N-deuterated fluoroalkyl-2beta-deuterated methyl ester tropane derivative

Abstract

The invention relates to an N-deuterated fluoroalkyl-2beta-deuterated methyl ester tropane derivative, and belongs to the technical field of chemistry. The invention provides an N-deuterated fluoroalkyl-2beta-deuterated methyl ester group tropane derivative which can be specifically combined with a dopamine transporter, and the N-deuterated fluoroalkyl-2beta-deuterated methyl ester group tropane derivative has the advantages that the N-deuterated fluoroalkyl-2beta-deuterated methyl ester group tropane derivative can be specifically combined with the dopamine transporter; the N-deuterated fluoroalkyl-2beta-deuterated methyl ester-based tropane derivative has the advantages of high affinity to a dopamine transporter, good selectivity and high PET (Polyethylene Terephthalate) imaging target / target ratio, and has an extremely high application prospect in the aspect of PET imaging of the dopamine transporter.

Description

Technical Field

[0001] The invention relates to an N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative, belonging to the technical field of chemistry. Background Art

[0002] Parkinson's disease (PD), also known as tremor paralysis, is clinically characterized by resting tremor, muscle rigidity, bradykinesia, and some other non-motor symptoms. PD is a progressive neurodegenerative disease and is currently the second largest neurodegenerative disease, second only to Alzheimer's disease. There are nearly six million PD patients worldwide. Current medical technology cannot completely cure PD, and existing treatment options can only relieve symptoms, but can neither reverse PD nor delay the progression of PD. Not only that, some PD cases, especially early cases, are easily misdiagnosed because of their great similarities with other diseases. Therefore, through non-destructive molecular imaging studies of PD pathological characteristics, it is possible to improve the accuracy of PD diagnosis, monitor the progression of PD, and provide timely monitoring methods for PD treatment research.

[0003] Studies have shown that the main pathological feature of PD is the depletion of dopamine (DA) neurons in the central nervous system and the reduction of DA neurons in the nigrostriatal pathway in the brain. The dopamine transporter (DAT) is a membrane protein on the presynaptic membrane of DA neurons. Its function is to transport DA in the synaptic cleft of DA neurons to the presynaptic membrane against the concentration gradient, which is beneficial to the reuse of DA and prevents DA from being further oxidized and degraded. Neuropathological studies have shown that changes in the density and distribution of DAT can directly and sensitively reflect the function and changes of the DA system. Therefore, in the field of basic and clinical research, in vivo tracing imaging of DAT can provide valuable clinical information for PD and other DA system-related diseases, which has clinical significance for the early diagnosis, differential diagnosis and efficacy monitoring of the disease.

[0004] Positron emission tomography (PET) is one of the representative technologies of modern molecular imaging in clinical practice. By using appropriate PET drugs (positron drugs), PET imaging can provide intuitive, timely and quantitative imaging information of physiological and biochemical processes in vivo without damage, which is beneficial to the diagnosis, classification and efficacy monitoring of the disease. Using PET imaging to image the DAT in the brain of PD patients can provide important clinical information for the diagnosis and treatment of PD, and can also conduct timely monitoring of the efficacy of PD. Therefore, radioactive drugs used for DAT PET imaging are an important research direction in the fields of pharmacy and Parkinson's disease.

[0005] At present, the radioactive drugs used in clinical DAT PET imaging are mainly positron-emitting radionuclides [ 11 C] or fluorine [ 18F] labeled tropane drugs. 11 For C, 18 F is the most widely used nuclide in the PET field because of its relatively long half-life (119 vs 20 min) and suitable positron energy. 18 F]-labeled tropane drugs are the main PET drugs used for PD imaging internationally, such as [ 11 C]PE2I, 18 F]LBT-999, 18 F]β-CFT and [ 18 F]FECNT, etc. 18 Drug F has the advantages of good affinity and selectivity for DAT.

[0006] However, studies have shown that the N-alkyl groups of these tropane structures are easily cleaved by enzymes such as cytochrome P450 in vivo to generate radioactive 18 These metabolites easily cross the blood-brain barrier and produce nonspecific uptake in the cerebellum, cortex and other areas of the brain, thus affecting the quantitative analysis results of PET (target / target ratio) (see the literature " KA, et al. Eur J Nucl Med 1997, 24: 596-601" and "Shin KH, et al. Nucl Med Mol Imaging 2012, 46: 27-33"). With [ 18 F]FECNT as an example, 18 F]FECNT produces three kinds of 18 F metabolites are fluorine [ 18 F] ethanol, fluorine [ 18 F] acetaldehyde and fluorine [ 18 F] acetic acid (see the document "ZoghbiSS, et al. J. Nucl. Med. 2006, 47: 520-527"), these three 18 F metabolites can cross the blood-brain barrier and enter the brain. Although they are not concentrated in the imaging target area (striatum, ST), they have high non-specific uptake in the reference area of ​​PET quantitative analysis (cerebellum (CB) or occipital cortex (OC)), and their uptake values ​​are similar to those of the original drug [ 18 This phenomenon is true in both animals and humans, which is disadvantageous for quantitative analysis of PET imaging (see the document "Zoghbi SS, et al. J. Nucl. Med. 2006, 47: 520-527").

[0007] There are also studies trying to modify the structure of these tropanes to improve their stability in vivo. 18 F]FP-CIT-d 6 For example, the series 18 Among the F-labeled N-deuterated fluoroalkyl tropane PET drugs, [ 18 F]FP-CIT-d 6 It has relatively good in vivo metabolic stability, and its affinity and selectivity for DAT are also good (see the document "Hu Q, et al. Arab J. Chem. 2023, 16: 105278"). However, it is worth noting that [ 18 F]FP-CIT-d 6 The 2β-position of the molecular structure is an ester group, which is also a group that is easily metabolized in the body (see the literature "Giron MC, et al. Q J Nucl Med Mol Imaging 2008, 52: 254-266" and "Guengerich FP. J Biochem Mol Toxicol 2007, 21: 163-168"). 18 F-labeled tropane drugs may also generate radioactive metabolites by hydrolysis of the 2β-ester group (see the literature " KA, et al. Nucl. Med. Biol. 1995, 22: 971-976" and "Peyronneau MA, et al. Nucl. Med. Biol. 2012, 39: 347-359), thereby affecting the accuracy of PET imaging.

[0008] For PET drugs, the better the in vivo stability is before the PET examination is completed, the longer the "original drug" of the PET drug stays in the body, and the more accurate the PET imaging results are. Therefore, the development of positron drugs that can inhibit (or reduce) the metabolic rate of the 2β-ester group in the tropane molecular structure is a practical clinical need. In addition, how to improve the in vivo stability of positron drugs while not affecting or even improving their affinity, selectivity and PET imaging target / target ratio for dopamine transporters to further improve their PET imaging performance is also a problem. Summary of the invention

[0009] In order to solve the above problems, the present invention provides an N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative, wherein the N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative has the following structure:

[0010]

[0011] in:

[0012] n is an integer from 1 to 3;

[0013] X is fluorine or an isotope of fluorine;

[0014] R is fluorine, chlorine, methyl, hydrogen, iodine, bromine or methoxy.

[0015] In one embodiment of the present invention, X is 18 F.

