time (TE) 3.4 ms, number of excitations 1, and frequency / phase 220. The MR images were aligned with the PET images and used as an anatomical reference when setting the Voids of Intake (VOI). PET data were acquired in 3D full detector mode within a 250–750 keV energy window, and reconstruction was performed under conditions of voxel size 0.5 mm, 8 iterations, and 6 subsets. For quantitative analysis, spherical VOIs (volumes of interest) with a diameter of 2 mm were established for each major organ (striatum, lumbar spine, femur).

[0201] SUV mean The value was calculated using the following formula: SUV mean = (Radiation concentration within the region of interest (target location) (MBq / cc)) / (Total amount of injected radioactivity (MBq) / Body weight (g)). Also, the SUV of muscle measured in the same individual mean Relative uptake rate of major organs (SUV) corrected based on the value ratio ) calculated. SUV ratio The value was calculated using the following formula: SUV ratio (SUV mean Ratio) = (SUV of the region of interest (target location) mean ) / (muscular SUV, which is the comparison standard (reference) areamean Through this process, the uptake characteristics of the two radiopharmaceuticals by major organs were quantitatively compared.

[0202]

[0203] 6-2. MicroPET Imaging Evaluation Results of Deuterium-Substituted D6-[18F]FP-CIT

[0204] Figure 3 is [ 18 F]FP-CIT and deuterium substitution D6-[ 18 [F]Primary tissue uptake rate of FP-CIT (SUV mean Figure 4 shows the SUV of muscle measured in the same individual. mean Relative uptake rate of major organs adjusted based on values ​​(SUV ratio This shows the results of comparing ).

[0205] Deuterium substitution D6-[ 18 F]FP-CIT is [ 18 It was confirmed that there was a slightly higher uptake in the target striatum compared to F]FP-CIT. On the other hand, in the lumbar spine and femur, which are non-target sites for evaluating in vivo safety, the free [ 18 Intake by F]fluoride is the existing [ 18 Compared to F]FP-CIT, D6-[ 18 It was significantly reduced in [F]FP-CIT. This difference is interpreted as a result of deuterium substitution increasing the in vivo metabolic stability of the radiopharmaceutical, thereby suppressing defluorination and unnecessary accumulation in non-target sites.

[0206] Therefore, the deuterium-substituted D6-[ of the present invention 18 F]FP-CIT, existing [ 18 [F]F FP-CIT relative to decomposition process by [ 18 This suggests that it can improve target-to-background contrast by reducing the generation of F]fluoride and thereby resolving the issue of nonspecific in vivo residue occurring in non-target sites.

[0207] In addition, from the above results, deuterium substitution D6-[ 18 F]FP-CIT is the existing [ 18 It can be confirmed that precise visualization of dopamine transporter (DAT) distribution is possible through improved image contrast compared to F]FP-CIT, and that superior selectivity and reliability can be provided by enhancing the diagnostic accuracy of Parkinson's disease and related neurodegenerative diseases.

[0208]

[0209] All embodiments in the present invention are [ 18 5 animals administered F]FP-CIT and D6-[ 18 The mean ± standard deviation values ​​were measured for 5 animals (n = 5 in each group) administered F]FP-CIT.

[0210]

[0211] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0212]

[0213] The deuterium-substituted FP-CIT linear precursor of the present invention inhibits the conversion of the linear precursor stabilized by deuterium into a cyclic salt form, thereby maintaining a linear form even at room temperature, and furthermore, the existing radiopharmaceutical [ 18 D6-[ having the same effect as F]FP-CIT 18 Since F]FP-CIT can be manufactured simply and with high yield, it can be usefully applied in the field of radiopharmaceuticals. Furthermore, the existing radiopharmaceutical [ 18F]FP-CIT had the disadvantage of rapid metabolite generation in the body, but the new radiopharmaceutical D6-[ 18 It has been confirmed that F]FP-CIT improves upon this to suppress metabolite formation, thus demonstrating industrial applicability.

Claims

1. Deuterium-substituted FP-CIT linear precursor represented by the following chemical formula 1: [Chemical Formula 1] (In Chemical Formula 1 above, LG is a leaving group, which is methanesulfonyl (Mesyl), toluenesulfonyl (Tosyl), or nitrobenzenesulfonyl (Nosyl).) 2. In Paragraph 1, A deuterium-substituted FP-CIT linear precursor characterized by being stored in a dissolved state in an organic solvent.

