CN113387927B - Nitroimidazole derivative for preparing hypoxia imaging agent and preparation method and application thereof - Google Patents
Nitroimidazole derivative for preparing hypoxia imaging agent and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a nitroimidazole derivative for preparing an oxygen-lack developer, which is selected from compounds with a structural formula shown as a formula I, a formula II or a formula III; wherein R is C1-8 alkyl, saturated alkoxy or acylamino. The invention also provides a preparation method of the nitroimidazole compound and application of the nitroimidazole compound in preparation of a PET (polyethylene terephthalate) developer. The nitroimidazole derivative provided by the invention has proper molecular weight and fat solubility, greatly improves the capability of a developer crossing blood brain barrier, and has higher sensitivity to hypoxia due to the introduction of an azide hypoxia response group.
Description
Technical Field
The invention relates to the technical field of medical imaging materials and pharmaceutical chemistry, in particular to nitroimidazole derivatives for preparing a hypoxia imaging agent, and a preparation method and application thereof.
Background
Hypoxia is a condition in which the intracellular oxygen concentration is too low to meet metabolic demand due to an imbalance between oxygen supply and oxygen consumption. Hypoxia is a common feature of most solid malignancies and can lead to reduced oxygen and nutrient supply and impaired drug delivery. The heterogeneity of hypoxic can promote the invasion and metastasis of tumors, angiogenesis and drug resistance increase, which all greatly reduce the treatment effect of anticancer drugs and further cause great obstacles to the treatment of tumors and the development of drugs. Meanwhile, hypoxia is also a main factor of diseases such as stroke and myocardial infarction, and plays a role in structural and functional changes of chronic cardiovascular and cerebrovascular diseases. The treatment of stroke is crucial by identifying hypoxic tissue and determining the extent of the penumbra. Therefore, based on the advantages of non-invasive, whole-body imaging, high sensitivity, high specificity and the like of the PET technology, the development of the PET imaging agent can diagnose hypoxia-related diseases at an early stage, and is beneficial to reducing morbidity and mortality.
The development of hypoxic imaging agents is mainly based on the modification of the structure of 2-nitroimidazoles. The hypoxia imaging agent mainly used in clinic at present is [ 2 ] 18 F]The process of FMISO, but because of the adverse factors of low brain-entering amount, slow clearance of normal tissues, poor sensitivity to hypoxia and the like 18 F]FMISO still needs to be optimized. In recent years, based on [ 2 ] 18 F]The structure of FMISO was developed 18 F]FAZA、[ 18 F]FETNIM、[ 18 F]HX4 and [ 2 ] 18 F]EF5, etc., and based on a metal chelate [ alpha ] 64 Cu]ATSM and [ 2 ] 64 Cu]ATSE has also been studied and newly developed imaging agents have improved tumor hypoxia, but have major drawbacks, such as: the diagnosis of hypoxia is severely restricted by the problems of low sensitivity to hypoxia and low brain intake. Therefore, based on [ 2 ] 18 F]The structure of FMISO is important to develop small-molecule hypoxia imaging agent with high hypoxia sensitivity and capability of entering brain.
Disclosure of Invention
In order to overcome the above [ 2 ] 18 F]FMISO deficiency, the invention takes nitroimidazole as basic framework, different types of side chains and hypoxic response groups to improve the [ 2 ] 18 F]Fat-soluble and hypoxic sensitivity of FMISO; meanwhile, the molecular weight of the compound is controlled to meet the theoretical requirement of entering the brain through a blood brain barrier, and a series of novel nitroimidazole derivatives are designed. The compound provided by the invention has azide characteristic groups, so that the sensitivity to hypoxic is improved. The invention provides a quilt suitable for use 18 Novel F-labeled nitroimidazole derivatives and corresponding derivatives 18 F-labelled nitroimidazole derivatives per se, their derivatives and their use 19 F analogs and their use as reference standards, methods of making such compounds, compositions comprising such compounds, kits comprising such compounds or compositions, and uses of such compounds, compositions or kits for Positron Emission Tomography (PET) imaging of hypoxia-related critical diseases such as tumors, stroke, atherosclerosis, and the like.
One of the purposes of the invention is to provide a category of hypoxic sensitive nitroimidazole derivatives. The compound has a hypoxia response characteristic group, and belongs to a brand new compound for diagnosing hypoxia-related diseases.
A nitroimidazole derivative for preparing a hypoxia imaging agent is characterized by being selected from compounds with structural formulas shown as a formula I, a formula II or a formula III;
wherein R is C1-8 alkyl, saturated alkoxy or amido, preferably- (CH) 2 ) n-or- (OCH) 2 CH 2 ) n-, n = an integer of 1-4.
In one embodiment according to the present invention, selected from the structural formulas
Any one of the compounds of (1).
In one embodiment according to the invention, F is 19 F or 18 F。
One of the objects of the present invention is to provide a method for preparing the nitroimidazole derivatives, which comprises:
providing a precursor compound with a structural formula IV, V or VI, and carrying out fluorination reaction to obtain the nitroimidazole derivative.