[0016] In one embodiment of the present invention, the N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the following structure:

[0017]

[0018] In one embodiment of the present invention, the N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the following structure:

[0019]

[0020] In one embodiment of the present invention, the N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the following structure:

[0021]

[0022] In one embodiment of the present invention, the N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the following structure:

[0023]

[0024] The present invention also provides a deuterated methyl ester of ecgonine, wherein the deuterated methyl ester of ecgonine has the following structure:

[0025]

[0026] The present invention also provides a 2β-deuterated methyl ester tropane derivative, wherein the 2β-deuterated methyl ester tropane derivative has the following structure:

[0027]

[0028] The present invention also provides a 2β-deuterated methyl ester tropane derivative, wherein the 2β-deuterated methyl ester tropane derivative has the following structure:

[0029]

[0030] Alternatively, the 2β-deuterated methylester tropane derivative has the structure shown below:

[0031]

[0032] The present invention also provides a demethylated 2β-deuterated methyl ester tropane derivative, wherein the demethylated 2β-deuterated methyl ester tropane derivative has the following structure:

[0033]

[0034] Alternatively, the demethylated 2β-deuterated methyl ester tropane derivative has the structure shown below:

[0035]

[0036] The present invention also provides a method for preparing the above-mentioned N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative, the method comprising: demethylating the demethylated 2β-deuterated methyl ester tropane derivative nor-CIT-d 3 、FCD 2 CD 2 CD 2 OTs and triethylamine are dissolved in toluene to obtain a mixed solution; the mixed solution is heated for reaction, and after the reaction is completed, the solvent is first removed and then purified to obtain the above-mentioned N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative;

[0037] The NOR-CIT-D 3 Has the following structure:

[0038]

[0039] In one embodiment of the present invention, the nor-CIT-d 3 The preparation method comprises: treating a 2β-deuterated methyl ester tropane derivative β-CIT-d 3 Add to 1-chloroethanol chloroformate to obtain a mixed solution; heat the mixed solution for reaction, and after the reaction is completed, first evaporate the excess 1-chloroethanol chloroformate, and then add methanol to obtain a reaction system; heat the reaction system for reaction, and after the reaction is completed, first remove the solvent, and then purify to obtain nor-CIT-d 3 ;

[0040] The β-CIT-d 3 Has the following structure:

[0041]

[0042] In one embodiment of the present invention, the β-CIT-d 3 The preparation method comprises: treating a 2β-deuterated methyl ester tropane derivative β-CT-d3 The precipitate is dissolved in dichloromethane to obtain a solution; acetic acid, acetic anhydride, elemental iodine and silver trifluoroacetate are added to the solution to obtain a reaction system; the reaction system is heated to react, and after the reaction is completed, the precipitate is first removed, and then the solvent is evaporated, and then purified to obtain β-CIT-d 3 ;

[0043] The β-CT-d 3 Has the following structure:

[0044]

[0045] In one embodiment of the present invention, the β-CT-d 3 The preparation method comprises: reacting dehydrated ecgonine deuterated methyl ester with phenylmagnesium bromide in dichloromethane, and after the reaction is completed, quenching the reaction to obtain a reaction solution; acidifying the reaction solution, separating the organic phase to obtain an aqueous solution; alkalizing the aqueous solution, first extracting with an organic solvent, and then evaporating the solvent to obtain dehydrated ecgonine deuterated methyl ester;

[0046] The deuterated methyl ester of anhydroecgonine has the structure shown below:

[0047]

[0048] The present invention also provides a method for preparing the above-mentioned N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative, the method comprising: demethylating the demethylated 2β-deuterated methyl ester tropane derivative nor-CCT-d 3 、FCD 2 CD 2 CD 2 OTs and triethylamine to obtain a mixed solution; heating the mixed solution for reaction, and after the reaction is completed, first removing the solvent and then purifying to obtain the above-mentioned N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative;

[0049] The NOR-CCT-D 3 Has the following structure:

[0050]

[0051] In one embodiment of the present invention, the nor-CCT-d 3 The preparation method comprises: treating a 2β-deuterated methyl ester tropane derivative β-CCT-d 3Add to 1-chloroethanol chloroformate to obtain a mixed solution; heat the mixed solution for reaction, and after the reaction is completed, first evaporate the excess 1-chloroethanol chloroformate, and then add methanol to obtain a reaction system; heat the reaction system for reaction, and after the reaction is completed, first remove the solvent, and then purify to obtain β-CCT-d 3 ;

[0052] The β-CCT-d 3 Has the following structure:

[0053]

[0054] In one embodiment of the present invention, the β-CCT-d 3 The preparation method comprises: reacting dehydrated ecgonine deuterated methyl ester with p-chlorophenylmagnesium bromide in dichloromethane, and after the reaction is completed, quenching the reaction to obtain a reaction solution; acidifying the reaction solution, separating the organic phase to obtain an aqueous solution; alkalizing the aqueous solution, first extracting with an organic solvent, and then evaporating the solvent to obtain dehydrated ecgonine deuterated methyl ester;

[0055] The deuterated methyl ester of anhydroecgonine has the structure shown below:

[0056]

[0057] The present invention also provides the use of the above-mentioned N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative or the above-mentioned dehydroecgonine deuterated methyl ester or the above-mentioned 2β-deuterated methyl ester tropane derivative or the above-mentioned 2β-deuterated methyl ester tropane derivative or the above-mentioned demethyl-2β-deuterated methyl ester tropane derivative in the preparation of a dopamine transporter imaging agent.

[0058] In one embodiment of the present invention, the imaging agent is a PET imaging agent.

[0059] The present invention also provides an imaging agent targeting a dopamine transporter, wherein the imaging agent contains the above-mentioned N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative.

[0060] In one embodiment of the present invention, the imaging agent is a PET imaging agent.

[0061] The technical solution of the present invention has the following advantages:

[0062] The present invention provides an N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative. The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative can specifically bind to a dopamine transporter, and the N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the advantages of high affinity for the dopamine transporter, good selectivity and high PET imaging target / substance ratio, and has extremely high application prospects in PET imaging of dopamine transporters. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 :Synthetic route of N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives.

[0064] Figure 2 :[ 18 F]FP-CCT-d 9 (Compound [ 18 F]6) and the reference substance FP-CCT-d 9 (High performance liquid chromatography analysis chart of compound 6).

[0065] Figure 3 :[ 18 F]FP-CIT-d 9 (Compound [ 18 F]10) and the reference substance FP-CIT-d 9 (HPLC analysis chart of compound 10).

[0066] Figure 4 :[ 18 F]FP-CIT-d 9 (Compound [ 18 F]10), [ 18 F]FP-CCT-d 9 (Compound [ 18 F]6) and [ 18 F]FP-CIT-d 6 MicroPET brain imaging of rats.

[0067] Figure 5 :[ 18 F]FP-CIT-d 9 (a), [ 18 F]FP-CCT-d 9 (b) and [ 18 F]FP-CIT-d 6 (c) Time-radioactivity curves of rat striatum and cerebellum and ST / CB comparison curves (d, e, f).

[0068] Figure 6: MicroPET brain images of normal group, DAT inhibitor (CFT) group and unilateral PD model rats (a) and time-dependent radioactivity-curves of ST and CB regions of normal group and DAT inhibitor group (b) as well as comparison of radioactivity standard uptake values ​​(SUV) of striatum on both sides of unilateral PD model group.

