CN116925067A - [ solution ] 18 F]Deuterated fluoropropyl tropane derivative and application thereof - Google Patents

[ solution ] 18 F]Deuterated fluoropropyl tropane derivative and application thereof Download PDF

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CN116925067A
CN116925067A CN202310334441.4A CN202310334441A CN116925067A CN 116925067 A CN116925067 A CN 116925067A CN 202310334441 A CN202310334441 A CN 202310334441A CN 116925067 A CN116925067 A CN 116925067A
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deuterated
fluoropropyl
tropane
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陈正平
胡潜岳
李庆明
刘春仪
唐婕
方毅
刘洁
齐美桧
谢敏浩
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Jiangsu Institute of Nuclear Medicine
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Abstract

The invention relates to a [ 18 F]Deuterated fluoropropyl tropane derivative and application thereof belong to the technical field of chemistry. The invention provides a [ 18 F]Deuterated fluoropropyl tropane derivative 18 F]Deuterated fluoropropyltropine derivatives can specifically bind to dopamine transporter and this [ 18 F]The deuterated fluoropropyl tropane derivative has the advantages of high affinity to the dopamine transporter, good in vivo stability, low metabolic degradation speed and high PET imaging target/background ratio, and has extremely high application prospect in the PET imaging of the dopamine transporter.

Description

[ solution ] 18 F]Deuterated fluoropropyl tropane derivative and application thereof
Technical Field
The invention relates to a [ 18 F]Deuterated fluoropropyl tropane derivative and application thereof belong to the technical field of chemistry.
Background
The dopamine transporter of the central nervous system (Dopamine transporter, DAT) is a protein located in the presynaptic membrane of Dopamine (DA) neurons, which functions to transport the DA of the synaptic cleft to the presynaptic neurons for reuse (see literature: ciliax B, et al J. Neurosci.1995, 15:1714-1723). DAT can on the one hand prevent further oxidation of DA in the synaptic cleft and on the other hand regulate the DA concentration in the synaptic cleft and thus the function of the DA transmitter system (see: poliis m.nat. Rev. Neurol.2014, 10:708-722).
Studies have shown that DAT function and density changes are associated with a variety of neuropsychiatric disorders, such as Parkinson's disease (see: nurmi E, et al, annals of neurology 2000,47:804-808;Innis RB,et al.Proceedings of the National Academy of Sciences of the United States of America 1993,90:11965-11969), schizophrenia (see: laakso A, et al, schizophrenia research 2001, 52:115-120), depression (see: meyer JH, et al, neuroreport 2001, 12:4121-4125), and some other neurological disorders (see: malison RT, et al, the American journal of psychiatry 1995, 152:1359-136). Therefore, DAT is used as a biomarker, can provide information on diagnosis, treatment and the like for various related diseases of the nervous system, and is an important target point for researching the related diseases of the nervous system.
By developing a proper DAT-targeted radiopharmaceutical and combining with the clinically common positron emission computed tomography (PET) or Single Photon Emission Computed Tomography (SPECT) technology, the method can realize the analysis of the DAT imaging in the brain, thereby being beneficial to diagnosis, disease course analysis, curative effect monitoring and the like of related diseases of the nervous system. Compared with SPECT, the PET technology has advantages in the development of DAT due to higher resolution, higher sensitivity and better quantitative analysis performance. Therefore, the in vivo distribution and functional imaging of DAT by using the PET technology has important clinical and research values for diagnosis and treatment of diseases related to the nervous system.
The application of PET technology to DAT imaging requires a radionuclide-labeled drug targeting DAT with excellent performance. Clinically, in order to realize PET imaging of DAT, researchers at home and abroad developed a series of radioisotopes (mainly 11 C and C 18 F) A labeled DAT-targeted radiopharmaceutical. Wherein, the liquid crystal display device comprises a liquid crystal display device, 18 f factor has a ratio of 11 C better nuclide properties (proper half-life, better PET resolution, etc.), which are most widely used and are also the most commonly used nuclides for PET imaging. At present, the DAT PET imaging research used at home and abroad is the most widely used [ 18 F]The labeling agent is an N-fluoroalkyl tropane derivative such as: [ 18 F]FP-CIT (see: yoo HS, et al Eur J Nucl Med Mol Imaging,2018, 45:1585-1595), [ 18 F]PE2I (see DelvaA, et al Eur J Nucl Med Mol Imaging,2020, 47:1913-1926.), [ 18 F]FECNT (see, nye JA, et al Nucl Med Biol,2014, 41:217-22) [ 18 F]LBT999 (see: maria-Joao Ribeiro, et al front neurol 2020,21 (11): 754), and the like.
However, these N-fluoroalkyl tropane derivatives still have some problems, mainly in the [ N-position ] in their molecular structure 18 F]Alkyl groups are subject to C-N bond cleavage under the action of metabolic enzymes such as cytochrome P450 in vivo to generate a polypeptide containing 18 F (see: guengrich FP. Methods in enzymology 2017,596:217-238;Peyronneau MA,et al.Nucl.Med.Biol.2012,39:347-359;Shetty HU,et al.European Journal of Nuclear Medicine and Molecular Imaging 2007,34:667-678), for example, 18 f-labeled tropane derivatives [ 18 F]FECNT dealkylation occurs in vivo at the N-position to produce three metabolites[ 18 F]Fluoroacetaldehyde, [ 18 F]Fluoroacetic acid and [ 18 F]Fluoroethanol (see Zoghbi SS, et al J.Nucl. Med.2006, 47:520-527), while not specific for DAT, all three metabolites cross the blood brain barrier with a relatively high distribution in the reference areas of PET brain imaging (cortex, cerebellum), thus affecting the quantitative analysis of PET imaging (target/non-target ratio), and this phenomenon was observed in both animals and humans (see Zoghbi SS, et al J.Nucl. Med.2006, 47:520-527); 18 f-labeled tropane derivatives [ 18 F]PE2I and [ 18 F]The major in vivo metabolite of LBT999 is also the N-position dealkylation product, which also adversely affects quantitative analysis of PET imaging (see, peyronneau MA, et al Nucl. Med. Biol.2012,39:347-359;Amini N,et al.Anal Bioanal Chem 2013,405:1303-1310); 18 f-labeled tropane derivatives [ 18 F]FP-CIT has a structure similar to that of [ although it has a good DAT affinity, excellent DAT selectivity, good in vivo kinetics, and a suitable half-life 18 F]FECNT is similar in vivo metabolic characteristics and N-site dealkylation under the action of metabolic enzymes such as cytochrome P450 in vivo to give a composition containing 18 N-position dealkylation metabolite of F (presumably likely to be [ [ 18 F]Fluoropropionaldehyde [ sic ] 18 F]Fluoropropionic acid [ sic ] 18 F]Fluoropropanol) to adversely affect the quantitative analysis result of PET imaging (see literature: shin KH, et al Nucl Med Mol Imaging 2012, 46:27-33). Therefore, there is a need to develop DAT PET imaging drugs with better in vivo stability and slower metabolic rate to provide better drug tools for accurate PET imaging of DAT clinically.
Disclosure of Invention
In order to solve the above problems, the present invention provides 18 F]A deuterated fluoropropyl tropane derivative having a structure as shown below:
wherein:
R 1 hydrogen, fluorine, chlorine, iodine, bromine, methyl, ethyl, methoxy or ethoxy;
R 2 is methyl or ethyl.
