CN103304493B - 2-fluoro-aniline quinazoline tumour positron imaging agents as well as preparation method and application thereof - Google Patents

Abstract

The invention provides an F-18-labeled 2-fluoroaniline quinazoline compound, which is produced by a cyclotron through a ¹⁸ O(pn) ¹⁸ F nuclear reaction to produce ¹⁸ F, which is automatically synthesized through a radiosynthesis module, or can be synthesized through an existing The domestic F-18 multifunctional synthesis device is produced after process modification. The invention is an aniline quinazoline structure substituted by 2-position positron nuclide fluorine-18, which can be modified at the 6-position, 7-position and the benzene ring connected to the amino group. The present invention provides a new type of tumor positron imaging agent. Compared with ¹⁸ F-fluorodeoxyglucose ( ¹⁸ FDG), this type of imaging agent has specificity and can identify those tumors with high expression of epidermal growth factor (EGFR) . The design of the preparation method is reasonable, the labeling method is simple, automatic production can be realized, and it is suitable for practical use. General structural formula of the present invention is as follows: .

Description

2-fluoroaniline quinazoline tumor positron imaging agent and its preparation and application

technical field

The invention belongs to the field of medicine, and relates to an aniline quinazoline compound, in particular to an F-18-labeled 2-fluoroaniline quinazoline compound and a preparation method thereof, as well as preparation of tumor positron emission tomography (PET) imaging application in agents.

Background technique

As the most advanced medical imaging technology at present, PET can realize high-resolution imaging of cell metabolism and function, and conduct non-invasive, three-dimensional and dynamic research on the physiological and biochemical processes of the human body at the molecular level. PET is used in tumors, including tumors. Diagnosis, identification of benign and malignant tumors, early diagnosis and identification of malignant tumor staging, typing, recurrence, and metastasis, selection of treatment options, monitoring of chemotherapy effects, observation of tumor changes, and detection of prognosis. PET examination is different from other examinations in that it relies on positron drugs (PET drugs), which rely on the specific concentration of positron drugs in target organs to achieve the purpose of diagnosis and evaluation. ¹⁸ F-fluorodeoxyglucose ( ¹⁸ FDG ) is the most important positron drug used in current PET examinations. As a tumor metabolic drug, ¹⁸ FDG plays a huge role in the diagnosis and differential diagnosis of malignant tumors. However, ¹⁸ FDG is a relatively non-specific imaging agent. If inflammation and tumor cannot be distinguished, many reports are false positive or false negative. The diagnosis and research of tumor still need to develop novel and more specific imaging. agent. Aniline quinazoline compounds are a class of important heterocyclic compounds with wide application and high biological activity so far, mainly for EGFR or its tyrosine kinase (EGFR-TK), vascular endothelial growth factor receptor ( VEGFR), Platelet-derived Growth Factor Receptor (PDGFR), Nerve Growth Factor Receptor (NGFR) and other multiple targets of inhibitory activity, so as to exert various pharmacological effects such as anticancer, antibacterial, antiviral, etc. Research hotspots in the fields of medicine and chemistry.

Contents of the invention

The object of the present invention is to provide a kind of F-18 labeled 2-fluoroaniline quinazoline compound, structural formula is as follows:

in:

The structural formula is characterized by the aniline quinazoline structure substituted by the 2-position positron nuclide fluorine-18, which can be modified at the 6-position, 7-position, and the benzene ring connected to the amino group.

Specific compounds relate to:

.

Another object of the present invention is to provide the preparation method of the 2-fluoroaniline quinazoline compound of F-18 mark, realize by following method 1 or method 2:

Method 1: Using a cyclotron to bombard ¹⁸ O water to produce ¹⁸ F ions through ¹⁸ O(p n) ¹⁸ F nuclear reaction, use 1mL mixed solution (mixed solution: 12.5 mg 4,7,13,16,21,24-6 Oxygen-1,10-diazabicyclo[8.8.8]hexacane (K ₂₂₂ ) plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile) to rinse ^18F into the reaction tube, Evaporate to dryness, add 2 mL of acetonitrile, and then evaporate to dryness, add 5 mg of organic solution of 2-position halogen substituted 4-aniline quinazoline precursor (dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, etc.) , react at 100-140°C for 10 minutes to obtain the corresponding 2-fluoro-18 substituted 4-aniline quinazoline compounds; the product is separated by C-18 column and HPLC, and the separation column is a preparative or semi-preparative C -18 column, the mobile phase is eluent of acetonitrile and water or eluent of ethanol and water. Reaction formula:

.

