CN110204484B - The method comprises the following steps of 18 F-labeled fluoropyridine formylglycine, and preparation method and application thereof - Google Patents
The method comprises the following steps of 18 F-labeled fluoropyridine formylglycine, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a kind of 18 F-labeled fluoropyridine formylglycine, preparation method and application thereof, belonging to the field ofIn the technical field of radiopharmaceutical chemistry. The invention provides 18 F-labeled fluoropyridine formylglycine is 6- [ 18 F]-fluoro-3-pyridineformylglycine, 5- [ 18 F]-fluoro-2-pyridineformylglycine or 4- [ 18 F]-fluoro-2-pyridine formylglycine. The invention provides 18 F marked fluoropyridine formylglycine has excellent stability, good biological performance, no adverse effect on organisms after decay, and is proved by in vivo distribution test, 18 f-labeled fluoropyridine formylglycine is mainly taken up by kidney and rapidly discharged from body 18 F-labeled fluoropyridine formylglycine is injected into a mouse body for 10min and then almost completely discharged into the bladder, and the invention provides 18 F-labeled fluoropyridine formylglycine is particularly advantageous for evaluation of renal function of renal lesions.
Description
Technical Field
The invention relates to the technical field of radiopharmaceuticals, in particular to a method for preparing a medicine 18 F marked fluoropyridine formylglycine, a preparation method and application thereof.
Background
Positron Emission Tomography (PET) technology is an important means for diagnosing diseases based on molecular level, and is widely applied and affirmed in clinic and scientific research due to the advantages of good spatial resolution, quantitative analysis and the like. However, the current nuclear medicine field remains on SPECT for urinary system imaging equipment, and the main imaging agent is still 99m Tc-DTPA 99m Tc-MAG3。 99m Tc-DTPA is mainly used for clinical determination of Glomerular Filtration Rate (GFR) due to almost total discharge from plasma via glomeruli, but is not very accurate in the determination of GFR due to limitations of SPECT imaging equipment, in part because of inaccurate manual delineation of double kidney ROI in clinic, and because of influence of background and kidney depth and surrounding tissues on radio detection, which influence to different extent in the clinically accurate determination of double kidney GFR. And in injection 99m Tc-DTPAIn the aspect of posterior kidney imaging, due to 99m The uptake rate of Tc-DTPA is only 20% of the injection dose, resulting in a lower kidney/background ratio, which is particularly detrimental to the visualization of the kidneys in patients with advanced renal insufficiency. Another developer 99m Tc-MAG3 is currently the most clinically used tubular secretory imaging agent with a renal extraction fraction of about 50% compared to 99m Tc-DTPA has a higher kidney/background ratio, thus obtaining a higher quality kidney image, and is more suitable for infants and patients with poor renal function, and is clinically mainly used for measuring the Effective Renal Plasma Flow (ERPF). But is provided with 99m Tc-MAG3 131 I-OIH is similar in kidney imaging, and cannot obtain high-quality kidney images. Thus, the above SPECT techniques using corresponding imaging drugs are incomparable in terms of both imaging quality and accurate quantitative analysis compared to PET/CT. For the above reasons, many domestic and foreign expert scholars are strived to develop a novel imaging agent with biological properties suitable for the PET/CT scanning of the kidney so as to replace the defects of the traditional imaging equipment and the imaging agent on the kidney imaging, thus 15 O-H 2 O、 13 N-NH 3 、 82 Rb-Rb 1 、 62 CuCu(II)pyruvaldehydebis-(N-4-methylthiosemicarbazonato)、 62 Cu-Cu(II)ethylglyoxal bis(thiosemicarbazone)、 68 Ga-Ga-ethylenediaminetetraaceticacid、 55 Co-Co-ethylenediaminetetraacetic acid 18 Positron imaging agents such as F-NaF and the like are sequentially applied, but the imaging agents have not been truly applied to clinically serving patients due to short half-life time, high cost and the like. In recent years Vibhudutta Awasthi et al developed a novel kidney imaging agent p- 18 F-fluorohippurate( 18 F-PFH), which is most preferably excreted by the urinary system, and 131 I-OIH shows higher kidney/background ratio than that of the liver, and is not metabolized by the biliary tract system of the liver, the uptake of other tissues and organs except the kidney is lower, and the kidney imaging effect is ideal, but 18 The F-PFH synthesis procedure is cumbersome and takes a long time, resulting in a decrease in yield. Based on the above research result of VibhuduttaAwasthi et alAnother structurally similar imaging agent was developed 18 F-CNPFH, compared with 18 The F-PFH synthesis step is relatively simple, but the background around the kidney is relatively high due to the metabolic phenomenon of the imaging agent in the biliary tract system of the liver, so that the imaging effect is not ideal.
Disclosure of Invention
The invention aims to provide a method for manufacturing a semiconductor device 18 F-labeled fluoropyridine formylglycine, and preparation method and application thereof, provided by the invention 18 F-labeled fluoropyridine formylglycine has the advantages of excellent stability, good biological performance, high kidney uptake rate and fast metabolism.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a kind of 18 F-labeled fluoropyridine formylglycine, an 18 F-labeled fluoropyridine formylglycine is 6- [ 18 F]-fluoro-3-pyridineformylglycine, 4- [ 18 F]-fluoro-2-pyridineformylglycine or 5- [ 18 F]-fluoro-2-pyridine formylglycine.
