CN112807276B - Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical - Google Patents
Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical Download PDFInfo
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Abstract
The invention discloses a preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceuticals. The invention employs high dose initiation18F activity mark, optimizes the precursor usage amount, reaction temperature and purification HPLC condition of the reaction, and improves the reaction yield, [ 2 ]18F]The preparation amount of Fmpp2 can reach 200mCi, the chemical impurity amount is reduced, the radiochemical purity is high, and the key quality index is kept stable within 6 h. The invention also improves the preparation of the [ alpha ], [ beta ] -cyclodextrin for injection18F]The method of the Fmpp2 solution is improved18F]Radiochemical purity and stability of Fmpp 2. The [ alpha ], [ beta ] prepared by the present invention18F]Fmpp2 shows the appearance of a small pig myocardium model by PET imaging, i.v.)18F]After Fmpp2, myocardial radioactivity uptake is high, peripheral organs have small influence on myocardial development, and normal myocardium, ischemic myocardium caused by chronic coronary stenosis and infarcted myocardium caused by acute coronary stenosis can be distinguished.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method and application of pyridazinone myocardial perfusion PET radioactive drugs.
Background
Radionuclide myocardial perfusion imaging has become a major means of assessing stress imaging in patients with suspected or known coronary heart disease (CAD). The PET myocardial perfusion imaging can absolutely and quantitatively measure myocardial blood flow volume and blood flow reserve function, can diagnose coronary heart disease at early stage, and has absolute advantages for patients with microvascular diseases, balanced three-branch pathological changes and obese patients.
[18F]Fmpp2, chemical name 2-tert-butyl-4-chloro-5- ((3- ((4- ((2- (2-fluoro-), [ 2 ])18F]Ethoxy) methyl) -1H-1,2, 3-triazol-1-yl) methyl) benzyl) oxy) pyridazin-3 (2H) -one. Chemical structural formula:
the molecular formula is as follows: c23H29Cl18FN5O4
Molecular weight 492.97
[18F]Fmpp2 containing radionuclide18F, can be used for Positron Emission Tomography (PET) imaging, has the characteristics of extremely low chemical content and incapability of separating a pure product, and the prepared [ alpha ], [ beta ] -cyclodextrin18F]Fmpp2 is present mostly in the solution state.
[18F]The mechanism of action of Fmpp2 as a myocardial perfusion imaging agent: [18F]Fmpp2 can rapidly react with a respiratory chain complex I (MC-I) in mitochondria once entering myocardial cells to stagnate in the myocardium for a long time, and previous animal research data show that 15 minutes after injection has high cardiac uptake and low liver uptake, maintains good heart-liver ratio after 60 minutes of injection and shows good myocardial perfusion imaging potential.
At present, the [ alpha ], [ alpha ] is prepared by the prior art18F]Fmpp2 is only used for animal experiments and has the following disadvantages:
1. a large number of uncertain parameters exist in the route and the process flow is not clear enough.
2. Animal experiment18F]The Fmpp2 activity requirement is low, and the applicability of the method to large-batch activity production is unclear.
3. This method cannot be automated.
Single batch prepared by the existing preparation method18F]Fmpp2 product Activity Up to about 185MBq (5mCi), start marker18The activity of F is about 20mCi, and can be used for in vivo and in vitro experiments of small animals (such as mice or rats) or small pigs. [18F]The Fmpp2 clinically intended for use in a single human dose of 222MBq-296MBq (6mCi-8mCi), in case of a single batch to be administered in 5 humans18F]The activity of Fmpp2 product is above 40mCi, start marker18The activity of F is more than 200mCi when calculated by 20% yield. The prior art can not meet the activity requirement.
Is prepared from18F]Fmpp2 is developed into a medicine for clinical use, and the preparation process needs to be optimized and researched, so that the process parameters in the route are defined, and the initial marker is improved18F activity, automatic instrument production and development are carried out, thereby meeting the requirements of clinical practiceThe need for medication, which is a problem and a primary object to be solved by the present invention.