Method 2: Using a cyclotron to bombard ¹⁸ O water to produce ¹⁸ F ions through ¹⁸ O(p n) ¹⁸ F nuclear reaction, use 1mL solution (mixed solution: 12.5 mg 4,7,13,16,21,24-hexaoxo -1,10-diazabicyclo[8.8.8]hexacane (K ₂₂₂ ) plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile) rinse ¹⁸ F into the reaction tube, evaporate Dry, add 2mL of acetonitrile, and then evaporate to dryness, add 5mg of organic solution of 4-N-tert-butylcarbonyl 2-position halogen substituted 4-aniline quinazoline precursor (dimethyl sulfoxide, N,N-dimethyl Formamide, acetonitrile, etc.), react at 100-140°C for 10 minutes, add hydrochloric acid, remove the protection, and obtain the corresponding 2-fluoro-18 substituted 4-aniline quinazoline compounds; separated by C-18 column and HPLC To obtain the product, the separation column is a preparative or semi-preparative C-18 column, and the mobile phase is the eluent of acetonitrile and water or the eluent of ethanol and water. Reaction formula:

.

The halogen mentioned in the reaction is chlorine, bromine or iodine.

The third object of the present invention is to provide the application of F-18 labeled 2-fluoroaniline quinazoline compounds in the preparation of PET imaging agents. Experiments prove that the F-18 labeled 2-fluoroaniline quinazoline compounds can be used in PET imaging of tumors, especially tumors with high epidermal growth factor (EGFR) expression. It is a new class of positron electron imaging agents in tumors.

In the invention, ¹⁸ F is produced by a cyclotron through ¹⁸ O(p n) ¹⁸ F nuclear reaction, and this type of imaging agent can be automatically synthesized through a radiation synthesis module. The present invention can be prepared by manual synthesis, and can also be produced through the existing domestic F-18 multifunctional synthesis device (Beijing Paite Company) after process modification. The production process is simple, and other commercial automatic synthesis devices can also be used.

The present invention provides a new type of positron imaging agent (2-fluoroaniline quinazoline-based positron imaging agent), its preparation method and application, compared with ¹⁸ F-fluorodeoxyglucose ( ¹⁸ FDG) , this type of imaging agent is specific and can identify those tumors with high expression of epidermal growth factor (EGFR); in the preparation method, the 2-position fluorine-18 is used to label aniline quinazoline compounds, the labeling method is simple, and automatic production can be realized , can meet the needs of scientific research and clinical experiments.

Description of drawings

Fig. 1 is a schematic flow diagram of an automatic synthesis device for 2-position fluorine labeling of 4-aniline quinazolines.

Fig. 2 is the radioactive HPLC spectrum of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-aniline.

Fig. 3 is the ultraviolet HPLC spectrum of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-aniline.

Fig. 4 is a radioactive HPLC spectrum of 2- ¹⁸ F-6,7-dimethoxyquinazolin-4-(3'-bromo)amine.

Fig. 5 is the ultraviolet HPLC spectrum of 2- ¹⁸ F-6,7-dimethoxyquinazolin-4-(3'-bromo)amine.

Fig. 6 is the radioactive HPLC spectrum of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-(3'-ynyl)aniline.

Figure 7 is the UV HPLC spectrum of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-(3'-ynyl)aniline.

Fig. 8 is the biodistribution of 2- ¹⁸ F-PD153035.

Figure 9 is a small animal PET image of 2- ¹⁸ F-PD153035 in PC9 tumor-bearing mice.

Detailed ways

The present invention is further described in conjunction with drawings and embodiments. However, the present invention is not limited thereto.

In the embodiment, the C18 cartridges are Sep-pak Plus C18, Sep-pak Plus tC18, Sep-Pak Light C18 cartridges, Oasisis HLB Plus cartridges [both are products of Waters Company in the United States] or self-made C18 cartridges.