The invention also provides the technical scheme 18 The preparation method of F-labeled fluoropyridine formylglycine comprises the following steps:
(1) Bromopyridine formylglycine ester, solvent and [ 18 F] - Mixing the sources, performing nucleophilic reaction, and purifying to obtain 18 F-fluoropyridine formylglycine ester; said [ 18 F] - The source contains 18 F] - And a catalyst; the bromopyridine formylglycine is 6-bromo-3-pyridine formylglycine, 5-bromo-2-pyridine formylglycine or 4-bromo-2-pyridine formylglycine;
(2) The said 18 F-fluoropyridine formylglycine is mixed with sodium hydroxide solution to carry out hydrolysis reaction, then the mixture is subjected to acidic ion exchange column, and then the mixture is filtered by a sterile filter membrane to obtain the product in solution 18 F-labeled fluoropyridine formylglycine.
Preferably, the ester group in the bromopyridine formylglycine is methyl ester group, ethyl ester group, propyl ester group, isopropyl ester group, butyl ester group, tert-butyl ester group, isobutyl ester group or benzyl ester group.
Preferably, the catalyst comprises a phase transfer catalyst and a base catalyst.
Preferably, the phase transfer catalyst is K222 or TBAHCO 3 。
Preferably, the base catalyst is K 2 CO 3 、KHCO 3 、K 2 (COO) 2 Or Cs 2 CO 3 。
Preferably, the nucleophilic reaction temperature is 90-150 ℃ and the time is 5-30 min.
Preferably, the purification is liquid chromatography purification.
The invention also provides the technical proposal 18 Use of F-labelled fluoropyridine formylglycine as PET/CT imaging agent.
Preferably, the said 18 F-labeled fluoropyridine formylglycine is used as a PET/CT kidney imaging agent.
The invention provides a kind of 18 F-labeled fluoropyridine formylglycine, an 18 F-labeled fluoropyridine formylglycine is 6- [ 18 F]-fluoro-3-pyridineformylglycine, 5- [ 18 F]-fluoro-2-pyridineformylglycine or 4- [ 18 F]-fluoro-2-pyridine formylglycine. The invention provides 18 F marked fluoropyridine formylglycine has excellent stability, the radiochemical purity is still more than 95% after being placed for 120min, the biological performance is good, no adverse effect is caused to organisms after decay, and the in vivo distribution test shows that, 18 f-labeled fluoropyridine formylglycine is mainly taken up by kidney and rapidly discharged from body 18 F-labeled fluoropyridine formylglycine is injected into a mouse body for 10min and then almost completely discharged into the bladder, and can be used as a PET/CT kidney imaging agent to realize the kidney function imaging of PET, so that the invention provides 18 F-labeled fluoropyridine formylglycine is particularly advantageous in early stages of renal function impairment in renal lesions.
Drawings
FIG. 1 is 6- [ 19 F]-fluoro-3-pyridineformylglycineIs a ultraviolet peak diagram of (2);
FIG. 2 is 6- [ 18 F]-emission peak pattern of fluoro-3-pyridine formylglycine;
FIG. 3 is 6- [ 18 F]-TLC profile of fluoro-3-pyridine formylglycine;
FIG. 4 is precursor compound 6- [ 18 F]-preparative HPLC separation chromatographic profile of fluoro-3-picolinalyl glycine methyl ester;
FIG. 5 shows injection 6- [ 18 F]-urine HPLC profile of healthy SD rats 30min after fluoro-3-picolinalyl glycine injection;
FIG. 6 is a PET/CT image obtained in application example 4;
FIG. 7 is a graph showing the time-activity of the double kidney obtained in application example 4.
Detailed Description
The invention provides a kind of 18 F-labeled fluoropyridine formylglycine, an 18 F-labeled fluoropyridine formylglycine is 6- [ 18 F]-fluoro-3-pyridineformylglycine, 5- [ 18 F]-fluoro-2-pyridineformylglycine or 4- [ 18 F]-fluoro-2-pyridine formylglycine; the 6- [ 18 F]The structure of the-fluoro-3-pyridine formylglycine is shown as a formula I, and the 5- [ 18 F]The structure of the-fluoro-2-pyridine formylglycine is shown as a formula II, and the 4- [ 18 F]The structure of the-fluoro-2-pyridine formylglycine is shown as a formula III;
the invention also provides the technical scheme 18 The preparation method of F-labeled fluoropyridine formylglycine comprises the following steps:
(1) Bromopyridine formylglycine ester, solvent and [ 18 F] - Mixing the sources, performing nucleophilic reaction, and purifying to obtain 18 F-fluoropyridine formylglycine ester; said [ 18 F] - The source contains 18 F] - And a catalyst; the bromopyridine formylglycine is 6-bromo-3-pyridine formylglycine, 5-bromo-2-pyridine methylAcyl glycinate or 4-bromo-2-pyridine formylglycinate;
(2) The said 18 F-fluoropyridine formylglycine is mixed with sodium hydroxide solution to carry out hydrolysis reaction, then the mixture is subjected to acidic ion exchange column, and then the mixture is filtered by a sterile filter membrane to obtain the product in solution 18 F-labeled fluoropyridine formylglycine.