Disclosure of Invention
The invention aims to develop the large-scale automatic preparation of the [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ] can18F]The Fmpp2 method meets the clinical medication requirement and designs a continuous and stable production process. By using large doses18F has marked activity, and can cause great harm to operators due to high radioactivity and high radiation dose, so the large dose18F is not conducive to manual labeling and requires the use of automated equipment placed in the shielding equipment for preparation. And adopts the existing preparation process to improve18After the dosage of F, not only the yield is reduced, but also the quality requirement can not be met18F]Fmpp 2. The invention employs high dose initiation18F activity mark, optimizes the precursor usage amount, reaction temperature and purification HPLC condition of the reaction, and improves the reaction yield, [ 2 ]18F]The preparation amount of Fmpp2 can reach 200mCi, the chemical impurity amount is reduced, the radiochemical purity is high, and the key quality index is kept stable within 6 h. The invention also improves the preparation of the [ alpha ], [ beta ] -cyclodextrin for injection18F]The method of the Fmpp2 solution is improved18F]Radiochemical purity and stability of Fmpp 2.
The preparation method of the pyridazinone myocardial perfusion PET radiopharmaceutical comprises the following steps:
1) accelerator fabrication18F, the ionic solution is prepared by the following steps of,18f has the initial activity of 10mCi-1 Ci;
2) subjecting the product obtained in step 1)18Enriching the F ion solution through an anion exchange column;
3) eluting with tetrabutylammonium salt phase transfer catalyst solution or cryptate and alkali metal salt catalyst solution to elute fluorine18F]Ions are put into a reaction bottle;
4) drying the solvent by controlling the temperature, nitrogen flow and vacuum degree through a program, and activating18F ions;
5) after activation, the activated18F ion and precursor mpp-2OTs are subjected to nucleophilic substitution reaction to produce [ 2 ]18F]Fmpp 2; the reaction solvent is aprotic polar solvent, the dosage of the solvent is 0.2-5mL, and the precursor mpp-2OTsThe dosage is 2-6mg, the reaction temperature is 100-140 ℃, the reaction time is 5-60min, and the reaction is closed;
6) purifying by semi-preparative HPLC18F]Fmpp2, wherein the chromatographic column is a C18 reverse chromatographic column, the mobile phase is a mixed solvent of water and acetonitrile with the volume ratio of 8/2-2/8, and the flow rate is 3-8 mL/min;
7) collecting the product of [ mu ], [ solution of ] a18F]Fmpp2, enriching by a solid phase extraction column; washing the solid phase extraction column with water or 0.9wt% sodium chloride injection, eluting with 0.5-5mL 50-100wt% ethanol solution to 10-30mL polyethylene glycol 400 with volume ratio of 2-20% and 0.9% sodium chloride injection to obtain injectable solution18F]Fmpp2 solution.
The precursor mpp-2OTs is methyl 2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethoxy) ethyl-4-methylbenzenesulfonate.
The preparation route of the precursor mpp-2OTs is as follows:
the preparation method of the pyridazinone myocardial perfusion PET radiopharmaceutical is characterized in that an automatic synthesizer is arranged in shielding equipment for operation, wherein the automatic synthesizer is controlled by a programmable controller; the automatic synthesizer comprises an injector electric rotor, a vacuum device and an HPLC purification unit, and protective gas is nitrogen or inert gas.
Said step 1) consisting of18O(p，n)18F preparation18F ion solution.
The anion exchange column in the step 2) is not activated or is subjected to K with the concentration of 0.2-5mol/L2CO3、Na2CO3、KHCO3、NaHCO3One or more of the solutionsThe seeds are mixed and then activated.