In one embodiment of the present invention, the ] 18 F]The deuterated fluoropropyl tropane derivative has the following structure:
in one embodiment of the present invention, the ] 18 F]The deuterated fluoropropyl tropane derivative has the following structure:
in one embodiment of the present invention, the ] 18 F]The control compound of the deuterated fluoropropyl tropane derivative is a non-radioactive deuterated fluoropropyl tropane derivative; the non-radioactive deuterated fluoropropyl tropane derivative has the following structure:
wherein:
R 1 hydrogen, fluorine, chlorine, iodine, bromine, methyl, ethyl, methoxy or ethoxy;
R 2 is methyl or ethyl.
In one embodiment of the present invention, the preparation method of the non-radioactive deuterated fluoropropyl tropane derivative comprises the following steps: compound TsOCD 2 CD 2 CD 2 OTs and tetrabutylammonium fluoride react in acetonitrile to obtain FCD 2 CD 2 CD 2 OTs; FCD 2 CD 2 CD 2 OTs and 2 beta-methyl ester-3 beta-para-substituted phenyl demethyl tropane under alkaline conditionAnd (3) carrying out the reaction to obtain the non-radioactive deuterated fluoropropyl tropane derivative.
In one embodiment of the invention, the FCD 2 CD 2 CD 2 OTs have the following structure:
the invention also provides a method for preparing the above [ 18 F]A method of deuterated fluoropropyl tropane derivatives, said method comprising: firstly, K is contained 222 And K 2 CO 3 CH of (2) 3 CN/H 2 O solution dissolution 18 F, in the reaction tube, then removing water from the liquid in the reaction tube, after the water removal is finished, adding TsOCD 2 CD 2 CD 2 Adding acetonitrile solution of OTs into a reaction tube to react to obtain a compound 18 FCD 2 CD 2 CD 2 Solutions of OTs; the compound is firstly added 18 FCD 2 CD 2 CD 2 The OTs solution is cooled and then the solution is cooled to the compound 18 FCD 2 CD 2 CD 2 Adding N, N-dimethylformamide solution containing 2 beta-methyl ester-3 beta-para-substituted phenyl demethyl tropane into OTs solution to make reaction so as to obtain the above-mentioned [ 18 F]Deuterated fluoropropyl tropane derivatives.
In one embodiment of the invention, the 2β -methyl-3β -p-substituted phenyl nortropane is 2β -methyl-3β -phenyl nortropane, 2β -methyl-3β -p-fluorophenyl nortropane, 2β -methyl-3β -p-tolyl nortropane, 2β -methyl-3β -p-iodophenyl nortropane, or 2β -methyl-3β -p-chlorophenyl nortropane.
In one embodiment of the invention, the TsOCD 2 CD 2 CD 2 OTs have the following structure:
in one embodiment of the invention, the 18 FCD 2 CD 2 CD 2 OTs have the following structure:
the invention also provides the above [ 18 F]Use of deuterated fluoropropyl tropane derivatives for the preparation of dopamine transporter imaging agents.
In one embodiment of the invention, the imaging agent is a PET imaging agent.
The invention also provides an imaging agent targeting dopamine transporter, which comprises the composition 18 F]Deuterated fluoropropyl tropane derivatives.
In one embodiment of the invention, the imaging agent is a PET imaging agent.
The technical scheme of the invention has the following advantages:
the invention provides a [ 18 F]Deuterated fluoropropyl tropane derivative 18 F]Deuterated fluoropropyltropine derivatives can specifically bind to dopamine transporter and this [ 18 F]The deuterated fluoropropyl tropane derivative has the advantages of high affinity to the dopamine transporter, good in vivo stability, low metabolic degradation speed and high PET imaging target/background ratio, and has extremely high application prospect in the PET imaging of the dopamine transporter.
Drawings
Fig. 1: synthetic routes for non-radioactive deuterated fluoropropyltrimethylene derivatives and non-radioactive fluoropropyltrimethylene compounds.
Fig. 2: [ 18 F]Synthetic route of deuterated fluoropropyl tropane derivative.
Fig. 3: FP-CIT-d 6 HPLC (ultraviolet detection) and [ 18 F]FP-CIT-d 6 HPLC (radioactivity detection) profile of (a) a sample.
Fig. 4: [ 18 F]FP-CIT-d 6 Intra-brain placement in normal and DAT blocked ratsAnd analyzing results of the autoradiography image and ST/CB data. In FIG. 4, (a) is an autoradiogram image, and (b) is the result of ST/CB data analysis.
Fig. 5: [ 18 F]FP-CIT-d 6 Sum [ 18 F]microPET imaging of FP-CIT in normal rat brain for 0-120 min. In FIG. 5, (a) is [ [ 18 F]FP-CIT-d 6 microPET brain image of normal rat for 0-30, 30-60, 60-90, 90-120 min, (b) is [ 18 F]FP-CIT is a microPET brain image of normal rats in 0-30, 30-60, 60-90, 90-120 min.
Fig. 6: [ 18 F]FP-CIT、[ 18 F]FP-CIT-d 6 Sum [ 18 F]FECNT-d 4 time-ST/CB ratio curve of brain microPET imaging at normal rats 0-120 min.
Fig. 7: results of microPET imaging and ST/CB data analysis of normal group rats, DAT blocking group and unilateral PD model rats. In FIG. 7, (a) is a microPET image, and (b) is the result of ST/CB data analysis.
Fig. 8: [ 18 F]FP-CIT-d 6 Sum [ 18 F]Ratio profile of FP-CIT for the drug substance at different time points in rat plasma, striatum and cerebellum.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The following examples do not identify specific experimental procedures or conditions, which may be followed by procedures or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Example 1: non-radioactive deuterated fluoropropyl tropane derivative
The present example provides a non-radioactive deuterated fluoropropyl tropane derivative having the structure shown below:
wherein 4a corresponds to FP-CHT-d 6 4b corresponds to FP-CFT-d 6 4c corresponds to FP-CCT-d 6 4d corresponds to FP-CMT-d 6 4e corresponds to FP-CIT-d 6 。
Example 2: method for preparing non-radioactive deuterated fluoropropyl tropane derivative
This example provides a method for preparing a non-radioactive deuterated fluoropropyl tropane derivative according to example 1, which method is (see fig. 1 for synthetic route):
reference "Zhao R, et al, nucl Med biol.2019,72-73:26-35" synthesized compound 1; compound 1 (666 mg,1.70 mmol) was dissolved in 8mL acetonitrile under the protection of nitrogen to obtain a solution; tetrabutylammonium fluoride solution (2.5 mL) is added dropwise into the solution, and then the mixture is heated at 80 ℃ for 2h for reaction, so as to obtain a reaction solution; concentrating and drying the reaction solution, and purifying by silica gel column chromatography to obtain compound FCD 2 CD 2 CD 2 OTs (200 mg, compound 2); wherein the mobile phase purified by silica gel column chromatography is n-hexane, ethyl acetate=4:1 (v/v);
reference "GuXH, et al Bioorg Med Chem Lett2001, 11:3049-3053; zheng QH, et al Nucl Med biol 1996,23:981-986; squaring, equiaxed nuclear techniques 2002,113-117 "to synthesize compounds 3 a-3 e; compounds 3a to 3e (1.0 mmol) were combined with FCD, respectively 2 CD 2 CD 2 OTs (1.0 mmol) and 0.8mL of triethylamine are dissolved in 30mL of toluene, and then reflux heating reaction is carried out for 4 hours at 115 ℃ under the protection of nitrogen, so as to obtain a reaction solution; concentrating the reaction solution under reduced pressure, and separating by silica gel column chromatography to obtain nonradioactive deuterated fluoropropyl tropane derivative 4a (FP-CHT-d) 6 )、4b(FP-CFT-d 6 )、4c(FP-CCT-d 6 )、4d(FP-CMT-d 6 ) And 4e (FP-CIT-d) 6 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the silica gel column chromatography is firstly performed with normal hexane to ethyl acetate=4:1 (v/vV.) unreacted compound 3 was removed by mobile phase separation, and then a second elution was performed using n-hexane: diethyl ether: triethylamine=1:1:0.01 (v/v/v) as mobile phase.
