CN111398465B - Method for measuring precursor FCPHA of PET imaging agent and cis-isomer thereof - Google Patents
Method for measuring precursor FCPHA of PET imaging agent and cis-isomer thereof Download PDFInfo
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Abstract
The invention discloses a method for measuring precursor FCPHA of a PET imaging agent and cis-isomer thereof. The determination method adopts a biphenyl derivative chiral chromatographic column, a mixed solvent is a mobile phase, a CAD electrospray detector detects chromatographic signals, and chromatograms of a test sample solution and a reference solution are compared to determine the content of the cis-isomer in the test sample. The biphenyl derivative chiral chromatographic column prepared by the invention has better chiral recognition capability, can be applied to the determination of a PET developer precursor FCPHA and a cis-isomer thereof, obtains good resolution and excellent peak shape which cannot be realized by a conventional chromatographic column, improves the signal-to-noise ratio, can simply, quickly and accurately separate FCPHA and a three-membered ring cis-isomer thereof, has excellent separation effect and low separation and detection cost, and can effectively control the quality of the precursor FCPHA.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for measuring a PET imaging agent precursor FCPHA and a cis-isomer thereof.
Background
According to the data provided by the recent research report of the Chinese disease prevention and control center, the proportion of the coronary heart disease death of the Chinese population in the total death is increased from 8.6% in 1990 to 15.2% in 2013; meanwhile, the proportion of coronary heart disease deaths among all cardiovascular deaths increased from 29% to 37%. The research estimates that the number of deaths caused by coronary heart disease in China in 2013 is 139.4 million, which is increased by 90% compared with that in 1990. At present, coronary heart disease becomes the first cause of death in six provinces and direct prefecture city/provincial administrative regions in China. Multiple research results show that the number of the coronary heart disease and the number of deaths in China will continuously increase with the aggravation of the aging process.
[18F]Cardiopet is an innovative PET agent and is currently undergoing phase II clinical research. The structure is similar to natural fatty acid, the absorption and enrichment behaviors are similar to natural fatty acid, and the structure is characterized in that after methylene is introduced into the 3 and 4 positions to form a three-membered ring, the beta-oxidation speed is reduced, so that the beta-oxidation speed can be retained in cardiac muscle cells, and further, the beta-oxidation speed can be reduced due to the fact that the methylene is introduced into the cardiac muscle cells18The decay of F produces positrons that form medically useful images for studying cardiac metabolism and disease diagnosis, particularly coronary heart disease.
Therefore, accurately estimating the number of the surviving cardiac muscle has great significance for clinical decision of patients with coronary heart disease, even prediction of postoperative effect and long-term prognosis.
Precursor FCPHA (chemical name is trans-tert-butyl 2- (2- (5- (methylsulfonyloxy) tridecyl) cyclopropyl) acetate, chemical structure shown in FIG. 1). Due to the fact that18The half-life of F is only 109.8min, and the F is clinically used18F]CardioPET must be produced in situ from the precursor compound FCPHA. Therefore, the purity of FCPHA is related to18F]The yield and purity of CardioPET, which affects the safety and efficacy of clinical applications. For this reason, the content of cis-impurities of its labeled precursor FCPHA must be strictly controlled to obtain a labeled precursor FCPHA with high purity.
The tag precursor FCPHA has 3 chiral centers, and theoretically 8 optical isomers exist18F]The precursors required for CardioPET are three-membered ring isomers of 4 of them in trans configuration. The cis isomer impurity, namely cis-FCPHA, can exist in the labeled precursor by analyzing the synthesis process of the labeled precursor. Due to the rigid backbone structure of the three-membered ring, no conversion occurs in subsequent reactions once synthesized. The impurity can remain in the PET developer [ 2 ] by a subsequent labeling reaction18F]In CardioPET, the quality of the drug is affected. Therefore, the content of cis-FCPHA impurity in FCPHA is controlled to increase the value of [ alpha ], [ alpha ] an18F]The quality of the CardioPET has great significance for ensuring the safety and effectiveness of the medication of the patients.