[0069] Figure 7 :Injection of rats 18 F]FP-CIT-d 9 The distribution of radioactivity in different brain regions at different time points after the injection (a) and the ST / CB ratio curve (b). DETAILED DESCRIPTION

[0070] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0071] If no specific experimental steps or conditions are specified in the following examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be purchased commercially.

[0072] Example 1-1: A non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative

[0073] This embodiment provides a non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative FP-CCT-d 9 The non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative FP-CCT-d 9 Has the following structure:

[0074]

[0075] Example 2-1: A method for preparing non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives

[0076] This example provides a non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative FP-CCT-d of Example 1-1. 9 The preparation method comprises the following steps (synthetic route see Figure 1 ):

[0077] 1. Preparation of deuterated methyl ester of anhydroecgonine

[0078] 10 mL of deuterated methanol CD 3 After adding OD to a three-necked flask, first 2 Under protection, the mixture was cooled in an ice-water bath, and then acetyl chloride (CH 3 COCl, 1.5 mL, 20 mmol), and then add CD containing dehydrated icagonine hydrochloride (compound 1, 2.0 g, 9.80 mmol) (the preparation of dehydrated icagonine hydrochloride refers to the document "Hu Q, et al. Arab J. Chem. 2023, 16: 105278") 3 OD solution (10 mL) was added to obtain a mixed solution; the mixed solution was heated to 80°C while stirring and maintained for 12 hours to react to obtain a reaction solution; the reaction solution was freed from the solvent under vacuum to obtain a residue; the residue was dissolved in 8 mL of water, and the pH was adjusted to 11 with 29% (w / v, g / 100 mL) concentrated ammonia water, and then extracted with dichloromethane three times (3×20 mL), and the organic phases were combined; the organic phases were washed with anhydrous Na 2 SO 4 After drying, the solvent was evaporated to obtain deuterated methyl ester of anhydroecgonine (compound 2);

[0079] The deuterated methyl ester of anhydroecgonine has the structure shown below:

[0080]

[0081] The hydrogen spectrum and mass spectrum of the obtained compound 2 are: 1 H NMR (400 MHz, CDCl 3 )δ6.74(t,J=3.7Hz,1H),3.71(d,J=5.6Hz,1H),3.17(t,J=5.9Hz,1H),2.55(d,J=19.8Hz,2H ),2.27(s,3H),2.14-2.03(m,2H),1.80-1.72(m,2H),1.47-1.38(m,1H).MS(ESI):m / z[M+H] + Theoretical value C 10 H 12 D 3 NO 2 + :185.13; measured value:185.23.

[0082] 2. 2β-deuterated methyl ester tropane derivative β-CCT-d 3 Preparation

[0083] Dehydroecgonine deuterated methyl ester (compound 2, 2.0 g, 11 mmol) was dissolved in dichloromethane (CH 2 Cl 2, 20 mL) and then in N 2 The mixture was cooled to -40°C in a low temperature reaction tank under protection, and then a solution of p-chlorophenylmagnesium bromide (1.0M, 22mmol) in ether (22mL) was slowly added dropwise while stirring (150rpm) to obtain a mixed solution; the mixed solution was stirred and reacted at -40°C for 3.5 hours, first cooled to -78°C, and then trifluoroacetic acid (1.6mL) in CH 2 Cl 2 (10mL) solution, and then stirred for 10 minutes to obtain a reaction solution; after the reaction solution was restored to 0°C, the pH was adjusted to 1 with 37% (w / v, g / 100mL) concentrated hydrochloric acid, and then allowed to stand for stratification, the organic phase was separated, and the aqueous phase was taken; the aqueous phase was washed with dichloromethane (CH 2 Cl 2 , 20mL) was washed once, and then the pH was adjusted to 10 with concentrated ammonia in an ice water bath, and then the base was extracted three times with acetic acid (3×20mL), and the organic phases were combined; the organic phases were washed with anhydrous Na 2 SO 4 After drying, the solvent was evaporated and then purified by silica gel column chromatography to obtain 2β-deuterated methyl ester tropane derivative β-CCT-d 3 (Compound 3); wherein the mobile phase used for silica gel chromatography is n-hexane / ethyl ether / triethylamine = 1 / 1 / 0.01 (v / v / v);

[0084] The 2β-deuterated methylester tropane derivative β-CCT-d 3 Has the following structure:

[0085]

[0086] The prepared β-CCT-d 3 It is a white solid with a mass of 1.44 g and a yield of 83%.

[0087] The prepared β-CCT-d 3 The hydrogen spectrum and mass spectrum are: 1 H NMR (400 MHz, CDCl 3 )δ7.31-7.17(m,4H),3.53-3.46(m,1H),3.31-3.27(m,1H),2.89(m,1H),2.8 0(t,1H),2.48(m,J=12.6,3.0Hz,1H),2.30-2.07(m,5H),1.79-1.58(m,3H). MS(ESI):m / z[M+H] + calcd.for C 16 H 17 D 3 ClNO2 + :297.14,299.13; found:297.41,299.44.

[0088] 3. Demethyl-2β-deuterated methyl ester tropane derivative nor-β-CCT-d 3 Preparation

[0089] The 2β-deuterated methyl ester tropane derivative β-CCT-d 3 (Compound 3, 500.0 mg, 1.69 mmol) was added to 1-chloroethanol chloroformate (ACE-Cl, 3.5 mL, 5.0 g), and the mixture was heated at 110°C and stirred (150 rpm) for 2 hours to obtain a reaction solution A; the reaction solution A was distilled under reduced pressure to remove excess ACE-Cl to obtain a residue A; methanol (25 mL) was added to the residue A, and the mixture was heated at 80°C and stirred for 1 hour to obtain a reaction solution B; methanol was distilled under reduced pressure to remove methanol from the reaction solution B to obtain a residue B; dichloromethane (25 mL) was added to the residue B, and the residue was washed twice (2×20 mL) with a 10% (w / v, g / 100 mL) NaOH solution, and then the solvent was evaporated, and the residue was purified by silica gel column chromatography to obtain a demethylated 2β-deuterated methyl ester tropane derivative nor-β-CCT-d 3 (Compound 4); wherein the mobile phase used for silica gel chromatography is diethyl ether / triethylamine = 95 / 5 (v / v);

[0090] The demethylated 2β-deuterated methyl ester tropane derivative nor-β-CCT-d 3 Has the following structure:

[0091]

[0092] The prepared nor-β-CCT-d 3 It is an off-white solid with a mass of 225 mg and a yield of 72%.

[0093] The prepared β-CCT-d 3 The hydrogen spectrum and mass spectrum are: 1 H NMR (600 MHz, CDCl 3 )δ7.21-7.15(m,2H),7.09-7.03(m,2H),3.65(m,2H),3.14(m,1H),2.66(dd,1H),2 .32(m,2H),2.06(m,1H),1.99-1.90(m,1H),1.71-1.53(m,3H).MS(ESI):m / z[M+H] + calcd.for C 15H 15 D 3 ClNO 2 + :283.12,285.12; found:283.33,285.36.