The separation column is a preparative or semi-preparative C-18 column. The mobile phase is the eluent of acetonitrile and water or the eluent of ethanol and water. The reaction mixture is separated by HPLC to obtain the target product.

Example 1 Radiochemical Synthesis of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-aniline

Referring to Fig. 1, the cyclotron is used to bombard ¹⁸ O water, and 100mCi ¹⁸ F ions are produced through the nuclear reaction of ¹⁸ O(p n) ¹⁸ F, and ^{the 18} F produced by the accelerator is captured by the QMA column;

⑴ Rinse ¹⁸ F into the reaction tube with 1mL solution in No. 1 bottle (12.5mg K ₂₂₂ plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile mixed solution);

(2) Dry the solution in the reaction tube at 116°C with nitrogen;

(3) Add 2 mL of dry acetonitrile in the No. 2 bottle to the reaction tube, and dry it with nitrogen at 116°C;

(4) Add 5 mg of 2-chloro-6,7-dimethoxyquinazoline-4-aniline precursor and 0.8 mL of dry DMSO in bottle No. 3 to the reaction tube, and react at 140 ° C for 10 min;

⑸ Add 30mL water to the No. 5 bottle three times into the reaction tube, pass the mixed liquid through the C-18 column between the V7 and V10 valves, the labeled product is captured on the C-18 column, and pass the precursor negative ions and other impurities through the V10 tee valve transfer to waste bottle;

⑹ Add 2 mL of ethanol solution in No. 6 bottle to the reaction tube to wash off the marker on the C-18 column. The crude product should be separated by HPLC. The separation condition is 50% ethanol: water mobile phase and C-18 semi-preparative column product.

Example 2 Radiochemical Synthesis of 2- ¹⁸ F-6,7-Dimethoxyquinazoline-4-aniline

The cyclotron is used to bombard ¹⁸ O water, and 100mCi ¹⁸ F ions are produced by ¹⁸ O(p n) ¹⁸ F nuclear reaction, and ^{the 18} F produced by the accelerator is captured by the QMA column;

⑴ Rinse ¹⁸ F into the reaction tube with 1mL solution in No. 1 bottle (12.5mg K ₂₂₂ plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile mixed solution);

(2) Dry the solution in the reaction tube at 116°C with nitrogen;

(3) Add 2 mL of dry acetonitrile in the No. 2 bottle to the reaction tube, and dry it with nitrogen at 116°C;

(4) Add 5 mg of 2-bromo-6,7-dimethoxyquinazoline-4-N-tert-butylcarbonyl-aniline and 0.8 mL of dry DMF in No. 3 bottle to the reaction tube, and react at 140 °C for 10 min;

⑸Add 2mL hydrochloric acid solution in No. 6 bottle to the reaction tube and hydrolyze for 15min

⑹Add 30mL water to the No. 5 bottle three times into the reaction tube, pass the mixed liquid through the C-18 column between the V7 and V10 valves, the labeled product is captured on the C-18 column, and pass the precursor negative ions and other impurities through the V10 tee valve transfer to waste bottle;

Add 2 mL of ethanol solution in No. 4 bottle to the reaction tube, wash off the marker on the C-18 column, and separate the crude product by HPLC under the mobile phase of 50% ethanol: water, and use the C-18 semi-preparative column to obtain the product .

Example 3 Quality control of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-aniline

See Figures 2 and 3 for the HPLC spectrum. The quality control conditions are 50% acetonitrile aqueous solution, C-18 (4.5mm×250mm) column, ultraviolet 254nm and radioactive detector. The results show that the standard Hu ultraviolet absorption is consistent with the radioactive absorption, which is the same Substance, synthesis time 45min, uncorrected synthesis yield 20-30%, radiochemical purity >98%. The spectrum of the standard product is: ESI-MS(m/z,%): 300([M+H] ⁺ ,100), ¹ H NMR(CDCl3, 400MHz): 7.69(2H,d, J =7.93, 4 digits benzene ring 2'-H,6'-H);7.45(1H,br.s,-NH); 7.42 (2H,dd, J ₁ =7.53Hz, J ₂ =8.32Hz, 4-position benzene ring 3'- H,5'-H); 7.20 (1H,dd, J ₁ =7.14Hz, J ₂ =6.34Hz, 4'-H);7.15(1H,s,8-H); 7.04(1H ,s,5-H); 4.00 (6H,s,2-OCH ₃ ).