The tetrabutylammonium salt is one or more of tetrabutylammonium bicarbonate, tetrabutylammonium carbonate and tetrabutylammonium fluoride. The cryptate is cryptate K222. The alkali metal salt is K2CO3、Na2CO3、Cs2CO3、KHCO3、NaHCO3One or more of them.
The concentration of the tetrabutylammonium salt phase transfer catalyst solution is 0.02-0.1M, and the dosage is 0.2-1 mL. 5-30mg of cryptate and 0.5-10mg of alkali metal salt in the cryptate and alkali metal salt catalyst solution; the solvent is a mixed solvent of acetonitrile and water with the volume ratio of 10/1-2/8, and the volume is 0.2-2 mL.
18F-labelling of the Fmpp2 precursor is carried out by nucleophilic substitution, step 3) is increased by catalyst elution18Electronegativity of F, and thus, increase18F nucleophilic substitution ability.
The program control conditions of the step 4) are as follows: the first step, evaporating for 60-120s at 100-120 ℃, positive pressure of nitrogen gas of 50-200mbar and vacuum pressure of-20 to-60 mbar; the second step, the temperature is increased to 130 ℃, the positive pressure of nitrogen is 50-200mbar, the vacuum pressure is-20 to-60 mbar, and the evaporation is increased to 200 s; thirdly, evaporating for 10-30s at the temperature of 120-; fourthly, evaporating for 80-120s at the temperature of 100-; fifthly, evaporating for 100 and 120 seconds at 80-100 ℃, wherein the positive pressure of nitrogen is 400 and 600mbar, the vacuum pressure is-800 to-1000 mbar; and a sixth step, evaporating for 10-20s at 80-100 ℃, under the positive pressure of nitrogen gas of 600-900mbar and the vacuum pressure of-800-1000 mbar.
The aprotic polar solvent in the step 5) is one or more of acetonitrile, dimethyl sulfoxide, N-dimethylformamide and 2-methyl-2-butanol.
Compound [ 2 ]18F]Fmpp2 has potential for use in Positron Emission Tomography (PET) imaging of myocardial perfusion. Preparation at present18F]The Fmpp2 method has low yield, long preparation time and poor stability; increase the initial18After the activity of F reaction, a product with high radiochemical purity cannot be obtained. Improvements in or relating to the inventionPreparation method, at the beginning of large dose18Under the activity of F, the prepared high radiochemical purity [ alpha ]18F]Fmpp2, significantly improved the radiochemical yield of the compound. The automatic preparation method is stable, the multi-batch synthesis shows that the corrected radiochemical yield can reach more than 50%, the total synthesis time is short, the radiochemical purity of the product is high, the content of chemical impurities is low, and the key quality indexes are stable within 6 hours. The term "prepared by the method18F]Fmpp2 shows the appearance of a small pig myocardium model by PET imaging, i.v.)18F]After Fmpp2, myocardial radioactivity uptake is high, peripheral organs have small influence on myocardial development, and normal myocardium, ischemic myocardium caused by chronic coronary stenosis and infarcted myocardium caused by acute coronary stenosis can be distinguished.
Drawings
FIG. 1: the invention prepares the large batch of the [ alpha ], [ alpha ] in the present invention18F]Fmpp2 technical roadmap.
FIG. 2: applying a PET imaging result comparison graph of the normal myocardium and the model myocardium in the example 1; a: normal myocardium, B: acute myocardial infarction, C: chronic ischemic myocardium.
Detailed Description
Example 1
The automation equipment is equipment with the model number of Allinone of the company Tracis. The plant power unit was high purity nitrogen with an injector motorized rotor, a vacuum system could be provided, and an HPLC purification system configured. Because the process uses the automation equipment which is arranged in the ray shielding box, the operation personnel can be protected from radiation damage, the operation dosage is increased, meanwhile, because of the control of the computer, the process steps can be controlled more accurately, the repeatability is higher, and the artificial deviation is reduced.
1) The prior art generally adopts 10-50mCi18F starting dose, this example uses a high dose start18F, preferably the initial activity is 800-.