[0094] 4. Non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative FP-CCT-d 9 Preparation

[0095] The demethylated 2β-deuterated methyl ester tropane derivative nor-β-CCT-d 3 (Compound 4, 60.0 mg, 0.21 mmol), FCD 2 CD 2 CD 2 OTs (compound 5, 50.0 mg, 0.21 mmol, FCD 2 CD 2 CD 2 The preparation of OTs refers to the literature "HuQ, et al. Arab J. Chem. 2023, 16: 105278") and triethylamine (Et 3 N, 0.5 mL) was dissolved in toluene (10 mL), and the mixture was heated at 115° C. for 4 hours to obtain a reaction solution. The reaction solution was decompressed to remove toluene, and then purified by silica gel column chromatography. During purification, the mobile phase was first eluted with n-hexane / ethyl acetate = 4 / 1 (v / v) to remove unreacted compound 5, and then the mobile phase was eluted with n-hexane / ethyl ether / triethylamine = 1 / 1 / 0.01 (v / v / v) to collect the product FP-CCT-d 9 The eluent was evaporated to remove the mobile phase and then dried in vacuo to obtain a non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative FP-CCT-d 9 (Compound 6).

[0096] Prepared FP-CCT-d 9 It is a white solid with a mass of 24 mg and a yield of 40%.

[0097] Prepared FP-CCT-d 9 The hydrogen spectrum and mass spectrum are: 1 H NMR (600 MHz, CDCl 3)δ7.20-7.14(m,2H),7.11(d,2H),3.62-3.57(m,1H),3.33-3.29(m,1H),2.90(m,J=12.8,5.0Hz,1H),2.84-2.80(m,1H) ,2.47(m,J=12.5,3.1Hz,1H),2.07-1.98(m,1H),1.98-1.89(m,1H),1.66(m,1H),1.62-1.52(m,2H).MS(ESI):m / z[M+H] + Theoretical value C 18 H 14 D 9 ClFNO 2 + :349.20,351.19; Experimental value:349.45,351.45.

[0098] Example 1-2: A [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives

[0099] This embodiment provides a [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CCT-d 9 ([ 18 F]6), said 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CCT-d 9 Has the following structure:

[0100]

[0101] Example 2-2: A preparation method 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives

[0102] This embodiment provides [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CCT-d 9 The preparation method comprises the following steps (synthetic route see Figure 1 ):

[0103] Produced by cyclotron 18 F, transported by nitrogen flow 18 F, so that 18F was adsorbed on a SepPak QMA column (purchased from Waters, USA). After adsorption, 1.0 mL of eluent (the eluent consisted of 15 mg K dissolved in 0.8 mL acetonitrile) was used to wash the column. 2.2.2 and 3.0 mg K dissolved in 0.2 mL water 2 CO 3 Composition) rinse and dissolve 18 F in the reaction tube; after elution, heat the liquid in the reaction tube to 105°C, and blow dry the liquid in the reaction tube with a nitrogen stream at 105°C; after drying, stop heating and cool to <60°C; after cooling, add anhydrous CH 3 CN (1 mL), continue to blow dry the liquid in the reaction tube with a nitrogen stream at 105 ° C; after drying, stop heating and cool to < 60 ° C, add 0.50 mL of anhydrous CH 3 TsOCD of CN 2 CD 2 CD 2 OTs (compound 5, 10.0 mg, TsOCD 2 CD 2 CD 2 The preparation of OTs refers to the literature "Zhao, R, et al. Nucl Med Biol. 2019, 72-73: 26-35."), heating the reaction at 90 ° C for 15 min; after the reaction is completed (the reaction is completed here to obtain the compound [ 18 F]5, 18 FCD 2 CD 2 CD 2 OTs), stop heating and cool to <50°C, add demethyl-2β-deuterated methyl ester tropane derivative nor-β-CCT-d dissolved in N,N-dimethylformamide (DMF, 0.5 mL) to the reaction tube. 3 (Compound 4, 8.0 mg), heated at 135°C for 25 min; after the reaction, stop heating and cool to <50°C, add 1.0 mL of high performance liquid chromatography (HPLC) mobile phase to the reaction tube to obtain a mixed solution; transfer the mixed solution to an HPLC injection loop and purify it by HPLC to obtain a mixture containing [ 18 F]FP-CCT-d 9 The mobile phase will contain [ 18 F]FP-CCT-d 9 The mobile phase was diluted with 30 mL of water to obtain a diluent; the diluent was first passed through a SepPak C18 column (at this time [ 18 F]FP-CCT-d 9was adsorbed on this column), and then the column was rinsed with 10 mL of water to remove possible water-soluble impurities, and then eluted with 2 mL of EtOH. 18 F]FP-CCT-d 9 , and collected in a cillin bottle, and obtained [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CCT-d 9 (Compound [ 18 F]6) (yield: 15%, pure product was diluted with physiological saline to the required concentration before use); wherein, the conditions for HPLC purification were: using a Phenomenex Luna C18 column (10 mm × 250 mm, 5 μm), the mobile phase was CH 3 CN / H 2 O / E 3 N=65 / 35 / 0.1 (v / v / v), flow rate was 4.0 mL / min, and detection was performed using a radioactivity detector.

[0104] High performance liquid chromatography (HPLC) was used to analyze the 18 F]FP-CCT-d 9 The structure of is verified, and the verification process is as follows: 18 F]FP-CCT-d 9 (Compound [ 18 F]6) and FP-CCT-d 9 (Compound 6) was mixed until the concentration of the radioactive compound was 37 MBq / mL and the concentration of the non-radioactive compound was 1.0 mg / mL to obtain a mixed solution; 20 μL of the mixed solution was injected into a high performance liquid chromatography (HPLC) for HPLC analysis; wherein the conditions for HPLC analysis were: using a Gemini NX-C18 column (5 mm × 150 mm, 3 μm), and the mobile phase was CH 3 OH / H 2 O / TFA = 40:60:0.1 (v / v / v), flow rate 1.0 mL / min, detector using radioactive detector and UV detector for simultaneous detection. Verification results: [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CCT-d 9 (Compound [ 18 The retention time of the radioactive detector (10.5 min) was similar to that of the corresponding non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative FP-CCT-d 9 The retention time of (compound 6) (UV detector) (10.5min) is consistent with ( Figure 2This verifies [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CCT-d 9 (Compound [ 18 F]6) structure.