In one embodiment according to the present invention, when the nitroimidazole derivative is a labeled compound, the method further comprises:
a) Will be dried 18 F - /K222/K 2 CO 3 Adding the complex into a solution containing a precursor compound to obtainA reaction solution; the solvent of the solution is acetonitrile;
b) Reacting the reaction solution for 10min at the temperature of 80-100 ℃;
c) After the reaction is finished and cooled, adding proper amount of high-purity water, and passing through an activated Oasis HLB solid-phase extraction column; preferably, the Oasis column is activated by a method comprising the steps of: eluting the Oasis column with 10mL of ethanol, then drying the column with 10mL of air under pressure, eluting the Oasis column with 10mL of high-purity water, and finally drying the column with 10mL of air under pressure;
d) The volume ratio is 9:1, washing the Oasis HLB solid-phase extraction column by using a water/ethanol mixed solution to obtain a washing solution;
e) Diluting the flushing liquid and then enriching the flushing liquid on an Oasis HLB solid-phase extraction column again;
f) And leaching with ethanol to obtain a crude product of the nitroimidazole derivative.
6. The method of claim 5, further comprising:
g) Purifying the crude nitroimidazole derivative product by semi-preparative HPLC, wherein the HPLC conditions comprise: phenomenex Gemini-Nx with the thickness of 250 multiplied by 4.6mM is taken as a chromatographic column, and 10mM ammonium acetate 90% -10% and acetonitrile 10% -90% are respectively taken as gradient mobile phases for 0-15min.
In one embodiment according to the present invention, the 18 F - /K222/K 2 CO 3 Is prepared by the following steps:
1) At K222/K 2 CO 3 The solution is to 18 F - Eluting from the QMA column into a reaction tube;
2) Removing the solvent from the eluate to obtain an evaporation residue;
3) Adding appropriate amount of anhydrous acetonitrile into the evaporation residue, evaporating to dryness, and repeating for several times to obtain dried product 18 F - /K222/K 2 CO 3 A complex compound.
In one embodiment according to the present invention, the K222/K 2 CO 3 The solution is prepared by mixing K222 in acetonitrile with K 2 CO 3 Is prepared by mixing the aqueous solution ofWherein K222 and K 2 CO 3 In a molar ratio of 1 to 4:1; preferably, the concentration of the acetonitrile solution of K222 is 0.1-0.4mol/L, and the K 2 CO 3 The concentration of the aqueous solution of (2) is 0.05-0.2mol/L. The invention also aims to provide the application of the nitroimidazole derivatives in preparing the imaging agent for diagnosing hypoxia-related diseases;
preferably, the hypoxia-related disease is selected from one or more of a tumor, stroke and atherosclerosis.
It is a further object of the present invention to provide a PET imaging agent for diagnosing hypoxia-related diseases, which comprises the nitroimidazole derivatives described above.
The technical scheme of the invention has the following beneficial effects:
1) The nitroimidazole derivative provided by the invention introduces an azide hypoxic response group on the basis of 2-nitroimidazole hypoxic response, so that the compound disclosed by the invention has higher sensitivity to hypoxic and is expected to be applied to diagnosis of hypoxic-related diseases.
2) Compared with the reported hypoxia imaging agent, the small-molecular hypoxia sensitive nitroimidazole derivative provided by the invention greatly improves the capability of the imaging agent crossing blood brain barrier by regulating the molecular weight and lipid solubility of the compound, and is beneficial to rapid diagnosis of brain serious diseases such as brain tumor, stroke and the like.
Drawings
FIG. 1 is a PET imaging picture of tumors using PET hypoxia imaging agents prepared based on nitroimidazole derivatives of example 5 of the present invention, the circled area being the tumor.
Detailed Description
In order to make the technical problems, technical solutions and advantages of the present invention more apparent, the following detailed description is given with reference to the accompanying drawings and specific embodiments.
EXAMPLE 1- (4- (2-fluoroethyl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one
The structural formula is as follows:
the synthetic route is as follows:
1) 2- (2-Nitro-1H-imidazol-1-yl) -1- (4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) piperidin-1-yl) ethane
Dissolving 2- (2-nitro-1H-imidazol-1-yl) acetic acid (120mg, 0.70mmol) in DMF, adding 5mL triethylamine, stirring at room temperature for 15min, sequentially adding 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) piperidine (150mg, 0.70mmol), 1-hydroxybenzotriazole (HOBT, 30mg, 0.19mmol), O-benzotriazol-tetramethyluronium hexafluorophosphate (HBTU, 800mg, 2.111mmol), reacting at room temperature for 1H, extracting with ethyl acetate, washing with saturated saline three times, collecting organic phase layer, and adding Na 2 SO 4 And (5) drying. Purification by flash chromatography (ethyl acetate) gave 2- (2-nitro-1H-imidazol-1-yl) -1- (4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) piperidin-1-yl) ethane (230mg, 90%). 1 H NMR(300MHz,CDCl 3 )δ7.08(d,J＝12.3Hz,2H),5.42–5.03(m,1H),4.62–4.35(m,2H),3.92–3.63(m,3H),3.57–3.33(m,2H),3.14(t,J＝12.2Hz,1H),2.64(t,J＝12.2Hz,1H),1.83-1.69(m,6H),1.65–1.40(m,7H),1.39–0.99(m,2H). 13 C NMR(75MHz,CDCl 3 )δ162.75,144.99,128.01,127.18,99.11,64.86,62.62,50.99,45.32,43.00,35.94,33.01,32.95,32.54,32.36,31.72,31.58,30.75,25.40,19.78.HRMS calcd for C17H26N4O5 366.1903；found,367.3111[M+H] + .