The prepared compound FCD 2 CD 2 CD 2 OTs is a colorless oily compound in 50% yield with mass spectrometry data MS (ESI) of: [ M+H ]] + Theoretical value of (C 7 H 7 D 6 FO 3 S) m/z 238.1, found m/z 238.1. 1 The H nuclear magnetic resonance data are: 1 H NMR(600MHz,Chloroform-d)δ：7.82-7.77(m,2H),7.36(d,J＝7.6Hz,2H),2.45(s,3H).
the resulting non-radioactive deuterated fluoropropyltrimethylene derivative 4a was a pale yellow oily compound in 43% yield and mass spectrum data MS (ESI) was: [ M+H ]] + Theoretical value of (C 18 H 19 D 6 FNO 2 ) m/z 312.22 found m/z 312.38. 1 The H nuclear magnetic resonance data are: 1 H NMR(600MHz,Chloroform-d)δ7.26(d,J＝6.3Hz,4H),7.15(td,J＝5.9,3.1Hz,1H),3.69-3.64(m,1H),3.46(s,3H),3.41-3.32(m,1H),3.02(dt,J＝12.8,5.1Hz,1H),2.97-2.89(m,1H),2.58(m,1H),2.09(m,1H),2.04-1.95(m,1H),1.77-1.61(m,3H).
the resulting non-radioactive deuterated fluoropropyltrimethylene derivative 4b was a white solid compound with a yield of 60% and mass spectrum data MS (ESI) of: [ M+H ]] + Theoretical value of (C 18 H 18 D 6 F 2 NO 2 ) m/z 330.21 found m/z 330.41. 1 The H nuclear magnetic resonance data are: 1 H NMR(600MHz,Chloroform-d)δ7.21(dd,J＝8.1,5.4Hz,2H),6.98-6.91(m,2H),3.66(dd,J＝7.5,3.2Hz,1H),3.48(s,3H),3.41-3.34(m,1H),2.98(m,1H),2.88(t,J＝3.7Hz,1H),2.55(m,1H),2.14-2.05(m,1H),2.05-1.96(m,1H),1.74(m,1H),1.64(m,2H).
the resulting non-radioactive deuterated fluoropropyltrimethylene derivative 4c was a white solid compound with a yield of 45% and mass spectrum data MS (ESI) of: [ M+H ]] + Theoretical value of (C 18 H 18 D 6 ClFNO 2 ) m/z 346.19 found m/z 346.49. 1 The H nuclear magnetic resonance data are: 1 H NMR(600MHz,Chloroform-d)δ7.24-7.17(m,3H),6.99-6.92(m,1H),3.72-3.61(m,1H),3.48(d,J＝1.6Hz,3H),3.41-3.34(m,1H),2.97(m,1H),2.89(q,J＝5.4,4.6Hz,1H),2.59-2.50(m,1H),2.14-2.05(m,1H),2.05-1.96(m,1H),1.73(m,1H),1.63(m,2H).
the resulting non-radioactive deuterated fluoropropyltrimethylene derivative 4d was a pale yellow oily compound in 40% yield and mass spectrum data MS (ESI) was: [ M+H ]] + Theoretical value of (C 19 H 21 D 6 FNO 2 ) m/z 326.24 found m/z 326.46. 1 The H nuclear magnetic resonance data are: 1 H NMR(600MHz,Chloroform-d)δ7.07(d,J＝8.0Hz,2H),7.00(d,J＝7.9Hz,2H),3.58(q,J＝2.7Hz,1H),3.41(s,3H),3.31(s,1H),2.94-2.89(m,1H),2.83(t,J＝4.1Hz,1H),2.49(td,J＝12.5,3.1Hz,1H),2.22(s,3H),2.05-1.98(m,1H),1.95-1.89(m,1H),1.67(m,1H),1.57(m,2H).
the resulting non-radioactive deuterated fluoropropyltrimethylene derivative 4e was a white solid compound with a yield of 54% and mass spectrum data MS (ESI) of: [ M+H ]] + Theoretical value of (C 18 H 18 D 6 FINO 2 ) m/z 438.12 found m/z 438.39. 1 The H nuclear magnetic resonance data are: 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J＝8.1Hz,2H),7.00(d,J＝8.1Hz,2H),3.66(d,J＝3.9Hz,1H),3.49(s,4H),3.01-2.73(m,2H),2.52(t,J＝10.9Hz,1H),2.15-1.91(m,2H),1.78-1.57(m,3H).
comparative example 1: non-radioactive fluoropropyl tropane derivative
This comparative example provides a non-radioactive fluoropropy tropane derivative having the structure shown below:
wherein 6a corresponds to FP-CHT,6b corresponds to FP-CFT,6c corresponds to FP-CCT,6d corresponds to FP-CMT, and 6e corresponds to FP-CIT.
Comparative example 2: method for preparing non-radioactive deuterated fluoropropyl tropane derivative
This comparative example provides a process for the preparation of non-radioactive deuterated fluoropropyl tropane derivatives according to comparative example 1, which process is (scheme see fig. 1):
reference "GuXH, et al Bioorg Med Chem Lett2001, 11:3049-3053; zheng QH, et al Nucl Med biol 1996,23:981-986; squaring, et al core technology 2002,113-117 "Synthesis of Compound 3; compound 3 (1.0 mmol), 1-p-toluenesulfonic acid-3-fluoropropyl ester (compound 5,1.0mmol, reference "Goswami R, et al, nucl Med Biol,2006,33:685-694." Synthesis) and 0.5mL triethylamine were dissolved in 20mL toluene, and the mixture was reacted under reflux heating at 115℃for 4 hours under the protection of nitrogen to obtain a reaction solution; concentrating the reaction solution under reduced pressure, and separating by silica gel column chromatography to obtain nonradioactive fluoropropyl tropane derivatives 6a (FP-CHT), 6b (FP-CFT), 6c (FP-CCT), 6d (FP-CMT) and 6e (FP-CIT); wherein, the silica gel column chromatography is carried out by taking normal hexane:ethyl acetate=4:1 (v/v /) as a mobile phase to separate and remove unreacted 1-p-toluenesulfonic acid-3-fluoropropyl ester, and then taking normal hexane:diethyl ether:triethylamine=1:1:0.01 (v/v/v) as a mobile phase to carry out secondary elution.