[0105] Example 3-1: A non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative

[0106] This example provides a non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative FP-CIT-d 9 The non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative FP-CIT-d 9 Has the following structure:

[0107]

[0108] Example 4-1: A method for preparing non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives

[0109] This example provides the non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative FP-CIT-d 9 The preparation method comprises the following steps (synthetic route see Figure 1 ):

[0110] 1. 2β-deuterated methyl ester tropane derivative β-CT-d 3 Preparation

[0111] Dehydroecgonine deuterated methyl ester (compound 2, 2.0 g, 11 mmol) was dissolved in dichloromethane (CH 2 Cl 2 , 20 mL) and then in N 2 The mixture was cooled to -40°C in a low temperature reaction tank under protection, and then an ether solution (22 mL) containing phenylmagnesium bromide (1.0 M, 22 mmol) was slowly added dropwise while stirring (150 rpm) to obtain a mixed solution; the mixed solution was stirred and reacted at -40°C for 3.5 hours, first cooled to -78°C, and then trifluoroacetic acid (1.6 mL) was added to CH 2 Cl 2 (10mL) solution, and then stirred for 10 minutes to obtain a reaction solution; after the reaction solution was restored to 0°C, the pH was adjusted to 1 with 37% (w / v, g / 100mL) concentrated hydrochloric acid, and then allowed to stand for stratification, the organic phase was separated, and the aqueous phase was taken; the aqueous phase was washed with dichloromethane (CH 2 Cl 2, 20mL) was washed once, and then the pH was adjusted to 10 with concentrated ammonia in an ice water bath, and then the base was extracted three times with acetic acid (3×20mL), and the organic phases were combined; the organic phases were washed with anhydrous Na 2 SO 4 After drying, the solvent was evaporated and then purified by silica gel column chromatography to obtain 2β-deuterated methyl ester tropane derivative β-CT-d 3 (Compound 7); wherein the mobile phase used for silica gel chromatography is n-hexane / ethyl ether / triethylamine = 1 / 1 / 0.01 (v / v / v);

[0112] The 2β-deuterated methyl ester tropane derivative β-CT-d 3 Has the following structure:

[0113]

[0114] The prepared β-CT-d 3 It is a white solid with a mass of 1.11 g and a yield of 74%.

[0115] The prepared βCT-d 3 The hydrogen spectrum and mass spectrum are: 1 HNMR (400MHz, CDCl 3 )δ7.29(d,J=2.2Hz,4H),7.17(m,1H),3.59(dd,J=7.2,3.1Hz,1H),3.40(m,J=6.7,3.2Hz,1H),3.04(m,J=12.8,5.1Hz,1 H),2.94(t,J=4.3Hz,1H),2.63(t,J=12.6,3.0Hz,1H),2.30–2.09(m,5H),1.74(m,2H),1.64(m,1H).MS(ESI):m / z[M+H] + Theoretical value C 16 H 18 D 3 NO 2 + :263.18; Experimental value:263.73.

[0116] 2. 2β-deuterated methyl ester tropane derivative β-CIT-d 3 Preparation

[0117] 2β-deuterated methyl ester tropane derivative β-CT-d 3 (Compound 7, 2.0 g, 11 mmol) was dissolved in dichloromethane (CH 2 Cl 2, 20 mL), acetic acid (0.5 mL), acetic anhydride (50 μL), elemental iodine (139 mg, 0.55 mmol) and silver trifluoroacetate (CF 3 COOAg, 300.7 mg, 1.17 mmol) to obtain a mixed solution; the mixed solution was placed in a dark place, stirred (150 rpm) at 28°C for 16 hours to obtain a suspension; the suspension was filtered to remove the precipitate, and the filtrate was taken; the filtrate was adjusted to pH 8 with concentrated ammonia water, and then washed three times with saturated NaCl solution (3×20 mL), and then the water phase was separated to take the organic phase; the organic phase was concentrated under reduced pressure, first separated by silica gel column chromatography, and then purified by semi-preparative high performance liquid chromatography (HPLC), and the product β-CIT-d was collected. 3 The mobile phase is firstly distilled under reduced pressure to remove the solvent, and then dried under vacuum to obtain 2β-deuterated methyl ester tropane derivative β-CIT-d 3 (Compound 8); wherein, the mobile phase used for silica gel column chromatography was: n-hexane / ethyl ether / triethylamine = 1 / 1 / 0.01 (v / v / v); the conditions for HPLC purification were: using a C18 reverse phase column, the mobile phase was methanol / water / triethylamine = 75 / 25 / 0.1 (v / v / v), the flow rate was 4.0 mL / min, the detector used was a UV detector, and the detection wavelength was 220 nm.

[0118] 2β-Deuterated methyl ester tropane derivative β-CIT-d 3 Has the following structure:

[0119]

[0120] The prepared β-CIT-d 3 It is a light yellow solid with a mass of 54 mg and a yield of 54%.

[0121] The prepared β-CIT-d 3 The hydrogen spectrum and mass spectrum are: 1 H NMR (400MHz, Chloroform-d) δ7.65-7.54(m,2H),7.02(m,J=8.5,2.8Hz,2H),3.58(m,J=7.1,3.2Hz,1H),3.39(m,J=6.7,3.2Hz,1 H),2.95(m,J=12.7,5.1Hz,1H),2.90-2.85(m,1H),2.60-2.52(m,1H),2.27-2.06(m,5H),1.80-1.56(m,3H).MS(ESI):m / z[M+H] + Theoretical value C 16 H 17 D 3 INO2 + :389.07; Measured value:389.34.

[0122] 3. Demethyl-2β-deuterated methyl ester tropane derivative nor-β-CIT-d 3 Preparation

[0123] 2β-deuterated methyl ester tropane derivative β-CIT-d 3 (Compound 8, 500.0 mg, 1.29 mmol) was added to 1-chloroethanol chloroformate (ACE-Cl, 3.5 mL, 5.0 g), and the mixture was heated at 110°C and stirred (150 rpm) for 2 hours to obtain a reaction solution A; the reaction solution A was distilled under reduced pressure to remove excess ACE-Cl to obtain a residue A; methanol (25 mL) was added to the residue A, and the mixture was heated at 80°C and stirred for 1 hour to obtain a reaction solution B; methanol was distilled under reduced pressure to remove methanol from the reaction solution B to obtain a residue B; dichloromethane (25 mL) was added to the residue B, and the residue was washed twice (2×20 mL) with a 10% (w / v, g / 100 mL) NaOH solution, and then the solvent was evaporated and purified by silica gel column chromatography to obtain a demethylated 2β-deuterated methyl ester tropane derivative nor-β-CIT-d 3 (Compound 9); wherein the mobile phase used for silica gel chromatography was diethyl ether / triethylamine = 95 / 5 (v / v).

[0124] The demethyl-2β-deuterated methyl ester tropane derivative nor-β-CIT-d 3 Has the following structure:

[0125]

[0126] The prepared nor-β-CIT-d 3 It is a light yellow solid with a mass of 280 mg and a yield of 56%.

[0127] The prepared β-CCT-d 3 The hydrogen spectrum and mass spectrum are: 1 H NMR (400 MHz, CDCl 3 )δ7.62(s,2H),7.05-6.82(m,2H),3.75(m,2H),3.19(m,J=12.9,5.4Hz,2H),2.74(d,J=3.7Hz ,1H),2.38(dd,J=13.0,3.0Hz,1H),2.21-1.96(m,2H),1.82-1.58(m,3H).MS(ESI):m / z[M+H] + Theoretical value C 15 H15 D 3 INO 2 + :375.06; measured value:375.33.

[0128] 4. Non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative FP-CIT-d 9 Preparation

[0129] The demethylated 2β-deuterated methyl ester tropane derivative nor-β-CIT-d 3 (Compound 9, 60.0 mg, 0.16 mmol), FCD 2 CD 2 CD 2 OTs (compound 5, 50.0 mg, 0.21 mmol) and triethylamine (Et 3 N, 0.5 mL) was dissolved in toluene (10 mL), and the mixture was heated at 115° C. for 4 hours to obtain a reaction solution. The reaction solution was decompressed to remove toluene, and then purified by silica gel column chromatography. During purification, the mobile phase was first eluted with n-hexane / ethyl acetate = 4 / 1 (v / v) to remove unreacted compound 5, and then the mobile phase was eluted with n-hexane / ether / triethylamine = 1 / 1 / 0.01 (v / v / v) to collect the product FP-CIT-d 9 The eluent was evaporated to remove the mobile phase and then dried in vacuo to obtain a non-radioactive N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative FP-CIT-d 9 (Compound 10).