2) 1- (4- (2-hydroxyethyl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one
2- (2-nitro-1H-imidazol-1-yl) -1- (4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) piperidin-1-yl) ethane (200mg, 0.54mmol) and pyridine p-toluenesulfonate (40mg, 0.16mmol) were dissolved in ethanol, reacted at 50 ℃ for 24H, then spin-dried to stir the sample, and 1- (4- (2-hydroxy-1)Ethyl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one (140mg, 90%). 1 H NMR(300MHz,CDCl 3 )δ7.10(s,2H),5.23(q,J＝16.0Hz,1H),3.86–3.56(m,4H),3.31–2.97(m,4H),2.67-2.58(m,1H),1.85-1.71(m,3H),1.39–0.93(m,3H). 13 C NMR(75MHz,CDCl 3 )δ162.89,148.51,145.24,137.11,127.94,127.39,77.56,77.14,76.71,59.65,51.08,45.36,43.08,38.76,32.46,32.39,31.67.HRMS calcd for C12H18N4O4 282.1328；found,283.1786[M+H] + .
3) 4-Methylbenzenesulfonic acid 2- (1- (2- (2- (2-nitro-1H-imidazol-1-yl) acetyl) piperidin-4-yl) ethyl
1- (4- (2-hydroxyethyl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one (140mg, 0.49mmol) was dissolved in DCM, and 4-toluenesulfonyl chloride (TsCl, 470mg, 2.47mmol), 5mL triethylamine, 4-dimethylaminopyridine (DMAP, 10mg, 0.08mmol) were sequentially added under ice bath to react at room temperature for 12 hours, followed by washing with water three times, and the organic phase layer was Na-washed 2 SO 4 Dried and purified by flash chromatography (dichloromethane: methanol, 10, 1) to give 4-methylbenzenesulfonic acid 2- (1- (2- (2- (2-nitro-1H-imidazol-1-yl) acetyl) piperidin-4-yl) ethyl (110mg, 51.4%). 1 H NMR(300MHz,CDCl 3 )δ7.76(d,J＝8.2Hz,2H),7.35(d,J＝8.0Hz,2H),7.10(d,J＝7.5Hz,2H),5.31-5.10(m,2H),4.41(d,J＝13.3Hz,1H),4.05(s,2H),3.73(d,J＝6.9Hz,2H),3.13-3.04(m,1H),2.55-2.44(m,4H),1.86–1.51(m,3H),1.23-0.99(m,3H). 13 C NMR(75MHz,CDCl 3 )δ162.87,145.11,132.65,129.98,128.02,127.84,127.28,67.84,50.99,45.10,42.75,34.90,32.11,31.92,31.11,21.65.HRMS calcd for C19H24N4O6S 436.1417；found,437.2475[M+H] + .
4) 1- (4- (2-fluoroethyl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one
4-Methylbenzenesulfonic acid 2- (1- (2- (2- (2-nitro-1H-imidazol-1-yl) acetyl) piperidin-4-yl) ethyl (90mg, 0.20mmol) was dissolved in a small amount of THF, 0.2mL of tetrabutylammonium fluoride solution (1M) was added under nitrogen protection, and the mixture was reacted at 50 ℃ for 12 hours, followed by washing with water three times, and the organic phase layer was Na-washed 2 SO 4 Drying and passing through a flash purification chromatograph (ethyl acetate) to obtain 1- (4- (2-fluoroethyl) ethyl acetateYl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one (30mg, 52.8%). 1 H NMR(300MHz,CDCl 3 )δ7.18(s,1H),7.03(s,1H),5.35-5.13(m,2H),4.64-4.54(m,2H),3.93–3.46(m,2H),3.21(t,J＝12.9Hz,1H),2.69(t,J＝11.9Hz,1H),1.96–1.56(m,5H),1.41–1.26(m,2H). 13 C NMR(75MHz,CDCl 3 )δ162.78,128.15,127.08,82.43,80.56,77.47,77.25,77.05,76.62,50.90,45.34,43.00,32.53,32.31,31.48.HRMS calcd for C12H17FN4O3 284.1285；found,285.3464[M+H] + .