2) Enrichment of18F ion anion exchange column QMA column of Waters brand, preferably 1mol/L NaHCO3And (4) activating.
3) With cryptate K222And K2CO3Leaching the solution to elute the fluorine [ 2 ]18F]Ions are put into a reaction bottle; cryptate K222Has a chemical amount of 15mg, K2CO3The chemical weight of (1) is 1.5mg, the solvent is a mixed solvent of acetonitrile and water with the volume ratio of 9/1, and the volume is 1 mL. The solvent content of the leacheate can also influence the efficiency of the next drying and activation step.
4)18F, the degree of drying and water removal has great influence on the labeling reaction, and the incomplete water removal directly reduces the labeling efficiency. The solvent removal process is program control: firstly, slowly supplying nitrogen near the boiling point of the leacheate, and slowly vacuumizing; after evaporating most of the liquid, the temperature is raised again, the nitrogen flow is increased, and the vacuum negative pressure value is increased. The specific process comprises the following steps:
| nitrogen pressure (mbar) | Vacuum (mbar) | Temperature (. degree.C.) | Time(s) |
| 100 | -40 | 115 | 80 |
| 100 | -40 | 125 | 160 |
| 100 | -70 | 125 | 20 |
| 1000 | -1000 | 110 | 100 |
| 500 | -1000 | 95 | 110 |
| 800 | -1000 | 95 | 15 |
The water removal process can ensure clean water removal and has high reaction efficiency. Compared with the prior art, the method has the advantages that the step of adding acetonitrile for removing water for multiple times is omitted, the process is simpler, and the requirement on equipment is simplified.
5)18The chemical quantity of the F-labeled reaction precursor mpp-2OTs is 4mg, the reaction solvent is 1mL of anhydrous acetonitrile, the reaction temperature is 110 ℃, the reaction time is 20min, and the reaction is closed.
6) Purifying by semi-preparative HPLC18F]Fmpp2, HPLC purification conditions:
a chromatographic column: xbridge BEH C18 OBD Prep column,130A,5 μm, 10X 250mm
Mobile phase: 4/6% acetonitrile/water
Flow rate: 5mL/min
A detector: radioactivity detector and ultraviolet detector
Monitoring and tracking the radioactive signal, and collecting18F]Fmpp2 main peak, and the peak-out time is about 18 min.
7) Collected [ alpha ], [ beta ], [ alpha ], [ beta ]18F]The mobile phase of Fmpp2 adopts octadecyl bonded silica gel small column for enriching and removing the solvent, and leaching18F]The solvent of Fmpp2 is 2mL absolute ethyl alcoholAnd leaching to 20mL of mixed solution containing 2g of polyethylene glycol 400 as a cosolvent and the balance of 0.9% sodium chloride injection.
Radiolabelling is characterized by trace chemical reactions and does not allow quality control of the product in intermediate steps, so that quantitative parameters in the overall process flow may have an impact on the quality and yield of the final product.
Examination example 1 selection of the catalyst for labeling reaction and base
Influence of the type and amount of catalyst and base18F label nucleophilic substitution reaction, for this, different catalysts and alkalis, and different ratio pairs were studied18F, the leaching efficiency and the reaction efficiency are influenced, and the other conditions are consistent. The results of the study are as follows:
the results show that K is selected222And K2CO3The catalyst is used and the proper amount is selected to achieve the optimal effect.
Examination example 2 labeling of reaction solvent, amount of precursor used, reaction temperature, and reaction time selection
The reaction solvent, the precursor dosage, the reaction temperature and the reaction time have obvious influence on the marking reaction, the influence of the parameters on the marking rate is inspected by adopting a single variable method, and the results are as follows:
the results of the precursor dosage show that the reaction efficiency increases with the increase of the precursor dosage, the marking rate can reach the optimum at 4mg, the marking rate can not be obviously increased by increasing the precursor, and the purification difficulty can be increased by excessive precursor. Therefore, the amount of the precursor is preferably 4 mg.