[0130] Prepared FP-CIT-d 9 It is a white solid with a mass of 26 mg and a yield of 43%.

[0131] Prepared FP-CCT-d 9 The hydrogen spectrum and mass spectrum are: 1 H NMR (600 MHz, CDCl 3 )δ7.51(d,J=7.9Hz,2H),6.93(d,J=8.2Hz,2H),3.60(t,J=5.1Hz,1H),3.31(d,J=6.0Hz,1H),2.91-2 .78(m,2H),2.50-2.34(m,1H),2.02(m,1H),1.98-1.91(m,1H),1.66-1.55(m,3H).MS(ESI):m / z[M+H] + Theoretical value C 18 H 14 D 9 FINO 2+ :441.13; Actual value:441.41.

[0132] Example 3-2: A [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives

[0133] This embodiment provides a [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CIT-d 9 ([ 18 F]10), said [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CIT-d 9 ([ 18 F]10) has the following structure:

[0134]

[0135] Example 4-2: A preparation method 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives

[0136] This embodiment provides [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CIT-d 9 The preparation method comprises the following steps (synthetic route see Figure 1 ):

[0137] Produced by cyclotron 18 F, transported by nitrogen flow 18 F, so that 18 F was adsorbed on a SepPak QMA column (purchased from Waters, USA). After adsorption, 1.0 mL of eluent (the eluent consisted of 15 mg K dissolved in 0.8 mL acetonitrile) was used to wash the column. 2.2.2 and 3.0 mg K dissolved in 0.2 mL water 2 CO 3 Composition) rinse and dissolve 18 F in the reaction tube; after elution, heat the liquid in the reaction tube to 105°C, and blow dry the liquid in the reaction tube with a nitrogen stream at 105°C; after drying, stop heating and cool to <60°C; after cooling, add anhydrous CH 3CN (1 mL), continue to blow dry the liquid in the reaction tube with a nitrogen stream at 105 ° C; after drying, stop heating and cool to < 60 ° C, add 0.50 mL of anhydrous CH 3 TsOCD of CN 2 CD 2 CD 2 OTs (compound 5, 10.0 mg), heated at 90°C for 15 min; after the reaction (the reaction is completed here, compound [ 18 F]5, 18 FCD 2 CD 2 CD 2 OTs), stop heating and cool to <50°C, add demethyl-2β-deuterated methyl ester tropane derivative nor-β-CIT-d dissolved in N,N-dimethylformamide (DMF, 0.5 mL) to the reaction tube. 3 (Compound 9, 8.0 mg), heated at 135°C for 25 min; after the reaction, stop heating and cool to <50°C, add 1.0 mL of high performance liquid chromatography (HPLC) mobile phase to the reaction tube to obtain a mixed solution; transfer the mixed solution to an HPLC injection loop and purify by HPLC to obtain a mixture containing [ 18 F]FP-CIT-d 9 The mobile phase will contain [ 18 F]FP-CIT-d 9 The mobile phase was diluted with 30 mL of water to obtain a diluent; the diluent was first passed through a SepPak C18 column (at this time [ 18 F]FP-CIT-d 9 was adsorbed on this column), and then the column was rinsed with 10 mL of water to remove possible water-soluble impurities, and then eluted with 2 mL of EtOH. 18 F]FP-CIT-d 9 , and collected in a cillin bottle, and obtained [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CIT-d 9 (Compound [ 18 F]10) (yield: 22%. The pure product was diluted with saline to the required concentration before use); wherein, the conditions for HPLC purification were: using a Phenomenex Luna C18 column (10 mm × 250 mm, 5 μm), and the mobile phase was CH 3 CN / H 2 O / E 3 N=65 / 35 / 0.1 (v / v / v), flow rate was 4.0 mL / min, and detection was performed using a radioactivity detector.

[0138] High performance liquid chromatography (HPLC) was used to analyze the 18 F]FP-CIT-d 9 The structure of is verified, and the verification process is as follows: 18 F]FP-CIT-d 9 (Compound [ 18 F]10) and FP-CIT-d 9 (Compound 10) was mixed to a radioactive compound concentration of 37 MBq / mL and a non-radioactive compound concentration of 1.0 mg / mL to obtain a mixed solution; 20 μL of the mixed solution was injected into a high performance liquid chromatography (HPLC) for HPLC analysis; wherein the HPLC analysis conditions were: using a Gemini NX-C18 column (5 mm × 150 mm, 3 μm), and the mobile phase was CH 3 OH / H 2 O / TFA = 40:60:0.1 (v / v / v), flow rate 1.0 mL / min, detector using radioactive detector and UV detector for simultaneous detection. Verification results: [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CIT-d 9 (Compound [ 18 The retention time of the radioactive detector (12.6 min) was similar to that of the corresponding non-radioactive N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative] FP-CIT-d 9 The retention time of (compound 10) (UV detector) (12.6 min) is consistent with ( Figure 3 This verifies [ 18 F] N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives [ 18 F]FP-CCT-d 9 (Compound [ 18 F]6) structure.

[0139] Experimental Example 1: 18 Stability Analysis Experiment of [F] N-deuterated Fluoroalkyl-2β-deuterated Methoxy-Tropane Derivatives

[0140] This experimental example provides [ 18 F] Stability analysis experiment of N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives, the specific process is as follows:

[0141] Will[ 18 F]FP-CIT-d 9 ([ 18F]10, ~37MBq) was added to 1.0mL of phosphate buffered saline (PBS, pH7.4) or 1.0mL of fetal bovine serum (FBS) to obtain a mixed solution; the mixed solution was incubated at 37°C for 6 hours. During the incubation process, 10μL of samples were taken at 1, 2, 4, and 6 hours, respectively, and injected into the HPLC injector for HPLC analysis, and the radiochemical purity at each time point was calculated. The conditions for HPLC analysis were: the chromatographic column was a Gemini NX-C18 chromatographic column (5mm×150mm, 3μm), and the mobile phase was CH 3 OH / H 2 O / TFA = 40:60:0.1 (v / v / v), flow rate 1.0 mL / min, detector used radioactive detector. 18 F]FP-CCT-d 9 ([ 18 F]6) in vitro stability test.

[0142] The results showed that [ 18 F]FP-CIT-d 9 ([ 18 F]10) and [ 18 F]FP-CCT-d 9 ([ 18 F]6) The radiochemical purity at all time points within 6 hours of incubation in PBS and FBS was greater than 98%. This result shows that [ 18 F]FP-CIT-d 9 and[ 18 F]FP-CCT-d 9 The in vitro stability is good and can meet the requirements of practical applications.

[0143] Experimental Example 2: 18 MicroPET Imaging Experiment of [F] N-deuterated Fluoroalkyl-2β-deuterated Methoxy-Tropane Derivatives

[0144] This experimental example provides [ 18 The microPET imaging experiment of N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivatives is as follows:

[0145] The experiment was divided into three groups: 18 F]FP-CIT-d 9 ([ 18 F]10) group, [ 18 F]FP-CCT-d 9 ([ 18 F]6) Group and [ 18 F]FP-CIT-d 6 Group([ 18F]FP-CIT-d 6 Recorded in the patent application with publication number CN116925067A).