Example 2- (2-fluoroethyl) -1- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidine
The structural formula is as follows:
the synthetic route is as follows:
1) 2- (1- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidin-4-yl) ethan-1-ol
4-Methylbenzenesulfonic acid 2- (2-nitro-1H-imidazol-1-yl) ethyl ester (353mg, 1.13mmol) and 4-piperidineethanol (220mg, 1.70mmol) were dissolved in acetonitrile and K was added 2 CO 3 (1.6 g, 11.59mmol), reacted at 90 ℃ for 20H, then spin-dried, and taken up by flash chromatography (dichloromethane: methanol: aqueous ammonia =90: 1) to give 2- (1- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidin-4-yl) ethan-1-ol (200mg, 66.0%). 1 H NMR(300MHz,CDCl 3 )δ7.14(s,1H),7.00(s,1H),4.42(t,J＝6.1Hz,2H),3.55(t,J＝6.5Hz,2H),3.04(s,1H),2.68(d,J＝11.2Hz,2H),2.58(t,J＝6.1Hz,2H),2.01(s,2H),1.56(d,J＝12.4Hz,2H),1.39(dd,J＝12.7,6.3Hz,3H),1.14–0.91(m,2H). 13 C NMR(75MHz,CDCl 3 )δ145.00,127.87,126.38,59.88,58.24,54.05,47.41,39.11,32.14,31.95.HRMS calcd for C12H20N4O3 268.1535；found,269.2187[M+H] + .
2) 4-Methylbenzenesulfonic acid 2- (1- (2- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidin-4-yl) ethyl
2- (1- (2- (2-Nitro-1H-imidazol-1-yl) ethyl) piperidin-4-yl) ethan-1-ol (400mg, 1.49mmol) was dissolved in DCM, and 4-toluenesulfonyl chloride (TsCl, 1.4g, 7.36mmol), triethylamine (8 mL), 4-dimethylaminopyridine (DMAP, 10mg, 0.08mmol) were added in this order under ice-cooling, reacted at room temperature for 12 hours, then washed with water three times, and the organic phase layer was washed with Na 2 SO 4 After drying, by flash chromatography (ethyl acetate), 4-methylbenzenesulfonic acid 2- (1- (2- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidin-4-yl) ethyl (300mg, 47.7%) was obtained. 1 H NMR(300MHz,CDCl 3 )δ7.77(d,J＝8.2Hz,1H),7.66(d,J＝8.0Hz,1H),7.35(d,J＝8.2Hz,1H),7.20–6.99(m,3H),5.18–4.89(m,1H),4.52(t,J＝6.1Hz,1H),4.03(t,J＝6.2Hz,1H),3.89–3.49(m,5H),2.90–2.59(m,2H),2.13–2.05(m,2H),1.93-1.85(m,4H),1.58-1.30(m,2H),1.45–0.79(m,2H). 13 C NMR(75MHz,CDCl 3 )δ143.36,139.80,132.82,129.89,128.82,128.11,127.86,126.54,125.65,77.48,77.26,77.06,76.63,68.20,55.09,53.81,35.01,31.40,23.75,21.64,21.25.HRMS calcd for C19H26N4O5S422.1624；found,423.3752[M+H] + .
3) 4- (2-fluoroethyl) -1- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidine
4-Methylbenzenesulfonic acid 2- (1- (2- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidin-4-yl) ethyl (100mg, 0.23mmol) was dissolved in a small amount of THF, 0.2mL of tetrabutylammonium fluoride solution (1M) was added under nitrogen protection, reacted at 50 ℃ for 12 hours, then washed three times with water, and the organic phase was Na 2 SO 4 After drying, the residue was purified by flash chromatography (ethyl acetate) to give 4- (2-fluoroethyl) -1- (2- (2-nitro-1H-imidazol-1-yl) ethyl) piperidine (20mg, 32.2%). 1 H NMR(300MHz,CDCl 3 )δ7.21(s,1H),7.07(s,1H),4.53(t,J＝5.9Hz,3H),4.37(t,J＝5.9Hz,1H),4.27(t,J＝6.7Hz,2H),2.94–2.63(m,4H),2.13(t,J＝10.9Hz,2H),1.66–1.31(m,5H). 13 C NMR(75MHz,CDCl 3 )δ167.66,132.26,130.90,128.78,128.06,126.36,83.04,80.86,65.51,58.01,53.93,47.16,36.78,36.52,31.70,30.51,19.13,13.68.HRMS calcd for C12H19FN4O2 270.1492；found,271.2657[M+H] + .
Example 3- (4- (2-fluoroethyl) piperidin-1-yl) -3- (2-nitro-1H-imidazol-1-yl) propanol
The structural formula is as follows:
the synthetic route is as follows:
1) 2- (1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidin-4-yl) ethanol
3- (2-Nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl 4-toluenesulfonate (150mg, 0.35mmol) and 4-piperidineethanol (68mg, 0.52mmol) were dissolved in acetonitrile and K was added 2 CO 3 (487mg, 3.52mmol), refluxed at 90 ℃ for 24H, then spin-dried and sample-stirred, by flash chromatography (ethyl acetate) to give 2- (1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidin-4-yl) ethanol (100mg, 74.8%). 1 H NMR(300MHz,CDCl 3 )δ7.19(s,1H),7.09(s,1H),4.99(dd,J＝14.0,2.9Hz,1H),4.36–4.28(m,2H),4.10(d,J＝5.0Hz,1H),3.82–3.65(m,1H),3.82–3.65(m,3H),3.42-3.39(m,1H),2.91(d,J＝10.5Hz,1H),2.76(d,J＝10.7Hz,1H),2.52(dd,J＝12.7,4.6Hz,1H),2.34–2.17(m,2H),2.17–1.85(m,3H),1.68(d,J＝9.5Hz,3H),1.48–1.39(m,9H),1.25(d,J＝9.0Hz,3H). 13 C NMR(75MHz,CDCl 3 )δ145.00,127.54,127.18,99.54,73.72,62.96,60.31,59.94,55.38,53.61,51.25,39.26,32.38,32.11,30.56,25.15,19.46.HRMS calcd for C18H30N4O5382.2216；found,383.1421[M+H] + .