The realization of the effective separation of the labeled precursor FCPHA and the cis-isomer thereof has important significance in the quality control of raw medicines and preparations thereof, and in order to effectively control the quality of the labeled precursor, the invention of a high performance liquid phase measurement method capable of effectively separating FCPHA and the cis-isomer thereof is required. However, as can be seen from the precursor structure, the saturated long chain fatty acid has no significant UV absorption and requires the selection of a suitable detector. Conventional uv detectors cannot detect a signal. The evaporative light detector can realize detection, but has low sensitivity and poor linearity, and is difficult to accurately quantify. Therefore, it is necessary to select an analytical method equipped with an appropriate detector to achieve efficient separation and quantitative determination. Secondly, the required analytical method needs to be moderate, only the trans-configured three-membered ring isomer (4 optical isomers on the left side of fig. 2) needs to be separated from the other cis-configured three-membered ring isomer (4 optical isomers on the right side of fig. 2), and one or more of the optical isomers does not need to be separated, so that proper immobilization needs to be selected. Conventional methods such as evaporation photodetectors, chiral chromatographic columns, and the like, and gas phase methods generally applicable to fatty acid separation, have not achieved separation or accurate quantitative determination. In addition, when the relevant fatty acid is measured in a gas phase, the precursor is unstable and decomposed by heating due to the high three-membered ring tension caused by high-temperature vaporization. At present, no existing method for effectively separating and sensitively and quantitatively measuring cis-trans three-membered ring isomers of saturated fatty acid exists.
Disclosure of Invention
The invention aims to solve the technical problem that a method for separating and detecting cis-trans three-membered ring isomers of saturated fatty acids does not exist in the prior art, and provides a method for measuring a PET imaging agent precursor FCPHA and cis-isomer thereof.
The method for measuring the precursor FCPHA of the PET imaging agent and the cis-isomer thereof comprises the following steps: a biphenyl derivative chiral chromatographic column is adopted, a mixed solvent is used as a mobile phase, a CAD electrospray detector detects chromatographic signals, and chromatograms of a test sample solution and a reference solution are compared to determine the content of the cis-isomer in the test sample.
The method for measuring the precursor FCPHA of the PET imaging agent and the cis-isomer thereof comprises the following steps:
(1) preparing a PET imaging agent precursor FCPHA into a test solution with the concentration of 0.2mg/mL by using a solvent acetonitrile;
(2) adopting a biphenyl derivative chiral chromatographic column; the mobile phase is a mixed solvent of a mobile phase A and a mobile phase B, the mobile phase A is a formic acid aqueous solution with the mass concentration of 0.1%, and the mobile phase B is acetonitrile; the column temperature is 30-35 ℃; the flow rate is 0.2-0.4 mL/min; the detector is a CAD electrospray detector, and the detection conditions are that: 5 seconds, Data rate: 5/sec, T: 35 ℃; the elution gradient was:
time (min) 035404255
A% 35 5 5 35 35
B% 65 95 95 65 65
(3) Injecting 5 mu L of test solution into a biphenyl derivative chiral chromatographic column for chromatographic detection, and recording a chromatogram.