The raw materials used in the preparation method provided by the invention are easy to obtain, and the method can obtain 18 F-labeled fluoropyridine formylglycine has the advantages of high chemical purity, simple process and easy operation, and can be automatically prepared by using a conventional multifunctional synthesis mode.
The invention combines bromopyridine formylglycine ester, solvent and [ 18 F] - Mixing the sources, performing nucleophilic reaction, and purifying to obtain 18 F-fluoropyridine formylglycine ester; said [ 18 F] - The source contains 18 F] - And a catalyst; the bromopyridine formylglycine is 6-bromo-3-pyridine formylglycine, 5-bromo-2-pyridine formylglycine or 4-bromo-2-pyridine formylglycine.
In the present invention, the ester group in the bromopyridine formylglycine ester is preferably a methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl or benzyl group.
The source of the bromopyridine formyl glycine ester is not particularly limited, and the bromopyridine formyl glycine ester can be self-made or purchased; in the embodiment of the invention, the bromopyridine formylglycine ester is preferably prepared by the following steps:
activating carboxyl of bromopicolinic acid to obtain activated bromopicolinic acid; the bromopicolinic acid is 6-bromo-3-picolinic acid, 5-bromo-2-picolinic acid or 4-bromo-2-picolinic acid;
and (3) carrying out an acylation reaction on the activated bromopyridine carboxylic acid and glycine ester or glycine ester hydrochloride to obtain bromopyridine formyl glycine ester.
The carboxyl of the bromopicolinic acid is activated to obtain activated bromopicolinic acid; the bromopicolinic acid is 6-bromo-3-picolinic acid (CAS number: 6311-35-9), 5-bromo-2-picolinic acid (CAS number: 30766-11-1) or 4-bromo-2-picolinic acid (CAS number: 30766-03-1).
The method of activation is not particularly limited, and a carboxyl group activation method commonly used in the art may be used. In an embodiment of the present invention, the method of activation preferably includes the steps of: mixing bromopicolinic acid, N-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and a solvent, and performing an activation reaction to obtain activated bromopicolinic acid; the bromopicolinic acid is 6-bromo-3-picolinic acid, 5-bromo-2-picolinic acid or 4-bromo-2-picolinic acid.
In the invention, the N, N-dicyclohexylcarbodiimide is taken as a carboxyl activator, and the 4-dimethylaminopyridine is taken as an alkaline catalyst, and in the activation process, the carboxyl of bromopyridine carboxylic acid is activated, so that the bromopyridine carboxylic acid can undergo an acylation reaction in a subsequent step. In the present invention, when bromopicolinic acid is 6-bromo-3-picolinic acid, the resulting product is 6- [ 18 F]-fluoro-3-picolinic acid glycine, which when 5-bromo-2-picolinic acid is the product obtained is 5- [ 18 F]-fluoro-2-picolinic acid glycine, which when 4-bromo-2-picolinic acid is 4- [ product 18 F]-fluoro-2-pyridine formylglycine.
In an embodiment of the present invention, the solvent used in the step of activating reaction is preferably dichloromethane, and the dichloromethane is preferably anhydrous dichloromethane; the amount of the solvent is not particularly limited in the present invention, and in the embodiment of the present invention, the ratio of the amount of the bromopicolinic acid to the solvent is preferably 1 g/20 mL.
In the embodiment of the present invention, the temperature of the activation reaction is preferably-10 to 10 ℃, more preferably-5 to 5 ℃, and the time is preferably 15 to 60min, more preferably 30 to 35min.
In an embodiment of the present invention, the molar ratio of bromopicolinic acid, N-dicyclohexylcarbodiimide and 4-dimethylaminopyridine is preferably 1:1.2:0.6.
In the embodiment of the present invention, after the activation is completed, the reaction liquid obtained by the activation is preferably directly used in the subsequent step.
After activated bromopyridine carboxylic acid is obtained, the activated bromopyridine carboxylic acid and glycine ester or glycine ester hydrochloride are subjected to acylation reaction to obtain bromopyridine formyl glycine ester.
In the present invention, when the activated bromopyridine carboxylic acid and glycine ester undergo an acylation reaction, it is particularly preferable that glycine ester and solvent are mixed and then added dropwise to the activated bromopyridine carboxylic acid to undergo an acylation reaction to obtain bromopyridine formylglycine ester.
In the present invention, the glycine ester is preferably at least one of methyl glycine, ethyl glycine, propyl glycine, isopropyl glycine, butyl glycine, t-butyl glycine, isobutyl glycine and benzyl glycine; the type of the bromopyridine formylglycine ester is a corresponding type of glycine ester, such as when glycine ester is methyl glycine ester, the bromopyridine formylglycine ester is methyl bromopyridine formylglycine ester.
In the present invention, when the activated bromopyridine carboxylic acid and glycine ester hydrochloride undergo an acylation reaction, it is particularly preferable that glycine ester hydrochloride, triethylamine and a solvent are mixed and then added dropwise to the activated bromopyridine carboxylic acid to undergo an acylation reaction, thereby obtaining bromopyridine formylglycine. In the invention, in the process of the acylation reaction, triethylamine is used as alkali to neutralize the hydrochloride in the glycine ester hydrochloride raw material, and the obtained glycine ester and the activated bromopyridine carboxylic acid undergo the acylation reaction to generate bromopyridine formyl glycine ester.