2) 2- (1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidin-4-yl) 4-toluenesulfonic acid ethyl ester
Reacting 2- (1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidin-4-yl) ethaneAlcohol (160mg, 0.41mmol) was dissolved in DCM, and 4-toluenesulfonyl chloride (TsCl, 250mg, 1.31mmol), triethylamine (5 mL), 4-dimethylaminopyridine (DMAP, 10mg, 0.08mmol) were sequentially added under ice-bath, reacted at room temperature for 12 hours, then washed three times with water, and the organic phase layer was washed with Na 2 SO 4 After drying by flash purification chromatography (petroleum ether: ethyl acetate = 3) ethyl 2- (1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidin-4-yl) 4-toluenesulfonate (120mg, 54.6%). HRMS calcd for C25H36N4O7S536.2305; found,537.1728[ m ] +H] + .
3) 4- (2-fluoroethyl) -1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidine
Ethyl 2- (1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidin-4-yl) 4-toluenesulfonate (100mg, 0.18mmol) was dissolved in a small amount of THF, 0.2mL of tetrabutylammonium fluoride solution (1M) was added under nitrogen protection, reacted at 50 ℃ for 2 days, and then washed three times with water, and the organic phase layer was Na-washed 2 SO 4 After drying, by flash purification chromatography (ethyl acetate), 4- (2-fluoroethyl) -1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidine (40mg, 57.8%) was obtained. HRMS calcd for C18H29FN4O4384.2173; found,385.2912[ 2 ] M + H] + .
4) 1- (4- (2-fluoroethyl) piperidin-1-yl) -3- (2-nitro-1H-imidazol-1-yl) propanol
4- (2-fluoroethyl) -1- (3- (2-nitro-1H-imidazol-1-yl) -2- ((tetrahydro-2H-pyran-2-yl) oxy) propyl) piperidine (20mg, 0.05mmol) and pyridine p-toluenesulfonate (3.7mg, 0.02mmol) were dissolved in ethanol, reacted at 50 ℃ for 12H, then spin-dried to stir the sample, and 1- (4- (2-fluoroethyl) piperidin-1-yl) -3- (2-nitro-1H-imidazol-1-yl) propanol (5mg, 33.3%) was obtained by flash purification chromatography (dichloromethane: methanol = 10. HRMS calcd for C13H21FN4O3300.1598; found,301.1928[ deg. ] M + H] + .
Example 4- (1-azido-3-fluoropropan-2-yl) -2-nitro-1H-imidazole
The structural formula is as follows:
the synthetic route is as follows:
1) 2-phenyl-1, 3-dioxa-5-yl 4-methylbenzenesulfonate
Cis-1, 3-O-benzyl allyl triol (2g, 11.1mmol) is dissolved in DCM, triethylamine (4 mL), 4-dimethylamino pyridine (DMAP, 30mg, 0.24mmol) and 4-toluene sulfonyl chloride (TsCl, 5.5g, 28.9mmol) are added in sequence under ice bath, reaction is carried out for 12h at room temperature, then washing is carried out for three times, and an organic phase layer is washed by Na 2 SO 4 After drying, by flash purification chromatography (petroleum ether: ethyl acetate = 70) the 2-phenyl-1, 3-dioxa-5-yl 4-methylbenzenesulfonate (2.4g, 64.7%) was obtained.
1H NMR(300MHz,CDCl3)δ7.87(d,J＝8.2Hz,2H),7.71(d,J＝8.2Hz,1H),7.59–7.44(m,2H),7.45–7.36(m,4H),5.52(s,1H),4.52(s,1H),4.29(d,J＝12.3Hz,2H),4.11(d,J＝12.2Hz,2H),3.24(q,J＝7.1Hz,1H),2.46(s,3H).13C NMR(75MHz,CDCl3)δ144.95,143.06,137.33,133.99,129.95,129.23,128.30,127.78,127.04,126.14,101.25,77.47,77.05,76.63,72.29,69.09,21.68,14.14.HRMS calcd for C17H18O5S 334.0875；found,335.0715[M+H] + .