The resulting non-radioactive fluoropropyltrimethylene derivative 6a was a pale yellow oily compound in 30% yield and mass spectrum data MS (ESI) was: [ M+H ]] + Theoretical value of (C 18 H 25 FNO 2 ) m/z 306.19 found m/z 306.88. 1 The H nuclear magnetic resonance data are: 1 H NMR(400MHz,Chloroform-d)δ7.26(d,J＝3.0Hz,4H),7.15(m,1H),4.58(t,J＝6.0Hz,1H),4.46(t,J＝6.0Hz,1H),3.67(dd,J＝6.4,3.5Hz,1H),3.47(s,3H),3.43-3.35(m,1H),3.02(m,1H),2.94(t,J＝3.7Hz,1H),2.59(m,1H),2.36(m,2H),2.17-1.93(m,2H),1.86-1.61(m,5H).
the resulting non-radioactive fluoropropyltrimethylane derivative 6b was a white solid compound with a yield of 67% and mass spectrum data MS (ESI) of: [ M+H ]] + Theoretical value of (C 18 H 24 F 2 NO 2 ) m/z 324.18, found m/z 324.35. 1 The H nuclear magnetic resonance data are: 1 H NMR(400MHz,Chloroform-d)δ7.21(dd,J＝8.6,5.5Hz,2H),6.95(t,J＝8.7Hz,2H),4.58(t,J＝6.0Hz,1H),4.46(t,J＝6.0Hz,1H),3.70-3.64(m,1H),3.48(s,3H),3.42-3.35(m,1H),2.98(dd,J＝12.8,5.1Hz,1H),2.88(t,J＝3.7Hz,1H),2.55(m,1H),2.36(m,2H),2.17-1.94(m,2H),1.82-1.60(m,5H).
the resulting non-radioactive fluoropropyltrimethylene derivative 6c was a white solid compound with a yield of 57% and mass spectrum data MS (ESI) of: [ M+H ]] + Theoretical value of (C 18 H 24 ClFNO 2 ) m/z 340.15 found m/z 340.27. 1 The H nuclear magnetic resonance data are: 1 H NMR(400MHz,Chloroform-d)δ7.26-7.14(m,4H),4.57(t,J＝6.0Hz,1H),4.46(t,J＝6.0Hz,1H),3.71-3.63(m,1H),3.49(s,3H),3.43-3.35(m,1H),2.97(m,1H),2.89(t,J＝3.7Hz,1H),2.54(td,J＝12.5,3.1Hz,1H),2.37(h,J＝6.0Hz,2H),2.17-1.94(m,2H),1.82-1.61(m,5H).
the resulting non-radioactive fluoropropyltrimethylene derivative 6d was a pale yellow oily compound in 50% yield and mass spectrum data MS (ESI) was: [ M+H ]] + Theoretical value of (C 19 H 27 FNO 2 ) m/z 320.20 found m/z 320.41. 1 The H nuclear magnetic resonance data are: 1 H NMR(600MHz,Chloroform-d)δ7.07(d,J＝7.9Hz,2H),7.00(d,J＝7.9Hz,2H),4.49(t,J＝6.0Hz,1H),4.41(t,J＝6.0Hz,1H),3.59(s,1H),3.41(s,3H),3.30(d,J＝19.1Hz,1H),2.94-2.89(m,1H),2.84(t,J＝4.3Hz,1H),2.53-2.46(m,1H),2.22(s,3H),2.04-1.99(m,1H),1.96-1.90(m,1H),1.74-1.53(m,6H).
the resulting non-radioactive fluoropropyltrimethylene derivative 6e was a white solid compound with a yield of 69% and mass spectrum data MS (ESI) of: [ M+H ]] + Theoretical value of (C 18 H 24 FINO 2 ) m/z 432.08 found m/z 432.26. 1 The H nuclear magnetic resonance data are: 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J＝8.4Hz,2H),7.00(d,J＝7.9Hz,2H),4.57(t,J＝5.9Hz,1H),4.45(t,J＝6.0Hz,1H),3.69-3.65(m,1H),3.52-3.48(m,3H),3.41-3.36(m,1H),2.98-2.86(m,2H),2.52(td,J＝12.4,3.1Hz,1H),2.36(h,J＝5.9Hz,2H),2.13-1.98(m,2H),1.81-1.69(m,3H),1.68-1.58(m,3H).
experimental example 1: DAT competitive binding assay for non-radioactive deuterated fluoropropyltetrazole derivatives
This experimental example provides DAT competitive binding experiments for non-radioactive deuterated fluoropropyl tropane derivatives 4 a-4 e of example 1 and non-radioactive fluoropropyl tropane derivatives 6 a-6 e of comparative example 1, as follows:
normal rats (SD rats, purchased from cavus laboratory animals, inc.) were anesthetized with diethyl ether, sacrificed, brains were taken, striatum was isolated and weighed, and then homogenized to prepare homogenates containing striatum tissue at 100 mg/mL; 20.0. Mu.L of the homogenate was added to 20. Mu.L 99m Tc-TRODAT-1(～18.5KBq)( 99m Tc-TRCDAT-1 is a known radiopharmaceutical having high affinity and specificity for DAT, and is prepared by reference to the document "Bao SY, et al J Neuroimaging,2000, 10:200-203"), to give a mixture; to the mixture were added 20.0. Mu.L of a solution (50 mM, commercially available from BBI life sciences Co., ltd.) of Tris HCl (concentration: 0.001, 0.010, 0.100, 1.000, 5.00, 10.0, 50.0, 100.0, 1000 nmol/L) containing the non-radioactive deuterated fluoroproplift-alkane derivatives 4a to 4e described in example 1 and the non-radioactive fluoroproplift-alkane derivatives 6a to 6e described in comparative example 1, respectively, followed by incubation at 37℃for 60 minutes, centrifugation at 4℃for 14000g for 20 minutes, separation of the supernatant, followed by addition of 0.400mL of the Tris HCl solution to a centrifuge tube, followed by centrifugation again at 4℃for 5 minutes at 14000g, separation of the supernatant; combining the two supernatants, transferring to a radioactive counting tube, uniformly mixing the precipitate with 0.400mL of Tris HCl solution, and transferring to another radioactive counting tube; measuring the radioactivity counts in the pellet and supernatant, respectively, with a gamma counter; the non-specific binding rate was determined in the presence of DAT reagent (CFT with 20. Mu.M for DAT reagent, and methods for determining the non-specific binding rate to DAT are described in Milius RA, et al J Med chem 1991, 34:1728-1731); based on the specific binding ratio of DAT and the concentration logarithmic values of the non-radioactive deuterated fluoropropy-alkane derivatives 4a to 4e described in example 1 or the non-radioactive fluoropropy-alkane derivatives 6a to 6e described in comparative example 1, IC50 values of the non-radioactive deuterated fluoropropy-alkane derivatives 4a to 4e described in example 1 and the non-radioactive fluoropropy-alkane derivatives 6a to 6e described in comparative example 1 were calculated by a nonlinear least square method, and the calculation results are shown in Table 1.
As can be seen from Table 1, example 1 describesThe IC50 values of the non-radioactive deuterated fluoropropyltrimethylene derivatives 4 a-4 e were not significantly changed compared with the corresponding non-deuterated structures (i.e., the non-radioactive fluoropropyltrimethylene derivatives 6 a-6 e described in comparative examples), which showed no significant effect on the binding ability of DAT after deuteration at the fluoropropyl position, wherein the non-radioactive deuterated fluoropropyltrimethylene derivative FP-CIT-d 6 (4e) Has a minimum IC50 value (2.7 nM) which is close to that of the fluoropropyltrimethylane derivative FP-CIT (6 e,3.2 nM), indicating its highest binding to DAT. Non-radioactive deuterated fluoropropyl tropane derivative FP-CCT-d 6 (4c) And non-radioactive deuterated fluoropropyl tropane derivative FP-CMT-d 6 (4d) The binding capacity for DAT was also good, with IC50 values of 5.9nM and 7.6nM, respectively.