In the present invention, the glycine ester hydrochloride is preferably at least one of glycine methyl ester hydrochloride, glycine ethyl ester hydrochloride, glycine propyl ester hydrochloride, glycine isopropyl ester hydrochloride, glycine butyl ester hydrochloride, glycine tert-butyl ester hydrochloride, glycine isobutyl ester hydrochloride and glycine benzyl ester hydrochloride; the type of the bromopyridine formylglycine ester is the type of the ester corresponding to glycine ester hydrochloride, such as when glycine ester hydrochloride is glycine methyl ester hydrochloride, the bromopyridine formylglycine ester is bromopyridine formylglycine methyl ester.
In the present invention, the solvent used in the step of the acylation reaction is preferably methylene chloride, and the methylene chloride is preferably anhydrous methylene chloride; the amount of the solvent is not particularly limited in the present invention, and in the embodiment of the present invention, the ratio of the amount of the bromopicolinic acid to the solvent is preferably 1 g/15 mL.
In the invention, the molar ratio of the bromopicolinic acid to the glycine ester or the corresponding glycine ester hydrochloride is preferably 1:1-1.8.
In the present invention, when the activated bromopicolinic acid is subjected to an acylation reaction with glycine ester hydrochloride, the molar ratio of bromopicolinic acid to triethylamine is preferably 1:1 to 1.8.
In the invention, the mixed solution of glycine ester and solvent or the mixed solution of glycine ester hydrochloride, triethylamine and solvent is added in a dropwise manner, so that a large amount of heat generated in the reaction can be avoided.
In the invention, the dripping process preferably keeps the temperature of the activated bromopyridine carboxylic acid at-10 to 10 ℃, and after the dripping is completed, the obtained reaction solution is heated to room temperature for acylation reaction; the temperature rising rate is not particularly limited, and the room temperature can be reached, in the embodiment of the invention, the temperature of the activated bromopyridine carboxylic acid is kept at-10 ℃ preferably through a low-temperature water bath, and after the dripping is completed, the low-temperature water bath is removed, so that the obtained reaction solution naturally rises to the room temperature; the temperature of the room temperature is preferably 20 to 35 ℃.
In the present invention, the time of the acylation reaction is preferably 0.1 to 20 hours; the time for the acylation reaction is preferably from the time when the reaction solution is warmed up to room temperature.
In the present invention, it is preferable to verify whether the acylation reaction is complete by TLC (thin layer chromatography), and if the reaction is complete, the subsequent step is performed, and if not, the reaction is continued.
After the acylation reaction is finished, the reaction liquid obtained by the acylation reaction is preferably filtered, and then the obtained filtrate is distilled to 0.1-2 mL, and column chromatography purification is carried out to obtain bromopyridine formyl glycine ester; the filtration can remove insoluble matters in the reaction solution.
In the invention, the chromatographic column used for the column chromatography purification is preferably a 300-400 mesh silica gel column; the eluent of the column chromatography purification is preferably a mixed solution of dichloromethane and methanol; the volume ratio of dichloromethane to methanol is preferably 50:1.
In the present invention, the solvent in the nucleophilic reaction step is preferably dimethyl sulfoxide, acetonitrile, N-dimethylformamide or tetrahydrofuran, more preferably dimethyl sulfoxide, the amount of the solvent is not particularly limited, and in the embodiment of the present invention, the ratio of the amount of the bromopyridine formylglycine to the amount of the solvent is preferably 1 to 25mg:0.5 to 2.0mL.
In the present invention, the catalyst preferably includes a phase transfer catalyst and a base catalyst; the phase transfer catalyst is preferably K222 (i.e. Kryptofix 2.2.2) or TBAHCO 3 (i.e., tetra-n-butyl ammonium bicarbonate), the base catalyst is preferably K 2 CO 3 、KHCO 3 、K 2 (COO) 2 Or Cs 2 CO 3 . The invention is directed to the [ 18 F] - The method for preparing the source is not particularly limited, and is conventional in the art 18 F] - The preparation method of the source is enough, in the embodiment of the invention, the 18 F] - The preparation method of the source is preferably capturing using a Sep Pak QMA column 18 F] - Then, the eluent of 0.5-3 mL phase transfer catalyst/alkali catalyst, preferably 1.5mL eluent, is used for eluting, the liquid obtained by eluting is heated to remove the solvent, then 1mL acetonitrile is added for azeotropic distillation, thus obtaining [ 18 F] - A source; the mass ratio of the phase transfer catalyst to the alkali catalyst in the phase transfer catalyst/alkali catalyst eluent is preferably 17.7:4.1, the solvent is acetonitrile and water, and the volume ratio of the acetonitrile to the water is 10:1; the mass of phase transfer catalyst in 1.5mL of the phase transfer catalyst/base catalyst eluate is preferably 17.7mg.
In the examples of the present invention, 1.5mL of phase transfer catalyst/base catalyst eluate was used to prepare the catalyst 18 F] - The source preferably requires 1 to 25mg of bromopyridine formylglycine, more preferably 10mg.