The preparation method of the biphenyl derivative chiral chromatographic column comprises the following steps:
1) soaking and activating silica gel with 6mol/L hydrochloric acid, washing with deionized water to neutrality, and drying in a vacuum drying oven to obtain activated silica gel; weighing 6g of activated silica gel, drying the silica gel at 180 ℃ under reduced pressure until no moisture exists, then adding 1mL of triethylamine, 50mL of toluene and 1.8mL of 3-aminopropyltriethoxysilane into the silica gel, placing the mixture into a 100mL round-bottom flask, refluxing the mixture for 16h at 80 ℃, washing the obtained product by using normal hexane, ether and absolute ethyl alcohol in sequence until no triethylamine exists, and drying the product in vacuum to obtain 3-aminopropylsilanized silica gel;
2) weighing 1.3G of 6,6 '-bis ((2-methylbenzo [ b ] thiophen-6-yl) oxy) - [1, 1' -biphenyldicarboxylic acid ] -2,2 '-diol, 1.2G of 3-aminopropylsilanized silica gel prepared in the step 1), 1.4G of N, N' -dicyclohexylcarbodiimide and 0.2G of 4-dimethylaminopyridine, adding the mixture into a 250mL round-bottom flask containing 150mL of tetrahydrofuran under the protection of nitrogen, refluxing at 60 ℃ for 14h, performing vacuum filtration on a product by using a G4 sand core funnel, washing for 3 times by using N-hexane and dichloromethane in sequence, and performing vacuum drying for 24h to obtain a biphenyl derivative chiral stationary phase;
3) packing of chromatographic column: loading a column by adopting a high-pressure homogenization method, taking a 150mm multiplied by 2mm empty liquid chromatographic column, and mixing 1.2g of the biphenyl derivative chiral stationary phase prepared in the step 2) with 23mL of the volume ratio of 95: 5, using a n-hexane-isopropanol mixed solvent as a homogenate, wherein the volume ratio of 120mL is 95: and (3) taking a mixed solvent of 5 n-hexane and isopropanol as a displacement liquid, and loading the column under the pressure of 40MPa to obtain the biphenyl derivative chiral chromatographic column.
The biphenyl derivative chiral chromatographic column prepared by the invention has better chiral recognition capability, is applied to the determination of a PET developer precursor FCPHA and a cis-isomer thereof, obtains good resolution and excellent peak shape which cannot be realized by a conventional chromatographic column, improves the signal-to-noise ratio, can simply, quickly and accurately separate FCPHA and a three-membered ring cis-isomer thereof, has excellent separation effect and low separation and detection cost, and can effectively control the quality of the precursor FCPHA.
Drawings
FIG. 1 shows the structural formula of FCPHA as a precursor of PET imaging agent.
FIG. 2 shows the structural formulas of FCPHA (left) and cis isomer cis-FCPHA (right) of PET imaging agent precursor.
FIG. 3 is an air white solution chromatogram of example 1.
FIG. 4 is a chromatogram of the cis-FCPHA control solution of example 1.
FIG. 5 is a chromatogram of the mixed control solution of example 1.
FIG. 6 is a chromatogram of the FCPHA test solution in example 1.
FIG. 7 is a chromatogram of the cis-FCPHA control of comparative example 1.
FIG. 8 is a chromatogram of the overlay of the cis-FCPHA control and FCPHA (PET 12 in the figure) samples of comparative example 1.
FIG. 9 is a chromatogram of the overlay of the cis-FCPHA control and FCPHA (PET 12 in the figure) samples of comparative example 2.
Detailed Description
The following detailed description of the present invention is provided in connection with the examples, and for reasons of brevity, the description of the experimental procedures is not intended to be exhaustive, and all parts not specifically described in the experiments are routine procedures well known to those skilled in the art.