The reaction solvent results show that different reaction solvents have no significant influence on the labeling rate, but acetonitrile is optimally selected as the reaction solvent in consideration of the subsequent purification and the simplicity and convenience of the whole process system.
The results of the reaction temperature show that the labeling rate increases with increasing temperature, and slightly decreases after 110 ℃, preferably the reaction temperature is 110 ℃.
The results of the reaction time show that the labeling rate increases with the increase of the reaction time, but the radioactive decay increases with the increase of the reaction time, and the actual yield decreases, and the reaction time is preferably 20 min.
Investigation example 3 HPLC purification method plus injectable solution preparation method selection
Process A
Purification was carried out using the following HPLC purification conditions.
A chromatographic column: c18 reverse phase chromatography column (10X 250mm, Venusil MP-C18, Agela Technologies Inc.)
Mobile phase: phase A-water, phase B-acetonitrile
Elution gradient:
| 0-5min | 95％A |
| 5.01-8min | 95-60％A |
| 8.01-19min | 60-30％A |
| 19.01-30min | 0％A |
flow rate: 5.0mL/min
Collection [ 2 ]18F]Fmpp2 radioactive signal peak, retention time about 20 min.
Collected [ 2 ]18F]Blowing the solvent by Fmpp2 at 100 deg.C under nitrogen flow, adding 10mL of 5% ethanol, and dissolving to obtain the product for injection18F]Fmpp2。
Process B
A chromatographic column: xbridge BEH C18 OBD Prep column,130A,5 μm, 10X 250mm
Mobile phase: 4/6% acetonitrile/water
Flow rate: 5mL/min
Collection [ 2 ]18F]Fmpp2 radioactive signal peak, retention time about 18 min.
Collected [ 2 ]18F]Fmpp2 was diluted with 0.9% sodium chloride injection and enriched by passing through a C18 cartridge, followed by washing the C18 cartridge with 0.9% sodium chloride injection to remove acetonitrile and possibly large polar impurities. Then 2mL of absolute ethanol is used for dissolving18F]The Fmpp2 was eluted into 0.9% sodium chloride injection (6.2mL) containing 2g of polyethylene glycol 400, and the C18 column was washed with 10mL of 0.9% sodium chloride injection18F]Fmpp2 solution.
Comparing the two processes to prepare the product18F]Key mass data for Fmpp2 solutions, the results are as follows:
| process for the preparation of a coating | Process A | Process B |
| 18F starting scalar quantity | 562mCi | 853mCi |
| Radiochemical purity (0h) | 79.3％ | 95.6％ |
| Radiochemical purity (6h) | 71.3％ | 94.8％ |
| Total amount of chemical impurities | 5.6 | 1.6 |
The above comparison results show that: the minimum radiochemical purity requirement for radiopharmaceutical applications is 90%, and therefore the existing process (process a) does not meet the requirements. The analysis reason is as follows: process A preparation [ alpha ], [ alpha ] and [ alpha ], [ alpha ] a18F]Fmpp2, the collected solution is heated again to remove impurities, and the resultant product is heated to18F]Fmpp2 decomposes. And the value obtained by the process B18F]The Fmpp2 is enriched by a C18 column and then eluted with an organic solvent avoiding a heating step, thereby inhibiting [ 2 ], [ 2 ]18F]Decomposition of Fmpp 2.
Used for producing18F]A flow chart (operation chart) of an Allinone automatic synthesizer production method of Fmpp2 injection is shown in figure 1.
Comparative example 1
In the Allinone Autosynthesizer from Tracis, Inc., the different startups were varied18F activity, investigating the influence on synthesis yield, product radiochemical purity and the like, keeping the other parameters consistent, and simplifying the synthesis method as follows:
accelerator producing fluorine containing [ alpha ], [ alpha ] and a18F]Ionic oxygen [ alpha ]18O]Water, transferred to an alinone synthesizer18The F ion was received in a syringe and enriched by passing through an anion exchange solid phase extraction cartridge (QMA).