In the present invention, the temperature of the nucleophilic reaction is preferably 90 to 150 ℃, more preferably 120 to 130 ℃, and the time is preferably 5 to 30min, more preferably 10 to 20min.
After the nucleophilic reaction is completed, the reaction solution obtained by the nucleophilic reaction is preferably purified in the present invention.
In the present invention, the purification is preferably liquid chromatography purification. In the present invention, the liquid chromatography purification can remove the phase transfer catalyst in the reaction system, and can also completely remove the unreacted precursor, namely bromopyridine formylglycine ester.
Purifying by liquid chromatography to obtain a liquid extract containing 18 F-fluoropyridine formylglycine ester eluent, and then evaporating the solvent to obtain 18 F-fluoropyridine formylglycine ester.
Obtaining 18 After F-fluoropyridine formylglycine ester, the invention leads to the following 18 Mixing F-fluoropyridine formylglycine with sodium hydroxide solution, performing hydrolysis reaction, passing through acidic ion exchange column (ICH-H column or IC-H column), and filtering with sterile filter membrane to obtain the final product 18 F-labeled fluoropyridine formylglycine, the obtained solution is a solution containing 18 F-labeled fluoropyridine formylglycine injection.
In the present invention, the concentration of the sodium hydroxide solution is preferably 1mol/L to 4mol/L, more preferably 2mol/L; in an embodiment of the present invention, when the bromopyridine formylglycine is 10.0mg, the sodium hydroxide solution is preferably used in an amount of 0.1 to 1mL.
In the present invention, the time of the hydrolysis reaction is preferably 2 to 10 minutes, more preferably 5 minutes; the temperature is preferably room temperature, which is preferably 10 to 35 ℃, more preferably 20 to 25 ℃.
After the hydrolysis reaction is completed, the reaction solution obtained by the hydrolysis reaction is preferably mixed with water and then passed through an acidic ion exchange column (i.e., ICH-H column or IC-H column). In the embodiment of the invention, the IC-H column is an ion chromatography SPE column purchased from AlltechMaxi-Clean manufacturer, and the filler is IC-H (namely H-type polystyrene strong acid resin). In the present invention, the IC-H column is capable of neutralizing sodium hydroxide used for alkaline hydrolysis.
In the practice of the inventionIn the examples, the amount of water to be mixed with the reaction solution obtained by the hydrolysis reaction is preferably 1 to 10mL, more preferably 3mL. In the present invention, the water is added to generate 18 F-labeled fluoropyridine formylglycine was passed through IC-H column to obtain a proper concentration 18 F-labeled fluoropyridine formylglycine injection.
After the acidic ion exchange column is passed through, the obtained eluent is sterile filtered, and in the solution the invented product is obtained 18 F-labeled fluoropyridine formylglycine. In the present invention, obtained 18 F-labelled fluoropyridine formylglycine dispersed in a solution comprising 18 F-labeled fluoropyridine formylglycine injection can be directly used as PET/CT imaging agent.
In the present invention, in the solution 18 The yield of F-marked fluoropyridine formylglycine is 10-25%.
The invention also provides the technical proposal 18 Use of F-labelled fluoropyridine formylglycine as PET/CT imaging agent.
In the present invention, the 18 F-labeled fluoropyridine formylglycine is preferably used as a PET/CT kidney imaging agent. In the invention, the preparation method of the technical scheme comprises the steps of 18 The F-labeled fluoropyridine formylglycine injection can be directly used as PET/CT imaging agent.
The invention is provided below in connection with the examples 18 F-labeled fluoropyridine formylglycine, a process for its preparation and its use are described in detail, but they are not to be construed as limiting the scope of the invention.
Example 1
6-bromo-3-pyridinecarboxylic acid (1.00 g,4.95 mmol), N-dicyclohexylcarbodiimide (1.22 g,5.94 mmol), 4-dimethylaminopyridine (0.36 g,2.97 mmol) and anhydrous dichloromethane (20 mL) were mixed, stirred uniformly in an ice-water bath (0deg.C), and reacted for 30 minutes to give a reaction solution containing activated 6-bromo-3-pyridinecarboxylic acid;
triethylamine (0.82 mL,5.94 mmol), glycine methyl ester hydrochloride (0.75 g,5.94 mmol) and anhydrous dichloromethane (15 mL) are mixed and added dropwise into a reaction solution containing activated 6-bromo-3-picolinic acid, after the dropwise addition is finished, the reaction solution is returned to room temperature (23 ℃), the reaction is continuously stirred for 20 hours, TLC detection is finished, then filtration is carried out, the obtained filtrate is subjected to reduced pressure rotary evaporation, then a 300-400-mesh silica gel column is used as a chromatographic column for column chromatography, eluent used by the column chromatography is a mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 50:1; sequentially performing rotary evaporation and drying on the collected eluent to obtain 0.98g of light yellow powdery solid, namely precursor compound 6-bromo-3-pyridine formylglycine methyl ester, with the yield of 73.13%; the molecular weight of the 6-bromo-3-picolinalyl glycine methyl ester was determined by high resolution mass spectrometry to be [ m+h ] = 272.9883, and the theoretical molecular weight was 273.00.