TABLE 1 IC50 values for different deuterated fluoropropyltropine derivatives
Short for chemical compound Code of the compound R X IC 50 (nM)
FP-CHT-d 6 4a D H 17.6
FP-CFT-d 6 4b D F 14.6
FP-CCT-d 6 4c D Cl 5.9
FP-CMT-d 6 4d D CH 3 7.6
FP-CIT-d 6 4e D I 2.7
FP-CHT 6a H H 20.5
FP-CFT 6b H F 15.9
FP-CCT 6c H Cl 5.6
FP-CMT 6d H CH 3 7.3
FP-CIT 6e H I 3.2
Example 3: [ solution ] 18 F]Deuterated fluoropropyl tropane derivative
The present embodiment provides a kind of [ 18 F]Deuterated fluoropropyl tropane derivatives, said [ [ 18 F]The deuterated fluoropropyl tropane derivative has the following structure:
wherein [ the 18 F]4a corresponds to [ 18 F]FP-CHT-d 6 ，[ 18 F]4b corresponds to [ 18 F]FP-CFT-d 6 ，[ 18 F]4c corresponds to [ 18 F]FP-CCT-d 6 ，[ 18 F]4d corresponds to [ 18 F]FP-CMT-d 6 ，[ 18 F]4e corresponds to [ 18 F]FP-CIT-d 6 。
Example 4: preparation [ 18 F]Process for deuterated fluoropropyl tropane derivatives
This example provides the method of example 3 18 F]A process for the preparation of deuterated fluoropropyltropine derivatives, said process comprising (scheme see figure 2):
[ 18 F]4e([ 18 F]FP-CIT-d 6 ) Is prepared from the following steps: production by cyclotron 18 F]KF, transported by nitrogen flow [ 18 F]KF, make [ 18 F]KF was adsorbed on SepPak QMA column, and after the adsorption was completed, 0.9mL of the eluent was used (eluent was prepared from 15mg of K dissolved in 0.8mL of acetonitrile 2.2.2 And 3.0mg K dissolved in 0.1mL of water 2 CO 3 Composition) rinsing and dissolving [ 18 F]KF is arranged in a reaction tube, after leaching, the liquid in the reaction tube is heated to 105 ℃, and is dried by nitrogen flow at 105 ℃, and after drying, the heating is stopped and cooled to<Cooling at 60deg.C, adding anhydrous CH into reaction tube 3 CN (1 mL), blow-drying the liquid in the reaction tube with nitrogen flow at 105 ℃, stopping heating and cooling to<At 60℃add 500. Mu.L anhydrous CH to the reaction tube 3 Compound TsOCD of CN 2 CD 2 CD 2 OTs (10.0 mg, compound 1, reference "Zhao, R, et al, nucl Med biol.2019,72-73:26-35." Synthesis) were reacted by heating at 90℃for 15min, after the reaction was completed (Compound [ wherein the reaction was completed ] 18 F]2， 18 FCD 2 CD 2 CD 2 OTs), stop heating and cool to<A compound nor-CIT (12.0 mg, 3,2 beta-methyl ester-3 beta-p-iodophenyl nortropane, reference "Zheng, et al, nucleic Med Biol,1996,23 (8): 981-986)" in 0.5mL DMF was added to the reaction tube, heated at 135℃for 25min, and after the completion of the reaction, the heating was stopped and cooled to<Adding 1.0mL of HPLC mobile phase into a reaction tube at 50 ℃ to obtain a mixed solution; transferring the mixture to an HPLC sample loop, and purifying with High Performance Liquid Chromatography (HPLC) to obtain the final product containing [ 18 F]FP-CIT-d 6 Is a mobile phase of (2); will contain [ 18 F]FP-CIT-d 6 Diluting the mobile phase of (C) with 30mL of water to obtain a diluent; the dilution was passed through a SepPak C18 column (now [ sic ] 18 F]FP-CIT-d 6 Adsorbed onto this column), then eluting the column with 10mL of water to remove possible water-soluble impurities, and eluting with 2mL of EtOH [ eluting with water ] 18 F]FP-CIT-d 6 And collecting in penicillin bottle 18 F]Deuterated fluoropropyl tropane derivatives 18 F]4e([ 18 F]FP-CIT-d 6 ) Is diluted to a required concentration with 0.9g/100mL physiological saline before the pure product is used (yield is 18 percent); wherein, the conditions of high performance liquid chromatography purification are as follows: using a Phenomenex Luna C column (10 mm. Times.250 mm,5 μm) with a mobile phase of CH 3 CN:H 2 O:Et 3 N=60:40:0.1 (v/v/v), flow rate 4.0mL/min, detected with a radioactivity detector.
High Performance Liquid Chromatography (HPLC) analysis method 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 The structure of (2) is verified, and the verification process is as follows: will [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]4e([ 18 F]FP-CIT-d 6 ) And non-radioactive deuterated fluoropropyl tropane derivative 4e are mixed until the concentration of the radioactive compound is 37MBq/mL and the concentration of the non-radioactive compound is 1.0mg/mL, so as to obtain a mixed solution; taking 20 mu L of mixed solution, and injecting the mixed solution into HPLC (high performance liquid chromatography) for analysis; wherein, the conditions of High Performance Liquid Chromatography (HPLC) analysis are as follows: using a GeminiNX-C18 column (3 mm. Times.150 mm,5 μm) with a mobile phase of CH 3 OH:H 2 O: tfa=40:60:0.1 (v/v/v), flow rate 1.0mL/min, detector using both radioactive and uv detector. The verification result is as follows: [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 The retention time (11.2 min) of (radioactive detector) was consistent with the retention time (11.1 min) of the corresponding non-radioactive deuterated fluoropropyltrimethylene derivative 4e (ultraviolet detector) (as shown in fig. 3). Thereby verifying [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 Is a structure of (a).
[ 18 F]4a([ 18 F]FP-CCT-d 6 ) Is prepared from the following steps: in [ 18 F]4e([ 18 F]FP-CIT-d 6 ) Based on the preparation method, the compound nor-CIT was replaced with the compound nor-CHT (12.0 mg, compound 3a, 2. Beta. -methyl-3. Beta. -phenyldesmethyltropane, see "Gu XH", et al Bioorg Med Chem Lett2001,11:3049-305. "Synthesis) to give [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]4a([ 18 F]FP-CHT-d 6 ) The yield was 11%.
Analysis of the pair using High Performance Liquid Chromatography (HPLC) 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CHT-d 6 Is verified by the structure of (a) and the verification process refers to [ 18 F]4e([ 18 F]FP-CIT-d 6 ) The HPLC mobile phase composition used was: CH (CH) 3 OH:H 2 O: tfa=30:70:0.1 (v/v/v). The verification result is as follows: [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CHT-d 6 The retention time (8.0 min) of (radioactive detector) corresponds to the retention time (7.9 min) of the corresponding non-radioactive deuterated fluoropropyltrimethylene derivative 4a (ultraviolet detector). Thereby verifying [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CHT-d 6 Is a structure of (a).