Example 1
First, experimental material
Biphenyl derivative chiral chromatography column (equipped with binary gradient pump, autosampler and CAD detector);
the purity of FCPHA and cis-FCPHA is not lower than 95%;
acetonitrile and purified water are chromatographically pure, and formic acid is purchased from Fisher company;
the preparation method of the biphenyl derivative chiral chromatographic column comprises the following steps:
1) soaking and activating silica gel with 6mol/L hydrochloric acid, washing with deionized water to neutrality, and drying in a vacuum drying oven to obtain activated silica gel; weighing 6g of activated silica gel, drying the silica gel at 180 ℃ under reduced pressure until no moisture exists, then adding 1mL of triethylamine, 50mL of toluene and 1.8mL of 3-aminopropyltriethoxysilane into the silica gel, placing the mixture into a 100mL round-bottom flask, refluxing the mixture for 16h at 80 ℃, washing the obtained product by using normal hexane, ether and absolute ethyl alcohol in sequence until no triethylamine exists, and drying the product in vacuum to obtain 3-aminopropylsilanized silica gel;
2) weighing 1.3G of 6,6 '-bis ((2-methylbenzo [ b ] thiophen-6-yl) oxy) - [1, 1' -biphenyldicarboxylic acid ] -2,2 '-diol, 1.2G of 3-aminopropylsilanized silica gel prepared in the step 1), 1.4G of N, N' -dicyclohexylcarbodiimide and 0.2G of 4-dimethylaminopyridine, adding the mixture into a 250mL round-bottom flask containing 150mL of tetrahydrofuran under the protection of nitrogen, refluxing at 60 ℃ for 14h, performing vacuum filtration on a product by using a G4 sand core funnel, washing for 3 times by using N-hexane and dichloromethane in sequence, and performing vacuum drying for 24h to obtain a biphenyl derivative chiral stationary phase;
3) packing of chromatographic column: loading a column by adopting a high-pressure homogenization method, taking a 150mm multiplied by 2mm empty liquid chromatographic column, and mixing 1.2g of the biphenyl derivative chiral stationary phase prepared in the step 2) with 23mL of the volume ratio of 95: 5, using a n-hexane-isopropanol mixed solvent as a homogenate, wherein the volume ratio of 120mL is 95: and (3) taking a mixed solvent of 5 n-hexane and isopropanol as a displacement liquid, and loading the column under the pressure of 40MPa to obtain the biphenyl derivative chiral chromatographic column.
Second, Experimental methods and results
Preparation of solution
Preparation of mobile phase A: using a 1mL pipette, 1mL of formic acid was removed and made up to 1000mL with water.
Preparation of mobile phase B: and (5) carrying out suction filtration and ultrasonic treatment on acetonitrile for later use.
Blank solution: measuring 5 mu L of dilute solution acetonitrile, injecting into a liquid chromatograph, and recording the chromatogram of the dilute solution.
Preparation of cis-FCPHA control solution: 2mg of cis-FCPHA reference substance is precisely weighed and placed into a 10ml measuring flask, acetonitrile is dissolved and diluted to scale, and the mixture is uniformly mixed; precisely measuring 100 mu L of the solution, putting the solution into a 10mL measuring flask, diluting acetonitrile to a scale, and uniformly mixing.
Preparation of test sample solution: 2mg of the sample is precisely weighed and placed in a 10ml measuring flask, acetonitrile (diluent) is dissolved and diluted to the scale, and the mixture is uniformly mixed.
The chromatographic conditions are as follows:
a chromatographic column: a biphenyl derivative chiral chromatographic column;
the mobile phase A is 0.1 percent formic acid water solution;
the mobile phase B is acetonitrile;
the column temperature is 30 ℃;
the elution gradient was:
time (min) 035404255
A% 35 5 5 35 35
B% 65 95 95 65 65
Flow rate: 0.2 mL/min;
the detection conditions of the CAD detector are as follows: a Filter: 5 seconds; data rate: 5/second; t: 35 ℃ is carried out.
Effects of detecting and separating the three samples
And respectively precisely measuring 5 mu L of a cis-isomer control solution, an FCPHA control solution and a mixed control solution, injecting the solution into a biphenyl derivative chiral chromatographic column, and recording a chromatogram. The chromatogram is shown in fig. 5, which shows that cis-isomers cis-FCPHA and FCPHA in the mixed control solution can achieve baseline separation and have excellent separation effect.
Comparative example 1
A Waters Symmetry ShieldRP183.5 μm 4.6X 150mm column and an ELSD detector were selected, and neither column temperature nor flow rate was adjusted. As can be seen from FIGS. 7 and 8, the cis-three-membered ring isomer impurity completely coincided with the main peak of FCPHA, and the two could not be separated.