[ 18 F] - 1.5mL of K222 (17.7 mg)/K was used after capture on a Sep Pak QMA column 2 CO 3 (4.1 mg) of the solution (solvent: acetonitrile/water mixed solution in a volume ratio of 10:1) was eluted, the resulting eluate was heated to 110℃and azeotropically evaporated to dryness to remove the solvent, and then 1mL of acetonitrile was added and azeotropically evaporated to dryness again to give [ the above-mentioned composition ] 18 F] - A source;
will 370MBq [ 18 F] - The source was mixed with 0.8mL of a dimethyl sulfoxide solution of the precursor compound, methyl 6-bromo-3-picolinate (containing 10.0mg of the precursor compound), and reacted for 15min at 120℃under sealed heating; after the reaction is finished, the HPLC is used for purification, the chromatographic column used for purification is a C18 reverse phase column, the mobile phase is acetonitrile and water, the flow rate of the mobile phase is 3mL/min, the purification adopts gradient elution, and the conditions of the gradient elution are as follows: 90% (0-1 min), 90% -20% (1-20 min), 20% (20-30 min), collecting liquid with retention time of 14-16 min, evaporating solvent, adding 0.5mL of 2mol/L NaOH solution, standing for 5min, adding 1.5mL of water, mixing uniformly, passing through ICH-H column, and obtaining eluent with sterile filter membrane to obtain 6- [ 18 F]-fluoro-3-pyridine formylglycine injection having a pH of 6.0-7.0, which is suitable for PET/CT imaging of animals, to obtain 6- [ 18 F]The activity concentration of the-fluoro-3-pyridine formylglycine injection is adjusted to be 37MBq/mL.
Product 6- [ 18 F]-fluoro-3-pyridinecarboxylic acid methyl esterThe activity of acylglycine divided by the one used [ 18 F] - The activity of the source gave a corrected storage yield of 20.+ -. 5% for this example.
The chemical purity and radiochemical purity of the injection were determined by HPLC as shown in FIGS. 1 and 2, FIG. 1 is 6- [ 19 F]The UV peak of the-fluoro-3-pyridine formylglycine is shown in FIG. 2 as 6- [ 18 F]The emission peak of the fluorine-3-pyridine formylglycine, in order to further determine the chemical purity, the chemical purity was further measured by Thin Layer Chromatography (TLC), the result is shown in FIG. 3, and FIG. 4 is a precursor compound 6- [ 18 F]-preparative HPLC separation chromatographic profile of methyl fluoro-3-picolinate. As can be seen from FIGS. 1 to 4, intermediate 6- [ 18 F]Radiation peaks of the methyl-fluoro-3-pyridine formylglycine occur between 14 and 16min, the retention time is 2min, and 6- 19 The retention time of the ultraviolet peak of F-3-pyridine formylglycine is close, which indicates that the product is the target product 6- [ 18 F]-fluoro-3-pyridine formylglycine. The injection has an Rf value of 0.6 as determined by TLC (under the TLC conditions [ sic ] 18 F] - Rf value of (2) is less than 0.1), the radiochemical purity of the injection is seen to be more than 99%.
Will 6- [ 18 F]-fluoro-3-pyridine formylglycine injection, standing at room temperature, performing HPLC radiochemical purity measurement at 0min, 30min, 60min, 120min after labeling, radiochemical purity of 98%, 97% and 96% at 30min, 60min, 90min and 120min respectively, all higher than 95%, indicating 6- [ 18 F]The fluoro-3-pyridine formylglycine has excellent stability.
Tail vein injection of healthy SD rats 0.2mL 8.4MBq 6- [ 18 F]After 30min of injection, the urine of rat is collected, and the collected urine is detected by HPLC, the result is shown in figure 5, no new radioactive peak appears in the spectrogram, the retention time of the unique radioactive peak and 6- [ in the injection ] 18 F]The fluorine-3-pyridine formylglycine is the same, and the imaging agent in urine is not changed obviously, so that the fluorine-3-pyridine formylglycine has certain advantages as a potential PET/CT kidney imaging agent.
Example 2
The starting material 6-bromo-3-pyridinemethyl was prepared according to the method of example 1Acid substitution to 5-bromo-2-picolinic acid, preparation of 5- [ 18 F]-fluoro-2-pyridine formylglycine.
Test 5- [ according to the method of example 1 ] 18 F]The corrected conversion yield of the fluorine-2-pyridine formylglycine is 10+/-3%.
Example 3
Preparation of 4- [ following the procedure of example 1, substituting starting 6-bromo-3-pyridinecarboxylic acid with 4-bromo-2-pyridinecarboxylic acid 18 F]-fluoro-2-pyridine formylglycine.
Test 5- [ according to the method of example 1 ] 18 F]The corrected conversion yield of the fluorine-2-pyridine formylglycine is 13+/-6%.
Application example 1
Abnormal toxicity experiment:
healthy ICR mice were given 4 groups of 10 mice each, each with 6-post-decay intravenous injection [ 18 F]-fluoro-3-pyridine formylglycine injection (0.2 mL), and the mice were routinely kept for 48 hours and observed for growth.
6-aftertail vein infusion decay of mice 18 F]After 48 hours and one week of observation after-fluoro-3-picolinaylglycine, no adverse reactions and death occurred, and no organ damage was observed after dissection.