Aminopolyethers (K)222)11mg and K2CO36mg of acetonitrile water (acetonitrile/water ═ 9/1) was prepared and mixed to elute fluorine [, ], a18F]The ions are put into a reaction bottle, and the solvent is heated and dried under negative pressure under the nitrogen flow.
1mL of 2mgFmpp2 adding the precursor acetonitrile solution into a reaction bottle, heating to 90 ℃ under a closed condition, and reacting for 30 min. Fmpp2 precursor and K18F/K222Subjected to nucleophilic substitution reaction to produce [ 2 ]18F]Fmpp2。
After completion of the reaction, purification was performed by the following chromatographic conditions.
A chromatographic column: c18 reverse phase chromatography column (10X 250mm, Venusil MP-C18, Agela Technologies Inc.)
Mobile phase: phase A-Water phase B-acetonitrile
Elution gradient:
| 0-5min | 95％A |
| 5.01-8min | 95-60％A |
| 8.01-19min | 60-30％A |
| 19.01-30min | 0％A |
flow rate: 5.0mL/min
A detector: radioactivity detector and ultraviolet detector
Monitoring and tracking the radioactive signal, and collecting18F]Fmpp2 major peak (peak at about 20 min).
Collected [ 2 ]18F]Heating and drying the solvent by Fmpp2, and then adding 10mL of 5% ethanol for dissolving to obtain the product.
The results of the study are as follows:
the results of the study found that the existing route is increasing the initiation18After the activity of F, the yield is greatly reduced (the yield is reduced from 30-60% to 15-20% after decay correction), the key quality inspection index radiochemical purity is reduced, the minimum requirement of 90% radiochemical purity of the radioactive drug is not met, and the stability result shows that the radiochemical purity is still lower than 90% after 6 hours.
Application example 1
[18F]Application of Fmpp2 injection in myocardial perfusion PET imaging: will 218F]Fmpp2 was used for imaging studies in normal myocardium, chronic ischemic myocardium and acute infarcted myocardium of Bama miniature pigs.
Separately, 3 healthy normal piglets and 3 chronic myocardial ischemia piglets were prepared (placing a narrowing ring on the anterior descending branch, and displaying the left anterior descending branch by coronary angiography before imaging>70% stenosis to total occlusion) and 3 acute myocardial infarction mini pigs (reperfusion 30min after mid left anterior descending branch occluded by balloon) were administered by the auricular vein by the method of example 118F]The Fmpp2 injection (injection dose: 3.0mCi, injection volume: 1-5 mL) is subjected to PET-CT imaging in a proper anesthesia state at 5min, 20min, 40 min, 60min and 120min after administration, animals are all in a supine position and are fixed by a fixed groove during PET data acquisition, wherein healthy normal pigs and acute myocardial infarction model pigs only carry out 1 day method rest myocardial perfusion imaging, chronic ischemia model pigs carry out 2 day method (rest + load) myocardial perfusion imaging, the 1 day rest myocardial perfusion imaging and the 2 day ATP load myocardial perfusion imaging.
The results of PET imaging of normal myocardium compared with model myocardium are shown in FIG. 2. Result display18F]The Fmpp2 injection can accurately distinguish normal myocardium, ischemic myocardium caused by chronic coronary stenosis and myocardial infarction caused by acute coronary stenosis in PET myocardial perfusion imaging of healthy and acute myocardial infarction and chronic myocardial ischemia miniature pigs, and maintain high image quality with clear myocardial contour, low background around the myocardium and no obvious non-target organ uptake interference around the myocardium within 5-120 min after injection.