[ 18 F]4b([ 18 F]FP-CFT-d 6 ) Is prepared from the following steps: in [ 18 F]4e([ 18 F]FP-CIT-d 6 ) Based on the preparation method, the compound nor-CIT was replaced with the compound nor-CFT (12.0 mg, compound 3b,2β -methyl-3β -p-fluorophenyl nortropane, see literature "GuXH", et al Bioorg Med Chem Lett2001,11:3049-305. "Synthesis) to give [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]4b([ 18 F]FP-CFT-d 6 ) The yield was 23%.
Analysis of the pair using High Performance Liquid Chromatography (HPLC) 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CFT-d 6 Is verified by the structure of (a) and the verification process refers to [ 18 F]4e([ 18 F]FP-CIT-d 6 ) The HPLC mobile phase composition used was: CH (CH) 3 OH:H 2 O: tfa=30:70:0.1 (v/v/v). The verification result is as follows: [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CFT-d 6 The retention time (9.8 min) of (radioactive detector) was consistent with the retention time (9.7 min) of the corresponding non-radioactive deuterated fluoropropyltrimethylene derivative 4b (ultraviolet detector). Thereby verifying [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CFT-d 6 Is a structure of (a).
[ 18 F]4c([ 18 F]FP-CCT-d 6 ) Is prepared from the following steps: in [ 18 F]4e([ 18 F]FP-CIT-d 6 ) Based on the preparation method, the compound nor-CIT was replaced with the compound nor-CCT (12.0 mg, compound 3c, 2. Beta. -methyl-3. Beta. -p-chlorophenyl nortropane, see literature "Gu XH", et al Bioorg Med Chem Lett2001,11:3049-305. "Synthesis) to give [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]4c([ 18 F]FP-CCT-d 6 ) The yield was 35%.
Analysis of the pair using High Performance Liquid Chromatography (HPLC) 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CCT-d 6 Is verified by the structure of (a) and the verification process refers to [ 18 F]4e([ 18 F]FP-CIT-d 6 ) The HPLC mobile phase composition used was: CH (CH) 3 OH:H 2 O: tfa=35:65:0.1 (v/v/v). The verification result is as follows: [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CCT-d 6 The retention time (12.0 min) of (radioactive detector) was consistent with the retention time (11.9 min) of the corresponding non-radioactive deuterated fluoropropyltrimethylene derivative 4c (ultraviolet detector). Thereby verifying [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CCT-d 6 Is a structure of (a).
[ 18 F]4d([ 18 F]FP-CMT-d 6 ) Is prepared from the following steps: in [ 18 F]4e([ 18 F]FP-CIT-d 6 ) Based on the preparation method, the compound nor-CIT was replaced with the compound nor-CMT (12.0 mg, compound 3d, 2. Beta. -methyl-3. Beta. -p-tolyl-desmethyltropane, see "Gu XH", et al Bioorg Med Chem Lett2001,11:3049-305. "Synthesis) to give [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]4d([ 18 F]FP-CMT-d 6 ) The yield was 25%.
Analysis of the pair using High Performance Liquid Chromatography (HPLC) 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CMT-d 6 Is verified by the structure of (a) and the verification process refers to [ 18 F]4e([ 18 F]FP-CIT-d 6 ) The HPLC mobile phase composition used was: CH (CH) 3 OH:H 2 O: tfa=35:65:0.1 (v/v/v). The verification result is as follows: [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CMT-d 6 The retention time (9.0 min) of (radioactive detector) was consistent with the retention time (8.9 min) of the corresponding non-radioactive deuterated fluoropropyltrimethylene derivative 4d (ultraviolet detector). Thereby verifying [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CMT-d 6 Is a structure of (a).
Experimental example 2: [ 18 F]In vivo autoradiography experiments of deuterated fluoropropyl tropane derivatives
This experimental example provides the method described in example 3 18 F]In vivo autoradiography experiments of deuterated fluoropropyl tropane derivatives were performed as follows:
normal group (Control) test: tail vein injection of 185MBq into Normal rats (SD rats, available from Calvens laboratory animal Co., ltd.) via the tail vein 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 Normal rats were sacrificed 40min after injection, and the brains of normal rats were rapidly removed and frozen; embedding brain with freezing embedding medium (purchased from the laboratory technology company of Jiangyuan of Wuxi city), storing at-25deg.C for 2 hr, and slicing into crown slice with thickness of 20 μm; the obtained coronal slice is firstly attached to a glass slide, and is dried at room temperature (25 ℃), then the dried glass slide is placed on an imaging plate for exposure for 60min, then a phosphorus screen imager is used for imaging, an autoradiography image of the brain of a normal rat is obtained, finally the image analysis is carried out by using the Opti Quant software carried by the instrument, the areas such as Striatum (ST), cerebellum (CB), cortex (CX) and the like are sketched, the optical density values of the two areas are respectively calculated, and the experimental result is shown in figure 3.
Blocking group (blocking) test: CFT (DAT selection-specific ligand, cf. Reference "Li Xiaomin, et al, chemical, 2004, 26:185-186") was used as DAT blocker, CFT (at a dose of 1.0 mg/kg) was combined with-185 MBq/0.5mL [ based on the normal group assay 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 After being evenly mixed, the mixture is injected into normal rats through tail vein and then is subjected to automatic radioactive displayThe shadow test and the experimental result are shown in figure 3.
As shown in FIG. 3, the striatal area of the normal rat brain (striatal area is the area of highest density of DAT in the brain) versus 18 F]FP-CIT-d 6 With high uptake, the radioactive uptake of cerebellum and cortical areas (cerebellum and cortical areas contain little DAT, being reference areas) is low, the ratio ST/CB and ST/CX (ratio) of target area to reference area is 11.3 and 7.2, respectively; whereas DAT, after blocking with the specific inhibitor CFT, the striatal areas were not developed, with optical density values close to those of the reference areas (CB and CX), ST/CB and ST/CX decreasing to 1.2 and 1.0, respectively (n=3, P)<0.0001). This result shows that [ 18 F]FP-CIT-d 6 Has high specific binding to DAT in rat brain.
Experimental example 3: [ 18 F]microPET imaging experiments of deuterated fluoropropyl tropane derivatives
This experimental example provides the method described in example 3 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 The specific process of the microPET imaging experiment is as follows:
normal rats (SD rats, purchased from the company of the experimental animal, karuss, usa) were placed in an anesthesia case, anesthetized with 3% (v/v) isoflurane, placed on a microPET imaging couch, the body position of the animal was adjusted and the brain position of the rat was fixed, and the anesthetized state was maintained with 2.5% (v/v) isoflurane; observing the respiratory state of a normal rat; after smooth breathing, tail vein injection-10 MBq/0.5mL [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 Collecting a brain image obtained by scanning within 0-120min from the moment of injection, wherein the scanning result is shown in figure 4; non-deuterated drugs by the same method 18 F]FP-CIT (see document: chen Zhengping, et al, journal of Chinese Nuclear medicine, 2003, 23:241-243.) and deuterated drugs [ A.C. ] 18 F]FECNT-d 4 microPET imaging experiments (see: cao S, et al mol. Imaging biol.2021, 23:733-744.) as a comparison; after the development is finished, analyzing the microPET development result of the normal rat, and respectively obtaining the normal rat after processing the image data acquired in 0-120min by utilizing IAW software and ASIPro VM image analysis software matched with a mciroPET instrumentSeparate injection [ 18 F]FP-CIT-d 6 、[ 18 F]FP-CIT sum [ 18 F]FECNT-d 4 The images at different times within the last 120min are then used to obtain the time-radioactivity curves of striatum and cerebellum by using the region of interest (ROI) technique, and the analysis result is shown in FIG. 4 (the radioactivity data represents the concentration of the medicine, and the larger the concentration is, the more beneficial to PET imaging); by pairing [ 18 F]FP-CIT-d 6 ，[ 18 F]FP-CIT sum [ 18 F]FECNT-d 4 Dynamic analysis of the 0-120min microPET images of (a) resulted in curves of striatum/cerebellum ratio (ST/CB) at different time points, and the analysis results are shown in fig. 5 (the larger ST/CB is more favorable for DAT visualization and evaluation of related disease states).