Example 4 Radiosynthesis of 2- ¹⁸ F -6,7-dimethoxyquinazoline-4-(3'-bromo)-aniline

The cyclotron is used to bombard ¹⁸ O water, and 100mCi ¹⁸ F ions are produced by ¹⁸ O(p n) ¹⁸ F nuclear reaction, and ^{the 18} F produced by the accelerator is captured by the QMA column;

⑴ Rinse ¹⁸ F into the reaction tube with 1mL solution in No. 1 bottle (12.5mg K ₂₂₂ plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile mixed solution);

(2) Dry the solution in the reaction tube at 116°C with nitrogen;

(3) Add 2 mL of dry acetonitrile in the No. 2 bottle to the reaction tube, and dry it with nitrogen at 116°C;

(4) Add 5 mg of 2-chloro-6,7-dimethoxyquinazoline-4-(3’-bromo)-aniline precursor and 0.8 mL of dry DMSO in bottle No. 3 to the reaction tube, and react at 140°C for 10 minutes;

⑸ Add 30mL water to the No. 5 bottle three times into the reaction tube, pass the mixed liquid through the C-18 column between the V7 and V10 valves, the labeled product is captured on the C-18 column, and pass the precursor negative ions and other impurities through the V10 tee valve transfer to waste bottle;

⑹ Add 2 mL of ethanol solution in No. 6 bottle to the reaction tube to wash off the marker on the C-18 column. The crude product should be separated by HPLC. The separation condition is 50% ethanol: water mobile phase, C-18 semi-preparative column get the product.

Example 5 Radiosynthesis of 2- ¹⁸ F -6,7-dimethoxyquinazoline-4-(3'-bromo)-aniline

The cyclotron is used to bombard ¹⁸ O water, and 100mCi ¹⁸ F ions are produced by ¹⁸ O(p n) ¹⁸ F nuclear reaction, and ^{the 18} F produced by the accelerator is captured by the QMA column;

⑴ Rinse ¹⁸ F into the reaction tube with 1mL solution in No. 1 bottle (12.5mg K ₂₂₂ plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile mixed solution);

(2) Dry the solution in the reaction tube at 116°C with nitrogen;

(3) Add 2 mL of dry acetonitrile in the No. 2 bottle to the reaction tube, and dry it with nitrogen at 116°C;

⑷ Add 5 mg of 2-iodo-6,7-dimethoxyquinazoline-4-N-tert-butylcarbonyl-(3'-bromo)-aniline precursor and 0.8 mL of dry DMF in the No. 3 bottle to the reaction tube , reacted at 140°C for 10 minutes;

(5) Add 2 mL of hydrochloric acid solution in No. 6 bottle to the reaction tube, and hydrolyze for 15 minutes;

⑹Add 30mL water to the No. 5 bottle three times into the reaction tube, pass the mixed liquid through the C-18 column between the V7 and V10 valves, the labeled product is captured on the C-18 column, and pass the precursor negative ions and other impurities through the V10 tee valve transfer to waste bottle;

Add 2 mL of ethanol solution in No. 4 bottle to the reaction tube, wash off the marker on the C-18 column, and separate the crude product by HPLC under the mobile phase of 50% ethanol: water, and use the C-18 semi-preparative column to obtain the product .

Example 6 Quality control of 2- ¹⁸ F-6,7-dimethoxyquinazolin-4-(3'-bromo)amine

The HPLC chromatograms are shown in Figures 4 and 5. The quality control conditions are 60% acetonitrile aqueous solution, C-18 (4.5mm×250mm) column, ultraviolet 254nm and radioactive detector. The results show that the ultraviolet absorption of the standard product is consistent with the radioactive absorption, and it is the same substance , synthesis time 45min, uncorrected synthesis yield 10-20%, radiochemical purity> 98%. The spectrum of the standard product is: ESI-MSm/z(%) : 378 ([M+1] , 100) , 380 ([M+3] , 100) , ¹ H NMR(CDCl ₃ , 400 Hz) δ : 7.88 (1H , t , J = 1.76 Hz , 2'-H) , 7.71 (1H , dt , J ₁ = 7.82 Hz , J ₂ = 1.76 Hz , 6'-H) , 7.32 (1H , br s , -NH- ) , 7.30 (1H ,dd , J ₁ = 7.82 Hz , J ₂ = 7.44 Hz , 5'-H) , 7.26 (1H, d , J = 7.44 Hz , 4'-H) , 7.16 (1H , s , 8 -H) , 6.99 (1H , s , 5-H) , 4.02 (3H , s , -OCH ₃ ), 4.01 (3H , s , -OCH ₃ ).