Comparative example 2
Adopting YMC beta-CDBR type chiral stationary phase chromatographic column, using normal phase mixed solvent as mobile phase, the flow rate of the mobile phase is 0.5mL/min, the column temperature of the chromatographic column is 30 ℃, the detector adopts CAD detector (Filter: 3s, date rate: 5/sec, T: 35 ℃), the detection wavelength is 254-280nm, and after adjusting different parameters, the main peaks coincide and can not be separated, as shown in figure 9.
Claims (1)
1. A method for measuring precursor FCPHA of PET imaging agent and cis-isomer thereof is characterized in that a biphenyl derivative chiral chromatographic column is adopted, a mixed solvent is used as a mobile phase, a CAD electrospray detector detects chromatographic signals, and chromatograms of a sample solution to be measured and a reference solution are compared to determine the content of the cis-isomer in the sample to be measured;
the specific operation steps of the determination method are as follows:
(1) preparing a PET imaging agent precursor FCPHA into a test solution with the concentration of 0.2mg/mL by using a solvent acetonitrile;
(2) adopting a biphenyl derivative chiral chromatographic column; the mobile phase is a mixed solvent of a mobile phase A and a mobile phase B, the mobile phase A is a formic acid aqueous solution with the mass concentration of 0.1%, and the mobile phase B is acetonitrile; the column temperature is 30-35 ℃; the flow rate is 0.2-0.4 mL/min; the detector is a CAD electrospray detector, and the detection conditions are that: 5 seconds, Data rate: 5/sec, T: 35 ℃; the elution gradient was:
(3) injecting 5 mu L of test solution into a biphenyl derivative chiral chromatographic column for chromatographic detection, and recording a chromatogram;
the preparation method of the biphenyl derivative chiral chromatographic column comprises the following steps:
1) soaking and activating silica gel with 6mol/L hydrochloric acid, washing with deionized water to neutrality, and drying in a vacuum drying oven to obtain activated silica gel; weighing 6g of activated silica gel, drying the silica gel at 180 ℃ under reduced pressure until no moisture exists, then adding 1mL of triethylamine, 50mL of toluene and 1.8mL of 3-aminopropyltriethoxysilane into the silica gel, placing the mixture into a 100mL round-bottom flask, refluxing the mixture for 16h at 80 ℃, washing the obtained product by using normal hexane, ether and absolute ethyl alcohol in sequence until no triethylamine exists, and drying the product in vacuum to obtain 3-aminopropylsilanized silica gel;
2) weighing 1.3G of 6,6 '-bis ((2-methylbenzo [ b ] thiophen-6-yl) oxy) - [1, 1' -biphenyldicarboxylic acid ] -2,2 '-diol, 1.2G of 3-aminopropylsilanized silica gel prepared in the step 1), 1.4G of N, N' -dicyclohexylcarbodiimide and 0.2G of 4-dimethylaminopyridine, adding the mixture into a 250mL round-bottom flask containing 150mL of tetrahydrofuran under the protection of nitrogen, refluxing at 60 ℃ for 14h, performing vacuum filtration on a product by using a G4 sand core funnel, washing for 3 times by using N-hexane and dichloromethane in sequence, and performing vacuum drying for 24h to obtain a biphenyl derivative chiral stationary phase;
3) packing of chromatographic column: loading a column by adopting a high-pressure homogenization method, taking a 150mm multiplied by 2mm empty liquid chromatographic column, and mixing 1.2g of the biphenyl derivative chiral stationary phase prepared in the step 2) with 23mL of the volume ratio of 95: 5, using a n-hexane-isopropanol mixed solvent as a homogenate, wherein the volume ratio of 120mL is 95: and (3) taking a mixed solvent of 5 n-hexane and isopropanol as a displacement liquid, and loading the column under the pressure of 40MPa to obtain the biphenyl derivative chiral chromatographic column.
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