2) 1, 3-dihydroxypropan-2-yl 4-methylbenzenesulfonate
2-phenyl-1, 3-dioxa-5-yl 4-methylbenzenesulfonate (2g, 5.98mmol) was dissolved in a mixed solution of 30mL of methanol and 15mL of dichloromethane, p-toluenesulfonic acid monohydrate (3.4 g, 17.94mmol) was added, reacted at room temperature for 12h, stirred dry, and purified by flash purification chromatography (petroleum ether: ethyl acetate =30: 70) to give 1, 3-dihydroxypropan-2-yl 4-methylbenzenesulfonate (1g, 67.9%).
HRMS calcd for C10H14O5S 246.0562；found,247.1429[M+H] + .
3) 2- (2-Nitro-1H-imidazol-1-yl) propane-1, 3-diol
2-Nitroimidazole (600mg, 5.31mmol) was dissolvedIn 0.5M aqueous potassium hydroxide (10.6mL, 5.31mmol), the solution was dissolved by heating to 60 ℃ and then spin-dried to give an orange-yellow solid. The above solid was dissolved in acetonitrile, and 1, 3-dihydroxypropan-2-yl 4-methylbenzenesulfonate (1.9 g, 7.97mmol), 18-crown-6 (1.40g, 5.31mmol), N were added 2 Reacted at 90 ℃ for 48H under protection, then spin dried and taken up, by flash chromatography (dichloromethane: methanol =90 10) to give 2- (2-nitro-1H-imidazol-1-yl) propane-1, 3-diol (450mg, 45.3%). HRMS calcd for C6H9N3O4 187.0593; found,188.3152[ M ] +H] + .
4) 2- (2-Nitro-1H-imidazol-1-yl) propane-1, 3-diylbis (4-methylbenzenesulfonate)
2- (2-Nitro-1H-imidazol-1-yl) propane-1, 3-diol (450mg, 2.41mmol) was dissolved in DCM, triethylamine (4 mL), 4-dimethylaminopyridine (DMAP, 10mg, 0.08mmol), 4-toluenesulfonyl chloride (TsCl, 1.83g, 9.64mmol) were added in this order under ice-cooling, reaction was carried out at room temperature for 12 hours, and then the mixture was washed three times with water, and the organic phase layer was washed with Na 2 SO 4 After drying by flash purification chromatography (petroleum ether: ethyl acetate = 50), 2- (2-nitro-1H-imidazol-1-yl) propane-1, 3-diylbis (4-methylbenzenesulfonate) (460mg, 38.5%) was obtained.
1H NMR(300MHz,CDCl3)δ7.83(d,J＝8.2Hz,2H),7.43(d,J＝7.0Hz,4H),7.22(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),4.88(dd,J＝9.4,2.9Hz,1H),4.72(dd,J＝14.5,2.5Hz,1H),4.69–4.32(m,2H),4.14(q,J＝7.1Hz,1H),2.46(s,6H).HRMS calcd for C20H21N3O8S2 495.0770；found,496.0198[M+H] + .
5) 4-Methylbenzenesulfonic acid 3-azido-2- (2-nitro-1H-imidazol-1-yl) propyl
Dissolving 2- (2-nitro-1H-imidazol-1-yl) propane-1, 3-diylbis (4-methylbenzenesulfonate) (200mg, 0.40mmol) in 15mL of DMF, adding sodium azide (36.7 mg, 0.56mmol), reacting at 80 ℃ for 48H, washing with saturated saline three times, and separating the organic phase layer with anhydrous Na 2 SO 4 After drying, by flash purification chromatography (petroleum ether: ethyl acetate = 50), 4-methylbenzenesulfonic acid 3-azido-2- (2-nitro-1H-imidazol-1-yl) propyl (50mg, 34.2%) was obtained.
1H NMR(300MHz,CDCl3)δ7.55(d,J＝8.2Hz,2H),7.26(s,1H),7.08(d,J＝2.4Hz,2H),4.99–4.80(m,1H),4.71–4.66(m,1H),4.45–4.37(m,1H),3.89-3.83(m,1H),3.58–3.53(m,1H),2.47(s,3H).13C NMR(75MHz,CDCl3)δ146.65,138.76,131.17,130.20,128.47,127.58,127.43,77.46,77.24,77.03,76.61,76.46,51.74,50.67,21.69.HRMS calcd for C13H14N6O5S 366.0746；found,367.0217[M+H] + .
6) 1- (1-azido-3-fluoropropan-2-yl) -2-nitro-1H-imidazole
4-Methylbenzenesulfonic acid 3-azido-2- (2-nitro-1H-imidazol-1-yl) propyl (50mg, 0.13mmol) was dissolved in 5mL of a mixed solution of tertiary nonalcoholic and 0.5mL of acetonitrile, and potassium fluoride (23mg, 0.39mmol), 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8] hexacosane (K222, 110mg, 0.29mmol), potassium carbonate (20mg, 0.14mmol) were added, reacted at 90 ℃ for 24 hours, followed by spin-dry sampling, and 1- (1-azido-3-fluoropropan-2-yl) -2-nitro-1H-imidazole (1mg, 35.9%) was obtained by flash purification chromatography (petroleum ether: ethyl acetate = 65).