Example 7 Synthesis of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-(3'-ynyl)aniline

The cyclotron is used to bombard ¹⁸ O water, and 100mCi ¹⁸ F ions are produced by ¹⁸ O(p n) ¹⁸ F nuclear reaction, and ^{the 18} F produced by the accelerator is captured by the QMA column;

⑴ Rinse ¹⁸ F into the reaction tube with 1mL solution in No. 1 bottle (12.5mg K ₂₂₂ plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile mixed solution);

(2) Dry the solution in the reaction tube at 116°C with nitrogen;

(3) Add 2 mL of dry acetonitrile in the No. 2 bottle to the reaction tube, and dry it with nitrogen at 116°C;

⑷ Add 5 mg of 2-chloro-6,7-dimethoxyquinazoline-4-(3'-alkynyl)-aniline precursor and 0.8 mL of dry DMSO in bottle No. 3 to the reaction tube, and react at 140 ° C for 10 min ;

⑸ Add 30 mL of water to the No. 5 bottle three times into the reaction tube, pass the mixed liquid through the C-18 column between the V7 and V10 valves, the labeled product is captured on the C-18 column, and pass the precursor negative ions and other impurities through the V10 tee valve transfer to waste bottle;

⑹ Add 2 mL of ethanol solution in No. 6 bottle to the reaction tube, wash off the markers on the C-18 column, and use HPLC to separate the crude product, the separation condition is 50% ethanol: water mobile phase, C-18 semi-preparative column product.

Example 8 Synthesis of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-(3'-ynyl)aniline

The cyclotron is used to bombard ¹⁸ O water, and 100mCi ¹⁸ F ions are produced by ¹⁸ O(p n) ¹⁸ F nuclear reaction, and ^{the 18} F produced by the accelerator is captured by the QMA column;

⑴ Rinse ¹⁸ F into the reaction tube with 1mL solution in No. 1 bottle (12.5mg K ₂₂₂ plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile mixed solution);

(2) Dry the solution in the reaction tube at 116°C with nitrogen;

(3) Add 2 mL of dry acetonitrile in the No. 2 bottle to the reaction tube, and dry it with nitrogen at 116°C;

⑷ Add 5 mg of 2-iodo-6,7-dimethoxyquinazoline-4-N-tert-butylcarbonyl-(3'-alkynyl)-aniline precursor and 0.8 mL of dry Acetonitrile, react at 140°C for 10 minutes;

(5) Add 2 mL of hydrochloric acid solution in No. 6 bottle to the reaction tube, and hydrolyze for 15 minutes;

⑹Add 30mL water to the No. 5 bottle three times into the reaction tube, pass the mixed liquid through the C-18 column between the V7 and V10 valves, the labeled product is captured on the C-18 column, and pass the precursor negative ions and other impurities through the V10 tee valve transfer to waste bottle;

(7) Add 2 mL of ethanol solution in No. 4 bottle to the reaction tube to wash off the marker on the C-18 column. The crude product should be separated by HPLC. The separation condition is 50% ethanol: water mobile phase, C-18 semi-preparation column to obtain the product.