As shown in fig. 4 [ the following ] 18 F]FP-CIT-d 6 Sum [ 18 F]FP-CIT is visualized clearly (as indicated by the open arrow) in the striatum of the target area in normal rat brain, bilaterally symmetrical, which is also similar to [ 18 F]FECNT-d 4 The results of the microPET brain imaging are similar, which shows that 18 F]FP-CIT-d 6 Has good affinity to DAT; [ 18 F]FP-CIT-d 6 Sum [ 18 F]Comparison of the microPET images of FP-CIT reveals that after 30min [ 18 F]FP-CIT-d 6 Uptake at bone sites (indicated by single-line arrows) was lower than [ 18 F]FP-CIT, the result shows that [ 18 F]FP-CIT-d 6 In vivo ratio [ 18 F]FP-CIT is more stable and defluorinated in vivo 18 F]At a speed lower than [ 18 F]FP-CIT is more beneficial to brain imaging.
As shown in FIG. 5, early in injection, [ solution ] 18 F]FP-CIT-d 6 、[ 18 F]FP-CIT sum [ 18 F]FP-CIT-d 6 Is a long upward trend, which is related to the uptake level of the three probes in the brain, retention properties, and clearance rate in the background (cerebellum) area; after 60min [ 18 F]FP-CIT-d 6 The ST/CB value of (C) tends to be stable, and [ 18 F]FP-CIT sum [ 18 F]FECNT-d 4 Then take a decreasing curve, indicating [ [ 18 F]FP-CIT-d 6 The retention performance in the body is better, and the PET imaging of the DAT in the brain is more facilitated; not only is it possible to do so,after 60min [ 18 F]FP-CIT-d 6 The ST/CB value of (2) is higher than [ 18 F]FP-CIT sum [ 18 F]FECNT-d 4 The method comprises the steps of carrying out a first treatment on the surface of the At 120min [ 18 F]FP-CIT-d 6 The value of ST/CB of (2) is 5.27, ratio [ 18 F]The ST/CB value of FP-CIT (2.83) is 86% higher than [ the 18 F]FECNT-d 4 The value of ST/CB (1.90) is increased by 177%. As ST/CB value is a quantitative analysis index applied to DAT PET imaging, the results of this experimental example show that 18 F]FP-CIT-d 6 Has better development performance than DAT 18 F]FP-CIT sum [ 18 F]FECNT-d 4 。
Experimental example 4: [ 18 F]In vivo DAT binding specificity experiments on deuterated fluoropropyl tropane derivatives
This experimental example provides the method described in example 3 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 The specific in vivo DAT binding assay of (c) is as follows:
the experiments were divided into three groups, normal (normal), CFT blocking (post-blocking) and 6-OHDA unilateral model (unilateral PD model).
Normal group (control): after anesthetizing a normal rat (SD rat, purchased from cavus laboratory animal limited) with 3% (v/v) isoflurane, placing the anesthetized rat on a microPET imaging bed and fixing the brain position of the rat, and continuing to maintain the anesthetized state with 2.5% (v/v) isoflurane; after the rat breathes smoothly, the tail vein is injected with 10MBq/0.5mL [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 The acquisition of microPET is carried out for 40-70 min from injection to obtain brain imaging chart, and the scanning result is shown in figure 6.
CFT blocking group (post-blocking): DAT blocking assays use selection-specific ligands (CFT). After normal rats are anesthetized by 3% (v%) isoflurane, the normal rats are placed on a micro PET imaging bed, animal body positions are adjusted and brain positions of the rats are fixed, and 2.5% (v/v) isoflurane is continuously used for maintaining an anesthetic state; after the rat breathes smoothly, CFT (dosage is 1.0 mg/kg) and 10MBq/0.5mL are injected through tail vein 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 Is a mixture of (2) microPETCollecting and scanning for 40-70 min from injection to obtain brain image, and scanning result is shown in figure 6.
6-OHDA unilateral model group (PD model): 6-OHDA unilateral model rats (6-OHDA unilateral model rats were model-built from normal rats, see: tang J, et al Nucl Med Biol,2020,90-91: 1-9.). After normal rats are anesthetized with 3% (v/v) isoflurane, the normal rats are placed on a microPET imaging bed and the brain position of the rats is fixed, and the anesthetized state is continuously maintained with 2.5% (v/v) isoflurane; after the rat breathes smoothly, the tail vein is injected with 10MBq/0.5mL [ 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 The acquisition of microPET is carried out for 40-70 min from injection to obtain brain imaging chart, and the scanning result is shown in figure 6.
The microPET imaging results of rats in each group are analyzed, the analysis software of ASIPro VM images matched with an mciro PET instrument is utilized, the analysis technology of region of interest (ROI) is utilized to the images, the radioactivity data of Striatum (ST) and Cerebellum (CB) areas are respectively obtained, ST/CB values are calculated, and the analysis results are shown in figure 6 (the larger ST/CB value is more beneficial to PET imaging of DAT).
As shown in fig. 6, the Striatum (ST) of the normal rat target region is clearly developed, bilaterally symmetrical, while the Cerebellum (CB) of the reference region, etc. is hardly developed; after the DAT is blocked by the CFT, the double striatum is not developed, and the image contrast between the visual striatum area and the reference area is not obvious; the undamaged side striatum of the unilateral PD model rat was developed clearly, while the damaged side striatum was no longer developed; after analysis of the images, the ST/CB value of normal rats reached-3.3, and the ST/CB value of blocking group was significantly reduced to-1.1 (/ P)<0.001 Single-sided PD model group rats with a non-destroyed ST/CB value of-3.0, whereas the destroyed ST/CB was significantly reduced to-1.0 (P)<0.001). The above results indicate that [ 18 F]FP-CIT-d 6 Binding to DAT in vivo is very specific and can distinguish between normal and PD model animals.