3. In Paragraph 2, A deuterium-substituted FP-CIT linear precursor characterized in that the organic solvent is one or more selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EA), chloroform (CHCl3), and dichloromethane (DCM).

4. In Paragraph 2, The deuterium-substituted FP-CIT linear precursor is characterized by being stored at a temperature of -20 to 50 ℃.

5. In Paragraph 2, A deuterium-substituted FP-CIT linear precursor characterized by being stored in an organic solvent at a concentration of 0.1 to 16 mg / mL.

6. A method for preparing a deuterium-substituted FP-CIT linear precursor of claim 1, comprising the following steps: (S1) A step of preparing 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate by reacting propane-d6-1,3-diol with p-toluenesulfonic acid anhydride (Ts₂O) and NaOH at room temperature; (S2) a step of mixing the 3-hydroxypropyl-1,1,2,2,3,3-d64-methylbenzenesulfonate obtained in the above step with triethylamine (Et₃N) and heating to produce methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate; and (S3) A step of reacting the methyl (2S,3S)-8-(3-hydroxypropyl-d6)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate obtained in the above step with p-toluenesulfonic acid anhydride (Ts₂O) and diisopropylethylamine (DIPEA) at room temperature to obtain a deuterium-substituted FP-CIT linear precursor.

7. The deuterium-substituted FP-CIT linear precursor of claim 1 and activated [ 18 D6-[ comprising the step of reacting F]fluoride 18 F] FP-CIT manufacturing method.

8. In Paragraph 7, The above-mentioned deuterium-substituted FP-CIT linear precursor is characterized by being dissolved in a reaction solvent, D6-[ 18 F] FP-CIT manufacturing method.

9. In Paragraph 8, The reaction solvent is one or more protic tertiary alcohols selected from the group consisting of t-butanol, t-amyl alcohol, and 1-methoxy-2-methyl-2-propanol; or D6-[ 18 F] FP-CIT manufacturing method.

10. In Paragraph 8, The above deuterium-substituted FP-CIT linear precursor is characterized by being dissolved in a reaction solvent after being heated at a temperature of 50 to 150 ℃ for 1 to 10 minutes, D6-[ 18 F] FP-CIT manufacturing method.

11. In Paragraph 7, Above D6-[ 18 The method for manufacturing F]FP-CIT involves a deuterium-substituted FP-CIT linear precursor and an activated [ 18 D6-[ 18 F] FP-CIT manufacturing method.

12. D6-[represented by the following chemical formula 2 18 F]FP-CIT: [Chemical Formula 2] .

13. D6 of Paragraph 12 [ 18 A radiopharmaceutical containing [F]FP-CIT as an active ingredient.

14. A radiopharmaceutical according to claim 13, characterized in that the radiopharmaceutical is a radiopharmaceutical for imaging diagnosis of degenerative brain diseases.

15. A radiopharmaceutical according to claim 14, characterized in that the imaging diagnosis is positron emission tomography (PET).

16. In paragraph 13, the radiopharmaceutical is characterized by visualizing the distribution of dopamine carriers (DAT).

17. A radiopharmaceutical product according to claim 14, characterized in that the degenerative brain disease is Parkinson's disease.

18. D6 of Paragraph 12 [ 18 Use of a pharmaceutical product containing F]FP-CIT as an active ingredient for the diagnosis or prognosis prediction of degenerative brain diseases.

19. D6 of Paragraph 12 [ 18 Use for manufacturing a drug containing [F]FP-CIT as an active ingredient for the diagnosis or prognosis prediction of degenerative brain diseases.

20. A method for diagnosing or predicting the prognosis of a degenerative brain disease comprising one or more of the following steps: (a) a step of treating a biological sample isolated from an individual with a pharmaceutical product containing D6-[18F]FP-CIT of claim 12 as an active ingredient; (b) a step of comparing the uptake rate in the sample with a control biological sample; and (c) A step in which the uptake rate is lower than that of the control biological sample, and the patient is diagnosed with a degenerative brain disease or judged to have a poor prognosis.

21. A method for treating a degenerative brain disease comprising one or more of the following steps: (a) to biological samples isolated from individuals, D6-[ of Paragraph 12 18 A step of processing a pharmaceutical product containing [F]FP-CIT as an active ingredient; (b) a step of comparing the uptake rate of the sample with a control biological sample; (c) a step of diagnosing a degenerative brain disease or determining a poor prognosis when the uptake rate is lower than that of a control biological sample; and (d) A stage of treating individuals diagnosed with degenerative brain disease or judged to have a poor prognosis.

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