1H NMR(300MHz,CDCl3)δ7.69(t,J＝10.1Hz,1H),7.23(s,1H),6.16–5.91(m,1H),5.11–4.60(m,1H),4.08(d,J＝6.0Hz,2H),3.90–3.32(m,1H).HRMS calcd for C6H7FN6O2 214.0615；found,215.1329[M+H] + .
Example 5- (2-azido-3-fluoropropyl) -2-nitro-1H-imidazole
The structural formula is as follows:
synthetic route to example 5 referring to example 4, yield 25%, HRMS calcd for C6H7FN6O2 214.0615; found,215.2314[ M ] +H] + .
Example 6 1- (4- (2- (fluoro-) 18 F) Synthesis and stability of ethyl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one
The structural formula is as follows:
the reaction formula is as follows:
the experimental steps are as follows:
a) Will be provided with 18 F - Use 1mL K222/K from QMA column 2 CO 3 Solution (220mg K222 in 18.6mL acetoonitrile/40 mg K 2 CO 3 in 3.4mL water) into a reaction tube;
b) At 80 ℃ and N 2 Purging to dry the eluent; adding 1mL of anhydrous acetonitrile to the evaporation residue and evaporating to dryness again, repeating three times to obtain dried product 18 F - /K222/K 2 CO 3 A complex compound;
c) Cooling the reaction solution; to the above-mentioned drying 18 F - /K222/K 2 CO 3 Adding 2mg of 4-methylbenzenesulfonic acid 2- (1- (2- (2- (2-nitro-1H-imidazole-1-yl) acetyl) piperidine-4-yl) ethyl solution (dissolved in 1mL of acetonitrile) into the complex, and reacting at 80 ℃ for 10min;
d) Adding 20mL of water into the reaction tube; passing the diluted reaction solution through an Oasis HLB solid phase extraction column;
e) Washing the Oasis HLB solid phase extraction column with 10mL of a 9/1 water/ethanol solution;
f) Diluting the flushing liquid and then enriching the flushing liquid on an Oasis HLB solid-phase extraction column;
g) The crude product was washed with 1mL of ethanol; purifying by semi-preparative HPLC (Phenomenex Gemini-Nx C18A (250 × 4.6 mm), 0-15min,10mM ammonium acetate 90-10%, acetonitrile 10-90%, peak-off time of 9.696min, purity of more than 95%;
h) Labeled 1- (4- (2- (fluoro-) - 18 F) Ethyl) piperidin-1-yl) -2- (2-nitro-1H-imidazol-1-yl) ethan-1-one was placed in PBS and mouse serum, incubated at 37 ℃ for 2 hours, removed at 5min, 30min, 60min and 120min and assayed for radiochemical purity (RCP) by Radio-HPLC, showing RCP within 2 hours of compound>95 percent, indicating that the compound has better stability.
Example 6 in vitro EMT-6 cell uptake assay
1. The experimental procedure was as follows:
1) Human breast cancer EMT-6 cell lines were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin/streptomycin. Digesting the cells from the culture dish into a single cell suspension, uniformly blowing, and taking 10mL (the concentration is 2 multiplied by 10) 6 cells/mL), transferred to two sterilized, sterilized 25mL three-necked bottles, with a constant water bath temperature of 37 ℃ and a rotation speed of 200-300rpm. Introducing 95% nitrogen-5% carbon dioxide saturated with water into the oxygen-lacking system, introducing 95% oxygen-5% carbon dioxide saturated with water into the oxygen-containing body, and stirring and pre-balancing for 1 hour;
2) Taking 100. Mu.L of the labeled compound and [ [ solution ] ] 18 F]FMISO (1 mCi/mL) is added into two reaction bottles respectively, the mixture is shaken up fully, and timing is started;
3) Respectively taking 200 μ L cell suspension sample in a centrifuge tube at 5min, 30min, 60min, 120min, 180min and 240min, and taking 4 times in parallel;
4) Centrifuging the sample at 2000rpm for 5min to separate cells and culture solution;
5) A radioactive count of 90. Mu.L of the supernatant was taken and measured, along with the radioactive count of the remaining 110. Mu.L of EMT-6-containing cell line solution. The uptake of the compound in the cell is expressed as Cin/Cout:
table 1: cellular uptake assay of Compounds
| Compound (I) | Hypoxic Cin/Cout | Normoxic Cin/Cout |
| 18 F-MISO | 0.19±0.12 | 0.13±0.03 |
| Example 5 | 0.25±0.13 | 0.18±0.02 |
| 18 F-example 2 | 0.29±0.05 | 0.19±0.03 |
| 18 F-example 3 | 0.26±0.06 | 0.16±0.05 |
| 18 F-example 4 | 0.33±0.07 | 0.19±0.06 |
As shown in Table 1, the compound of the present invention has high tumor cell uptake and is suitable for hypoxia imaging.
Example 7 biodistribution in EMT-6 tumor mice
Female EMT-6 breast cancer model mice (BALB/c mice) were selected, 5 mice per group. Adding 10% ethanol-normal saline a diluted labeled compound and [ 2 ] 18 F]FMISO (. About.100 MBq/mL) was injected tail vein (0.1 mL) into mice and timed. Killing at 60min, dissecting viscera, weighing, measuring radioactivity count of each tissue, and calculating uptake value and target-to-non-target ratio (including tumor-to-blood ratio, and tumor ratio)To muscle ratio). As shown in Table 2, the compounds of the present invention have high tumor uptake and are suitable for hypoxia imaging.