Testing 5- [ Using the same method ] 18 F]-fluoro-2-pyridine formylglycine injection and 4- [ 18 F]Abnormal toxicity of the-fluoro-2-pyridine formylglycine injection, and 6- [ 18 F]The fluoro-3-pyridine formylglycine injection is similar, the mice have no adverse reaction and death phenomenon, and no organ damage is observed after dissection.
The above results illustrate 6- [ 18 F]-fluoro-3-pyridine formylglycine injection, 5- [ 18 F]-fluoro-2-pyridine formylglycine injection and 4- [ 18 F]The fluorine-2-pyridine formylglycine injection is nontoxic to the body and can be further used for in vivo research.
Application example 2
Testing of blood cell binding Rate and plasma protein binding Rate, erythrocyte binding Rate:
3 female SD rats (200-220 g) were abdomen-fitted with 3.8% chloral hydrateAfter cavity anesthesia, 200. Mu.L of 6-obtained in example 1 was injected into the tail vein 18 F]-fluoro-3-pyridine formylglycine injection (radioactivity 7.4 MBq), after 5min 2.5mL of blood was taken, placed in heparin tubes, centrifuged for 5min and the blood cells were separated from the plasma samples. Radioactivity of blood cells and plasma was measured separately, and the blood cell binding rate after time correction and attenuation correction was equal to (blood cell radioactivity count/whole blood radioactivity count) ×100%, resulting in 29.8±7.7%.
1mL of the plasma specimen was placed in a ultrafiltration tube (molecular cut-off 30000), the ultrafiltration tube was washed with 500. Mu.L of a 5mg/mL PBS solution of 6-fluoro-3-picolinaylglycine in advance, centrifuged at 1667g for 45min, and the ultrafiltrate was collected. 50. Mu.L of plasma and 50. Mu.L of ultrafiltrate were counted in an r-counter, and the results were time-corrected and background-corrected. The plasma protein binding rate was equal to (1- [ ultrafiltrate count/plasma count ]) 100% and, as a result, 37.6.+ -. 5.3%.
By 5- [ 18 F]-fluoro-2-pyridine formylglycine injection and 4- [ 18 F]The fluoro-2-pyridine formylglycine injection shows similar properties when subjected to the above experiments.
Application example 3
In vivo biodistribution
Healthy SD rats 6 groups, 3 in each group, were injected with 0.2mL of 6-fluoro-3-pyridine formylglycine injection (7.4 MBq) obtained in example 1, and after 5min and 60min after injection, the 6-fluoro-3-pyridine formylglycine injection was sacrificed by neck breakage, and the tissue organs such as blood, heart, liver, lung, kidney, spleen, stomach, small intestine, large intestine, brain, muscle and bone were dissected, the radioactivity counts of the tissues or organs were measured, and the percent injection dose rate (% ID/g) per gram of tissue was calculated after decay correction, and the results are shown in Table 1.
The injection is mainly absorbed by kidneys and rapidly discharged out of the body after being injected into rats, the radioactive uptake rate of the kidneys is 1.00+/-0.28% ID/g and 0.07+/-0.04% ID/g respectively in 10min and 1h, the uptake amount of other tissue organs is small, the radioactive uptake of each organ or tissue except the bladder is obviously reduced along with the extension of time, the clearance is faster in blood, and the radioactive counts are 0.35+/-0.29% ID/g and 0.02+/-0.007% ID/g respectively after 10min and 1h. Accompanied by gradual concentration of radioactivity in urine; the bones have slight radioactive uptake, but the uptake value does not change obviously with time, which indicates that defluorination does not occur in the body and the physiological uptake of the bones is adopted.
Watch 1 6- [ 18 F]Biodistribution results of fluoro-3-picolinic acid glycine in healthy SD rats (% ID/g, n=3)
| Viscera | 10min | 1h |
| Blood vessel | 0.35±0.29 | 0.02±0.007 |
| Heart shape | 0.04±0.01 | 0.008±0.003 |
| Liver | 0.08±0.03 | 0.01±0.005 |
| Lung (lung) | 0.28±0.14 | 0.02±0.01 |
| Kidney and kidney | 1.00±0.28 | 0.07±0.04 |
| Spleen | 0.09±0.01 | 0.01±0.002 |
| Urine collection | 15.71±1.37 | 10.71±4.10 |
| Large intestine | 0.08±0.02 | 0.03±0.01 |
| Brain | 0.01±0.001 | 0.008±0.003 |
| Muscle | 0.03±0.01 | 0.01±0.001 |
| Bone | 0.10±0.05 | 0.05±0.006 |
By 5- [ 18 F]-fluoro-2-pyridine formylglycine injection and 4- [ 18 F]The fluoro-2-pyridine formylglycine injection shows similar properties when subjected to the above experiments.
Application example 4
PET/CT imaging test:
3 healthy ICR mice were anesthetized by induction with 2% isoflurane gas, and then fixed in a Minerve mouse animal cabin (Minerve)Venetirinaine, esternay, france) to maintain the animal's body temperature constant while administering 2L/min of air with 2% isoflurane to the animalInhalation of the mixture was anesthetized, followed by tail vein injection of the 6- [ obtained in example 1 ] 18 F]-fluoro-3-pyridine formylglycine injection (0.2 mL,7.4 MBq) while dynamic collection was performed.