Claims (6)
1. A preparation method of pyridazinone myocardial perfusion PET radioactive drugs is characterized by comprising the following specific steps:
1) accelerator fabrication18F, the ionic solution is prepared by the following steps of,18f initial activity of 800-;
2) subjecting the product obtained in step 1)18Enriching the F ion solution through an anion exchange column;
3) with cryptate K222And K2CO3The catalyst solution is leached and the fluorine is eluted18F]Ions are put into a reaction bottle;
4) drying the solvent by controlling the temperature, nitrogen flow and vacuum degree through a program, and activating18F ions;
5) after activation, the activated18F ion and precursor mpp-2OTs are subjected to nucleophilic substitution reaction to produce [ 2 ]18F]Fmpp 2; the reaction solvent is an aprotic polar solvent, the solvent dosage is 0.2-5mL, the precursor mpp-2OTs dosage is 4-6mg, the reaction temperature is 110-140 ℃, the reaction time is 15-60min, and the reaction is carried out in a closed manner, wherein the precursor mpp-2OTs is 2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethoxy) ethyl-4-methylbenzenesulfonic acid methyl ester;
6) purifying by semi-preparative HPLC18F]Fmpp2, wherein the chromatographic column is a C18 reverse chromatographic column, the mobile phase is a mixed solvent of water and acetonitrile with the volume ratio of 8/2-2/8, and the flow rate is 3-8 mL/min;
7) collecting the product of [ mu ], [ solution of ] a18F]Fmpp2, enriching by a solid phase extraction column; washing the solid phase extraction column with water or 0.9wt% sodium chloride injection, eluting with 0.5-5mL 50-100wt% ethanol solution to 10-30mL polyethylene glycol 400 with volume ratio of 2-20% and 0.9% sodium chloride injection to obtain injectable solution18F]Fmpp2 solution;
wherein the program control conditions of the step 4) are as follows: the first step, evaporating for 60-120s at 100-120 ℃ under the positive pressure of 50-200mbar nitrogen and under the vacuum pressure of-20 to-60 mbar; secondly, evaporating at 120 ℃ and 130 ℃ for 150 seconds under the positive pressure of 50-200mbar and the vacuum pressure of-20-60 mbar; thirdly, evaporating for 10-30s at the temperature of 120-; fourthly, evaporating for 80-120s at 100-120 ℃, under the positive pressure of nitrogen gas of 800-1200mbar and under the vacuum pressure of-800-1000 mbar; fifthly, evaporating for 100 and 120 seconds at 80-100 ℃, wherein the positive pressure of nitrogen is 400 and 600mbar, the vacuum pressure is-800 and-1000 mbar; sixthly, evaporating for 10-20s at 80-100 ℃, under the positive pressure of nitrogen gas of 600-900mbar and under the vacuum pressure of-800-1000 mbar.
2. The manufacturing method according to claim 1, wherein the manufacturing method is performed by placing an automatic synthesizer in the shielding device, wherein the automatic synthesizer is a synthesizer controlled by a programmable controller; the automatic synthesizer comprises an injector electric rotor, a vacuum device and an HPLC purification unit, and protective gas is nitrogen or inert gas.
3. The method according to claim 1, wherein the step 1) is performed by a nuclear reaction18O（p，n）18F preparation18F ion solution.
4. The method according to claim 1, wherein the anion exchange column of step 2) is not activated or is subjected to K at a concentration of 0.2 to 5mol/L2CO3、Na2CO3、KHCO3、NaHCO3One or more of the solutions is mixed and then activated.
5. The method of claim 1, wherein the cryptate K is222And K2CO3Cryptand K in catalyst solution2225-30mg, K2CO30.5-10 mg; the solvent is a mixed solvent of acetonitrile and water with the volume ratio of 10/1-2/8, and the volume is 0.2-2 mL.
6. The preparation method according to claim 1, wherein the aprotic polar solvent in step 5) is one or more selected from acetonitrile, dimethyl sulfoxide, N-dimethylformamide and 2-methyl-2-butanol.
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