Experimental example 5: [ 18 F]In vivo metabolic analysis experiments of deuterated fluoropropyl tropane derivatives
This experimental example provides the method described in example 3 18 F]Deuterated fluoropropyl tropane derivativeBiology [ 18 F]FP-CIT-d 6 The specific process is as follows:
after anesthesia of normal rats (SD rats, purchased from Kwangsi laboratory animal Co., ltd.) the mice were injected via the tail vein 18 F]Deuterated fluoropropyl tropane derivatives 18 F]FP-CIT-d 6 Non-deuterated drugs [ 18 F]FP-CIT([ 18 F]The preparation method of the FP-CIT is disclosed in the literature: chen Zhengping, et al, journal of Chinese Nuclear medicine, 2003, 23:241-243), the injection doses were 185MBq (0.5 mL), normal rats were sacrificed at a cervical fracture 5,15, 30, 60, 120min post injection, blood samples were taken 0.200mL, whole brains were taken, and Striatum (ST) and Cerebellum (CB) tissues were isolated; adding 1.0mg/mL of non-radioactive deuterated fluoropropyl tropane derivative 4e (FP-CIT-d) to a blood sample 6 ) After homogenization treatment of 0.50mL acetonitrile solution of non-radioactive non-deuterated drug 6e (FP-CIT), centrifuging the suspension at 4deg.C and 12000g in a centrifuge, collecting 20 μL supernatant, performing high performance liquid chromatography, collecting mobile phases of 0.500mL each section with an automatic collector for 30min, measuring the radioactivity count of each collected liquid on a gamma counter, plotting and calculating 18 F]FP-CIT-d 6 Or [ 18 F]The percentage of FP-CIT drug substance and the results are shown in FIG. 7; the striatum or cerebellum sample is placed in an EP tube containing 0.2mL Acetonitrile (ACN) (0.2 mg non-radioactive deuterated fluoropropyltropine derivative 4e or non-radioactive non-deuterated drug 6e in ACN), homogenized, centrifuged at 4deg.C and 14000g for 20min on a centrifuge, supernatant is collected, 20 μl supernatant is analyzed by high performance liquid chromatography, each mobile phase is collected by an automatic collector for 0.500mL for 30min, the radioactivity count of each collected liquid is measured on a gamma counter, and the graph is constructed and calculated 18 F]FP-CIT-d 6 Or [ 18 F]The percentage of FP-CIT original drug is calculated, and the calculation result is shown in FIG. 7; wherein, the chromatographic conditions are as follows: the chromatographic column is 5 mu m C column, the mobile phase is MeOH H 2 O: TFA=60:40:0.1 (v/v/v), flow rate was 1.0mL/min.
As shown in FIG. 7, in injection [ 18 F]FP-CIT-d 6 After 5,15, 30, 60 and 120min, rat bloodPlasma, striatum in brain (striatum) and cerebellum (cerebellum) area 18 F]FP-CIT-d 6 The ratio of the original drugs is higher than that of the corresponding non-deuterated drugs [ 18 F]FP-CIT-d 6 Indicating [ 18 F]FP-CIT-d 6 In vivo compared to non-deuterated drugs [ 18 F]FP-CIT is more stable. The result and experimental example 3 are mutually proved to show that 18 F]FP-CIT-d 6 The in vivo stability is better, which is very beneficial to PET imaging of DAT in brain.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.

Claims (10)

1. [ solution ] 18 F]Deuterated fluoropropyl tropane derivative characterized in that said [ 18 F]The deuterated fluoropropyl tropane derivative has the following structure:
wherein:
R 1 hydrogen, fluorine, chlorine, iodine, bromine, methyl, ethyl, methoxy or ethoxy;
R 2 is methyl or ethyl.
2. As claimed in claim 1 18 F]Deuterated fluoropropyl tropane derivative characterized in that said [ 18 F]The deuterated fluoropropyl tropane derivative has the following structure:
3. as claimed in claim 1 18 F]Deuterated fluoropropyl tropane derivative characterized in that said [ 18 F]The deuterated fluoropropyl tropane derivative has the following structure:
4. as claimed in claim 1 18 F]Deuterated fluoropropyl tropane derivative characterized in that said [ 18 F]The control compound of the deuterated fluoropropyl tropane derivative is a non-radioactive deuterated fluoropropyl tropane derivative; the non-radioactive deuterated fluoropropyl tropane derivative has the following structure:
wherein:
R 1 hydrogen, fluorine, chlorine, iodine, bromine, methyl, ethyl, methoxy or ethoxy;
R 2 is methyl or ethyl.
5. As claimed in claim 1 18 F]The preparation method of the deuterated fluoro-propyl tropane derivative is characterized by comprising the following steps of: compound TsOCD 2 CD 2 CD 2 OTs and tetrabutylammonium fluoride react in acetonitrile to obtain FCD 2 CD 2 CD 2 OTs; FCD 2 CD 2 CD 2 OTs and 2 beta-methyl ester-3 beta-para-substituted phenyl demethyl tropane react under alkaline condition to obtain non-radioactive deuterated fluoropropyl tropane derivative.
6. As in claim 5 [ the 18 F]Deuterated fluoropropyl tropaneA derivative, characterized in that the FCD 2 CD 2 CD 2 OTs have the following structure:
7. preparation of a product as claimed in any one of claims 1 to 3 18 F]A process for deuterated fluoropropyltrimethylane derivatives, wherein the process is: firstly, K is contained 222 And K 2 CO 3 CH of (2) 3 CN/H 2 O solution dissolution 18 F, in the reaction tube, then removing water from the liquid in the reaction tube, after the water removal is finished, adding TsOCD 2 CD 2 CD 2 Adding acetonitrile solution of OTs into a reaction tube to react to obtain a compound 18 FCD 2 CD 2 CD 2 Solutions of OTs; the compound is firstly added 18 FCD 2 CD 2 CD 2 The OTs solution is cooled and then the solution is cooled to the compound 18 FCD 2 CD 2 CD 2 Adding N, N-dimethylformamide solution containing 2 beta-methyl ester-3 beta-para-substituted phenyl demethyl tropane into OTs solution to react so as to obtain the [ 1-3 ] 18 F]Deuterated fluoropropyl tropane derivatives.
8. The method of claim 7, wherein the TsOCD 2 CD 2 CD 2 OTs have the following structure:
9. a process according to claim 1 to 3 18 F]Use of deuterated fluoropropyl tropane derivatives for the preparation of dopamine transporter imaging agents.
10. An imaging agent targeting a dopamine transporter, characterized in that the imaging agent comprises the agent according to any one of claims 1 to 3 18 F]Deuterated fluoropropyl tropane derivatives.
CN202310334441.4A 2023-03-30 2023-03-30 [ solution ] 18 F]Deuterated fluoropropyl tropane derivative and application thereof Pending CN116925067A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008059349A1 (en) * 2006-11-14 2008-05-22 Orphachem Method of fluorine-18 labelling of tropane derivatives
CN110678465A (en) * 2017-05-31 2020-01-10 五一一制药股份有限公司 Novel deuterium-substituted Positron Emission Tomography (PET) imaging agents and their pharmacological use
CN113024542A (en) * 2021-03-11 2021-06-25 江苏省原子医学研究所 Deuterated tropane derivative and application thereof
CN113372348A (en) * 2021-03-22 2021-09-10 深圳鼎邦生物科技有限公司 Deuterated FP-beta-CIT and preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008059349A1 (en) * 2006-11-14 2008-05-22 Orphachem Method of fluorine-18 labelling of tropane derivatives
CN110678465A (en) * 2017-05-31 2020-01-10 五一一制药股份有限公司 Novel deuterium-substituted Positron Emission Tomography (PET) imaging agents and their pharmacological use
CN113024542A (en) * 2021-03-11 2021-06-25 江苏省原子医学研究所 Deuterated tropane derivative and application thereof
CN113372348A (en) * 2021-03-22 2021-09-10 深圳鼎邦生物科技有限公司 Deuterated FP-beta-CIT and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOODMAN, MM等: "18F-labeled FECNT:: A selective radioligand for PET imaging of brain dopamine transporters", NUCLEAR MEDICINE AND BIOLOGY, vol. 27, no. 1, 1 January 2000 (2000-01-01), pages 1 - 12, XP004188282, DOI: 10.1016/S0969-8051(99)00080-3 *

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