[0146] [ 18 F] Group 10: Normal rats (SD rats, purchased from Changzhou Cavens Laboratory Animal Co., Ltd.) were placed in an anesthesia box, anesthetized with 3% (v / v) isoflurane, placed on a microPET imaging bed, and maintained in anesthesia with 2.5% (v / v) isoflurane. 11.1 MBq / 0.5 mL [ 18 F]FP-CIT-d 9 ([ 18 F]10), starting from the injection time, collect microPET brain images scanned within 0 to 120 minutes, and then use the region of interest (ROI) technology to obtain the time-radioactivity curves of the striatum and cerebellum respectively. The relative size of the radioactivity data represents the drug concentration. The higher the concentration, the more conducive to PET imaging. Use the analysis software that comes with the instrument to analyze the time-radioactivity curves (TAC) of the brain regions of interest (striatum ST and cerebellum CB) within 120 minutes. The experimental results are shown in Figure 4 .

[0147] [ 18 F]6 group: the experimental process is the same as [ 18 F]FP-CIT-d 9 group, the drugs injected were [ 18 F]FP-CCT-d 9 ([ 18 F]6), the injection dose is ~11.1MBq / 0.5mL. The experimental results are shown in Figure 4 .

[0148] [ 18 F]FP-CIT-d 6 Group: The experimental process is the same as [ 18 F]FP-CIT-d 9 group, the drugs injected were [ 18 F]FP-CIT-d 6 The injection dose is ~~11.1MBq / 0.5mL. The experimental results are shown in Figure 4 .

[0149] like Figure 4 As shown, 18 F] The striatum, the target area of ​​DAT in the brain of group 10 rats, was clearly visualized and bilaterally symmetrical (as shown by the arrows in the figure), while there was no obvious concentration of radioactive signals in other brain areas such as the cortex and cerebellum; [ 18The striatum of rats in group F6 was also clearly visualized, but the background area was clearly visualized, especially the nasal cavity and skull, where there was a high concentration of radioactivity, indicating that [ 18 The nonspecific uptake of F]10 was lower than that of 18 F]6,[ 18 F]10 is more conducive to in vivo PET imaging; [ 18 F]FP-CIT-d 6 The striatum of group rats was also clearly visualized, but compared with [ 18 F]10 group, the non-specific uptake in the background area is high, and the image quality is inferior to [ 18 F]10. 18 F]6 and [ 18 F]FP-CIT-d 6 In comparison, the striatum development effect is similar.

[0150] Further TAC analysis results are as follows Figure 5 a~ Figure 5 As shown in f, [ 18 The radioactivity uptake of F10 in the striatum was higher than that of [ 18 F]6, and the radioactivity concentrations in the cerebellum of the two were similar ( Figure 5 a~ Figure 5 c) in the above equation, therefore, [ 18 The target / substance ratio (ST / CB) of F]10 was higher than that of [ 18 F]6( Figure 5 d); Moreover, [ 18 The target / substance ratio (ST / CB) of F]10 was higher than that of [ 18 F]FP-CIT-d 6 ( Figure 5 e), the result shows that [ 18 The microPET imaging effect of F]10 is better than that of 18 F]6 and [ 18 F]FP-CIT-d 6 ;[ 18 F]6 and [ 18 F]FP-CIT-d 6 In comparison, the target / binding ratio (ST / CB) is close to ( Figure 5 f), but because [ 18 The non-specific uptake of F]6 (e.g., cerebellum) is lower than that of 18 F]FP-CIT-d 6 , the ST / CB ratio has a relatively small error range, compared with [ 18 F]FP-CIT-d6 It is more conducive to the quantitative analysis of PET images.

[0151] In summary, the microPET imaging results show that compared with the existing technology [ 18 F]FP-CIT-d 6 compared to,[ 18 F]10 and [ 18 F]6 is more conducive to DAT PET imaging in vivo, while [ 18 F]10 is optimal.

[0152] Experimental Example 3: 18 In vivo DAT binding specificity experiments of [F] N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivatives

[0153] This experimental example provides [ 18 The in vivo DAT binding specificity experiment of [F] N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivatives is as follows:

[0154] The experiment was divided into three groups: normal group, PD animal model group and CFT blocking group.

[0155] Normal group: Normal rats (SD rats, purchased from Changzhou Cavens Laboratory Animal Co., Ltd.) were placed in an anesthesia box, pre-anesthetized with 3% (v / v) isoflurane, placed on a microPET imaging bed, and maintained in anesthesia with 2.5% (v / v) isoflurane. Then, ~11MBq / 0.5mL [ 18 F]FP-CIT-d 9 From the moment of injection, brain images were collected within 0 to 120 minutes. The experimental results are shown in Figure 6 .

[0156] CFT blocking group: DAT blocking test uses a selected specific ligand (CFT) to pair the tracer [ 18 F]FP-CIT-d 9 The microPET imaging process was the same as that of the normal group, but the drug injected was 300 μCi [ 18 F]FP-CIT-d 9 and 1.0mg / kg CFT mixture, collected the brain imaging images obtained by scanning, the experimental results are shown in Figure 6 .

[0157] PD animal model group: First, 6-OHDA unilateral PD model rats were prepared according to the method of the literature "Tang J, et al. Nucl Med Biol, 2020, 90-91: 1-9", and then microPET imaging analysis was performed on this PD animal model. The microPET imaging process was the same as that of the normal group. The experimental results are shown in Figure 6 .

[0158] like Figure 6 As shown in a, [ 18 F] The striatum, the target area of ​​DAT in the brain of group 10 rats, was clearly visualized and bilaterally symmetrical (as shown by the arrows in the figure); after blocking with the DAT inhibitor CFT, the striatum area was not visualized ([ 18 F]10+CFT); TAC curve results show that ( Figure 6 In b), after CFT blockade, the radioactivity concentration of ST in rats decreased rapidly and approached the level of cerebellum after 30 minutes; while the radioactivity signal of cerebellum did not change significantly before and after blockade. The above results show that [ 18 F]10 has specific binding to DAT in the brain; the DA neurons in the left striatum (called the "affected side") of unilateral PD model rats were damaged during the modeling process, while the right side (called the "healthy side") was not damaged. Figure 6 As shown in a, the radioactive uptake in the striatum of the affected side of the unilateral PD model rat is low and basically not visible (semi-PD), while the radioactive uptake in the healthy side is still high and clearly visible; the quantitative analysis results show that ( Figure 6 In the figure (c), the radioactivity concentration on the affected side was much lower than that on the healthy side, with a decrease of 62%, and the difference was statistically significant (P<0.001). 18 F]FP-CIT-d 9 ([ 18 F]10) has specific binding to DAT and also shows that [ 18 F]FP-CIT-d 9 [ 18 F]10 can differentiate normal and PD by imaging, suggesting that [ 18 F]FP-CIT-d 9 ([ 18 F]10) It has clinical application value for DAT-related diseases such as Parkinson's disease.