Image reconstruction employs a 3D Ordered Subsets Expectation Maximization (OSEM) algorithm based on the monte carlo system model. After PET acquisition, the mice are subjected to CT scanning once, the bulb tube voltage is 80kV, the current is 1mA, 576 projections are acquired in total, and the total scanning time is 1h. CT image reconstruction uses Feldkamp filter back projection algorithm and performs beam hardening correction and ring artifact correction. Image analysis was performed using PMOD software (PMOD Technologies LLC, zurich, switzerland) to delineate regions of interest (Volume ofinterest, VOI) for kidneys, bladder, left ventricle, etc., and to make a time-activity curve (TAC) for the double kidneys. The resulting PET image is shown in FIG. 6, and the time-activity curve of the double kidney is shown in FIG. 7.
As can be seen from FIG. 6, the contrast agent (6- [ solution ] is injected 18 F]-fluoro-3-pyridine formylglycine injection) for 1min, the double kidneys are clearly developed with a clearer border, the kidney parenchyma is initially shown, the radioactivity is gradually concentrated at the bladder, the peripheral images gradually fade over time, the radioactivity is concentrated at the renal pelvis, then the renal pelvis shadow is obviously lightened, and the double kidney imaging agent is almost completely discharged into the bladder after 10 min. As can be seen from FIG. 7, the time for the curve to peak is about 1.25min, the time required for the radioactivity to drop half the peak is about 2.6min, illustrating 6- [ 18 F]The fluorine-3-pyridine formylglycine can be excreted rapidly through the kidney and has little damage to organisms.
By 5- [ 18 F]-fluoro-2-pyridine formylglycine injection and 4- [ 18 F]The fluoro-2-picolinalyl glycine injection exhibits similar performance when subjected to the PET/CT imaging test described above.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (6)
1. The method comprises the following steps of 18 F-labeled fluoropyridine formylglycine, characterized in that 18 F-labeled fluoropyridine formylglycine 5- [ 18 F]-fluoro-2-pyridineformylglycine or 4- [ 18 F]-fluoro-2-pyridine formylglycine.
2. The method of claim 1 18 The preparation method of F-labeled fluoropyridine formylglycine is characterized by comprising the following steps:
(1) Bromopyridine formylglycine ester, solvent and [ 18 F] - Mixing the sources, performing nucleophilic reaction, and purifying to obtain 18 F-fluoropyridine formylglycine ester; said [ 18 F] - The source contains 18 F] - And a catalyst; the bromopyridine formylglycine is 5-bromo-2-pyridine formylglycine or 4-bromo-2-pyridine formylglycine;
the ester group in the bromopyridine formylglycine is methyl ester group, ethyl ester group, propyl ester group, isopropyl ester group, butyl ester group, tert-butyl ester group, isobutyl ester group or benzyl ester group;
the bromopyridine formylglycine ester is prepared by the following steps:
activating carboxyl of bromopicolinic acid to obtain activated bromopicolinic acid; the bromopicolinic acid is 5-bromo-2-picolinic acid or 4-bromo-2-picolinic acid;
acylating the activated bromopyridine carboxylic acid with glycine ester or glycine ester hydrochloride to obtain bromopyridine formyl glycine ester;
the catalyst is a phase transfer catalyst and a base catalyst, and the phase transfer catalyst is K222 or TBAHCO 3 The alkali catalyst is K 2 CO 3 、KHCO 3 、K 2 (COO) 2 Or Cs 2 CO 3 ；
Said [ 18 F] - The preparation method of the source comprises the following steps: capture Using Sep Pak QMA column 18 F] - Then, eluting with 0.5-3 mL of phase transfer catalyst/alkali catalyst eluent, heating the liquid obtained by eluting to remove the solvent, then adding 1mL of acetonitrile for azeotropic evaporation to drynessObtain [ 18 F] - A source; the mass ratio of the phase transfer catalyst to the alkali catalyst in the phase transfer catalyst/alkali catalyst eluent is 17.7:4.1, the solvent is acetonitrile and water, and the volume ratio of the acetonitrile to the water is 10:1;1.5mL of the phase transfer catalyst in the phase transfer catalyst/base catalyst eluate was 17.7mg in mass;
(2) The said 18 F - Mixing fluoropyridine formylglycine with sodium hydroxide solution, performing hydrolysis reaction, passing through acidic ion exchange column, and filtering with sterile filter membrane to obtain the final product 18 F-labeled fluoropyridine formylglycine; the said 18 F-labeled fluoropyridine formylglycine 5- [ 18 F]-fluoro-2-pyridineformylglycine or 4- [ 18 F]-fluoro-2-pyridine formylglycine.
3. The preparation method according to claim 2, wherein the nucleophilic reaction is carried out at a temperature of 90 ℃ to 150 ℃ for a period of 5min to 30min.
4. The method of claim 2, wherein the purification is liquid chromatography purification.
5. The method of claim 1 18 Use of F-labelled fluoropyridine formylglycine in the preparation of PET/CT imaging agents.
6. The use according to claim 5, wherein the PET/CT imaging agent is a PET/CT kidney imaging agent.
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