Table 2: tumor to blood ratio and tumor to meat ratio of the compound
| Compound (I) | Tumor to blood ratio | Tumor meat ratio |
| F-MISO | 0.95±0.08 | 1.06±0.11 |
| Example 5 | 2.15±0.18 | 2.91±0.08 |
| 18 F-example 2 | 2.76±0.13 | 3.11±0.12 |
| 18 F-example 3 | 2.85±0.10 | 2.53±0.04 |
| 18 F-example 4 | 3.91±0.14 | 2.86±0.09 |
Example 8 example 5 Micro-PET imaging in EMT-6 tumor mice
EMT-6 breast cancer model mice (BALB/c mice) are prepared before the experiment, micro-PET imaging is carried out when tumors grow to be about 0.5cm, and fasting is carried out for 8 hours before imaging. On the day of the experiment, the labeled compound was diluted with saline, and the drug (-4mbq, 0.2ml) was aspirated through an insulin needle and injected into mice via the tail vein. The mice were anesthetized with 2% isoflurane gas and then fixed on a PET examination table, then CT scout scan was performed, and PET scan was performed 60min after injection, and the scan images were analyzed using AMIDE software. As can be seen from FIG. 1, example 5 can be used for hypoxic tumor imaging.
While the foregoing is directed to the preferred embodiment of the present invention, it will be appreciated by those skilled in the art that various changes and modifications may be made therein without departing from the principles of the invention as set forth in the appended claims.
Claims (11)
1. A nitroimidazole derivative for preparing oxygen-lacking developer is selected from the group consisting of the derivatives of formula
wherein F is 18 F。
2. The method of preparing nitroimidazole derivatives according to claim 1, comprising:
providing a precursor compound with the structural formula, and carrying out fluorination reaction to obtain the nitroimidazole derivative.
3. The method according to claim 2, wherein when the nitroimidazole derivative is a labeled compound, the method further comprises:
a) Will be dried 18 F - /K222/K 2 CO 3 Adding the complex into a solution containing a precursor compound to obtain a reaction solution; the solvent of the solution is acetonitrile;
b) Reacting the reaction solution for 10min at the temperature of 80-100 ℃;
c) After the reaction is finished and cooled, adding proper amount of high-purity water, and passing through an activated Oasis HLB solid-phase extraction column;
d) The volume ratio is 9:1, washing the Oasis HLB solid-phase extraction column by using a water/ethanol mixed solution to obtain a washing solution;
e) Diluting the flushing liquid and then enriching the flushing liquid on an Oasis HLB solid-phase extraction column;
f) And leaching with ethanol to obtain a crude product of the nitroimidazole derivative.
4. The method of claim 3, wherein the Oasis HLB solid phase extraction column is activated by a method comprising the steps of: the Oasis column was rinsed with 10mL of ethanol, then the column was air-dried with 10mL, then the column was rinsed with 10mL of high purity water, and finally the column was air-dried with 10 mL.
5. The method of claim 3, further comprising:
g) Purifying the crude nitroimidazole derivative product by using semi-preparative HPLC, wherein the semi-preparative HPLC purification conditions comprise: phenomenex Gemini-Nx with the thickness of 250 multiplied by 4.6mM is taken as a chromatographic column, and 10mM ammonium acetate 90% -10% and acetonitrile 10% -90% are respectively taken as gradient mobile phases for 0-15min.
6. The method of claim 3, wherein the step of preparing the composition is carried out in the presence of a catalyst 18 F - /K222/K 2 CO 3 Is prepared by the following steps:
1) At K222/K 2 CO 3 The solution is to 18 F - Eluting from the QMA column into a reaction tube;
2) Removing the solvent from the eluate to obtain an evaporation residue;
3) Adding appropriate amount of anhydrous acetonitrile into the evaporation residue, evaporating to dryness, and repeating for several times to obtain dried product 18 F - /K222/K 2 CO 3 A complex compound.
7. The method of claim 6, wherein K222/K is 2 CO 3 The solution is prepared by mixing K222 in acetonitrile with K 2 CO 3 Wherein K222 is mixed with K 2 CO 3 In a molar ratio of 1 to 4:1.
8. the method according to claim 7, wherein the concentration of the acetonitrile solution of K222 is 0.1 to 0.4mol/L, and the K is 2 CO 3 The concentration of the aqueous solution of (a) is 0.05 to 0.2mol/L.
9. Use of nitroimidazole derivatives according to claim 1 for the preparation of imaging agents for the diagnosis of hypoxia-related diseases.
10. The use of claim 9, wherein the hypoxia-related disease is selected from one or more of a tumor, stroke, and atherosclerosis.
11. A PET imaging agent for diagnosing hypoxia-related diseases, comprising the nitroimidazole derivative according to claim 1.
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