[0159] Experimental Example 4: 18 Experimental study on brain distribution of F]N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivatives

[0160] This experimental example provides [ 18 The brain distribution experiment of N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivatives is as follows:

[0161] The experimental rats (SD rats, purchased from Changzhou Cavens Experimental Animal Co., Ltd.) were divided into 5 groups, 5 rats in each group, and injected with [ 18 The mice were killed by cervical dislocation at 5, 15, 30, 60 and 120 min after administration, and the brain tissues were quickly removed, and the striatum (ST), cerebellum (CB), hippocampus (HP), cortex (CX) and other tissues were separated. The wet weights were measured and the tissues were placed in γ counting tubes. The radioactivity counts of each brain tissue were measured with a γ counter, and the radioactivity concentration value ID% / g of each brain tissue was calculated based on the wet weight and radioactivity counts of each brain tissue.

[0162] The radioactivity count results are as follows Figure 7 As shown in a, 5 minutes after administration, the radioactivity concentration in each brain region was the highest, among which the striatum had the highest radioactivity concentration, followed by the hippocampus, while the background regions of cortex and cerebellum, which contained almost no DAT, had the lowest radioactivity concentration; 5 minutes after administration, as time went on, the radioactivity concentration in each brain region continued to decrease. The trend of the target / binding ratio (ST / CB) in the target region striatum and the background region cerebellum is shown in Figure 1. Figure 7 As shown in b, at 60 minutes after administration, the ST / CB ratio reached a maximum value of 6.80±1.19 and remained at 5.89±0.58 at 120 minutes. This result is consistent with the microPET imaging results, indicating that the [ 18 F]FP-CIT-d 9 It can enter the brain tissue and has a good affinity for DAT in the brain, resulting in high radioactivity concentration in the target area (striatum) where DAT is densely distributed.

[0163] Experimental Example 5: 18 In vivo Metabolism Analysis of F]N-deuterated Fluoroalkyl-2β-deuterated Methoxy-Tropane Derivatives

[0164] This experimental example provides [ 18 The in vivo metabolic analysis experiment of N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivatives is as follows:

[0165] Normal rats (SD rats, purchased from Changzhou Cavens Experimental Animal Co., Ltd.) were anesthetized and injected via the tail vein with [ 18 F]FP-CIT-d 9 ([ 18 F]10) or [ 18 F]FP-CIT-d 6The injection dose was ~5mCi (0.5mL). At 5, 30, and 60 minutes after injection, normal rats were killed by cervical dislocation, and 0.200mL of blood samples were taken. Then the whole brain was taken to separate the striatum (ST) and cerebellum (CB) tissues. The blood samples were centrifuged at 4°C and 12000g in a centrifuge, and the supernatant (plasma) was taken for high-performance liquid chromatography analysis; the chromatographic conditions were: the chromatographic column was a 5μm C18 column, and the mobile phase was CH 3 OH / H 2 O / TFA = 40:60:0.1 (v / v / v), flow rate 1.0 mL / min, detector is radioactive detector. Record chromatogram, calculate plasma [ 18 F]FP-CIT-d 9 ([ 18 F]10) or [ 18 F]FP-CIT-d 6 The results are shown in Table 1. The striatum and cerebellum samples were placed in EP tubes containing 0.2 mL of acetonitrile, and after homogenization, they were centrifuged at 4°C and 12,000 g for 2 minutes, and the supernatant was collected. 20 μL of the supernatant was analyzed on the above-mentioned high-performance liquid chromatograph, and the chromatogram was recorded. Then, the percentage of ST and CB was calculated based on the chromatogram. 18 F]FP-CIT-d 9 ([ 18 F]10) or [ 18 F]FP-CIT-d 6 The calculation results are shown in Table 1.

[0166] As shown in Table 1, after injection [ 18 F]FP-CIT-d 9 5, 30, and 60 minutes after treatment, the original drug proportions in the rat plasma, striatum, and cerebellum were higher than [ 18 F]FP-CIT-d 6 , the results show that [ 18 F]FP-CIT-d 6 The methyl ester group at the 2β-position in the molecule is replaced by a deuterated methyl ester group [ 18 F]FP-CIT-d 9 ([ 18 F]10), which can further improve the metabolic stability in vivo and is more conducive to the DAT tracing imaging analysis in vivo.

[0167] Table 1 Rat injection 18 F]10 or [ 18 F]FP-CIT-d 6After administration, the percentage of original drug in striatum (ST), cerebellum (CB) and plasma (%, mean ± SD, n = 3)

[0168]

[0169]

[0170] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. An N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative, characterized in that: The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the structure shown below: in: n is an integer from 1 to 3; X is fluorine or an isotope of fluorine; R is fluorine, chlorine, methyl, hydrogen, iodine, bromine or methoxy.

2. The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative according to claim 1, characterized in that: The X is 18 F.

3. The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative according to claim 1, characterized in that: The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the structure shown below:

4. The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative according to claim 1 or 2, characterized in that: The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the structure shown below:

5. The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative according to claim 1, characterized in that: The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the structure shown below:

6. The N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative according to claim 1 or 2, characterized in that: The N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative has the structure shown below:

7. A deuterated methyl ester of anhydroecgonine, characterized in that: The deuterated methyl ester of anhydroecgonine has the structure shown below:

8. A 2β-deuterated methyl ester tropane derivative, characterized in that: The 2β-deuterated methyl ester tropane derivative has the structure shown below:

9. A 2β-deuterated methyl ester tropane derivative, characterized in that: The 2β-deuterated methylester tropane derivative has the structure shown below: Alternatively, the 2β-deuterated methylester tropane derivative has the structure shown below:

10. A demethylated 2β-deuterated methyl ester tropane derivative, characterized in that: The demethylated-2β-deuterated methyl ester tropane derivative has the structure shown below: Alternatively, the demethylated 2β-deuterated methyl ester tropane derivative has the structure shown below:

11. A method for preparing the N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative according to claim 3, characterized in that: The method comprises: dissolving a demethylated-2β-deuterated methylester tropane derivative nor-CIT-d3, FCD2CD2CD2OTs and triethylamine in toluene to obtain a mixed solution; heating the mixed solution for reaction, and after the reaction is completed, first removing the solvent and then purifying to obtain the N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative according to claim 3; The nor-CIT-d3 has the following structure:

12. A method for preparing the N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative according to claim 5, characterized in that: The method comprises: demethylating-2β-deuterated methyl ester tropane derivative nor-CCT-d3, FCD2CD2CD2OTs and triethylamine to obtain a mixed solution; heating the mixed solution for reaction, and after the reaction is completed, first removing the solvent and then purifying to obtain the N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative according to claim 5; The nor-CCT-d3 has the structure shown below:

13. Use of the N-deuterated fluoroalkyl-2β-deuterated methyl ester tropane derivative according to any one of claims 1 to 6, the dehydroecgonine deuterated methyl ester according to claim 7, the 2β-deuterated methyl ester tropane derivative according to claim 8, the 2β-deuterated methyl ester tropane derivative according to claim 9, or the demethyl-2β-deuterated methyl ester tropane derivative according to claim 10 in the preparation of a dopamine transporter imaging agent.

14. An imaging agent targeting dopamine transporter, characterized in that: The developer contains the N-deuterated fluoroalkyl-2β-deuterated methylester tropane derivative according to any one of claims 1 to 6.

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