Example 9 Manual Synthesis of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-(3'-ynyl)aniline

¹⁸ O water was bombarded by a cyclotron, and 20mCi ¹⁸ F ions were produced by ¹⁸ O(p n) ¹⁸ F nuclear reaction, and ^{the 18} F produced by the accelerator was captured by a QMA column; 1mL solution (12.5 mg K ₂₂₂ plus 2.5 mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile) rinse ¹⁸ F into a 10mL glass reaction tube; dry the solution in the reaction tube at 116°C with nitrogen; add 2 mL of dry acetonitrile to the reaction tube, Evaporate to dryness under nitrogen at ℃, add 2-iodo-6,7-dimethoxyquinazoline-4-(3'-alkynyl)-aniline precursor and 0.8mL dry DMSO to the reaction tube, and react at 140℃ for 10min ; Add 10mL of water into the reaction tube, manually transfer to the C-18 small column, then continue to wash the C-18 small column with 20mL of water, and use 2mL of ethanol solution to remove the crudely purified compound on the C-18 column. Wash down and apply HPLC separation, the separation condition is 50% ethanol: water mobile phase, C-18 semi-preparative column to obtain the product.

Example 10 Quality control of 2- ¹⁸ F-6,7-dimethoxyquinazoline-4-(3'-ynyl)aniline

See Figures 6 and 7 for the HPLC chromatograms. The quality control conditions are 65% acetonitrile aqueous solution, C-18 (4.5mm×250mm) column, ultraviolet 254nm and radioactive detector. The results show that the ultraviolet absorption of the standard product is consistent with the radioactive absorption. Substance, synthesis time 45min, uncorrected synthesis yield 10-20%, radiochemical purity >98%. The spectrum of the standard product is: ESI-MSm/z(%) : 324 ([M+1] , 100) , ¹ H NMR(CDCl ₃ , 400 Hz) δ : 7.78 (1H , d , J = 8.21 Hz , 6 '-H) , 7.75 (1H , s , 2'-H) , 7.40 (1H , br s , -NH-) , 7.36 (1H ,dd , J ₁ = 7.82 Hz , J ₂ = 7.83 Hz , 5'- H) , 7.29 (1H, d , J = 7.83 Hz , 4'-H) , 7.14 (1H , s , 8-H) , 7.01 (1H , s , 5-H) , 4.01 (3H , s , -OCH ₃ ), 3.99 (3H , s , -OCH ₃ ).

Example 11 Stability experiment of 2- ¹⁸ F-PD153035

The stability test of 2- ¹⁸ F-PD153035 showed that the radiochemical purity can still reach more than 98% when observed in calf serum at 37 degrees Celsius for 8 hours, and the stability is good. The biodistribution in normal Kunming mice is shown in Figure 8, which shows that the drug is mainly metabolized by the liver and intestines, the blood clearance is fast, and the radioactive uptake in the bone is not high, suggesting that the drug is not defluorinated in the body and is stable in the body.

Example 12

The PET imaging of 2- ¹⁸ F-PD153035 in PC9 tumor-bearing mice (Fig. 9) showed radioactive uptake in the tumor site. This shows that 2-fluoroaniline quinazoline compounds can perform tumor PET imaging on tumors with high expression of EGFR, and this class of drugs can be used as a new class of tumor imaging agents.

Claims (7)

1. A 2-fluoroaniline quinazoline compound of F-18 label, it is characterized in that, described compound is the aniline quinazoline structure that 2 positron nuclide fluorine-18 replaces, in 6, 7 , and the modified structure on the benzene ring connected to the amino group, specifically related to the following compounds: . 2. the preparation method of the 2-fluoroaniline quinazoline compound of F-18 label according to claim 1, is characterized in that, realizes by the following steps: Use a cyclotron to bombard ¹⁸ O water, produce ¹⁸ F ions through ¹⁸ O(p n) ¹⁸ F nuclear reaction, rinse ¹⁸ F into the reaction tube with 1 mL of mixed solution, evaporate to dryness, add 2 mL of acetonitrile, and evaporate to dryness again, Add 5mg of organic solution of 2-position halogen substituted 4-aniline quinazoline precursor, and react at 100-140°C for 10 minutes to obtain 2-position fluorine-18 substituted 4-aniline quinazoline compounds; through C-18 small column and The product was separated by HPLC. The separation column was a preparative or semi-preparative C-18 column. The mobile phase was the eluent of acetonitrile and water or the eluent of ethanol and water. The composition of the mixed solution: 12.5 mg 4,7 ,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8]hexacane plus 2.5mg K ₂ CO ₃ dissolved in 0.1mL water and 0.9mL acetonitrile, the reaction formula: . 3. the preparation method of the 2-fluoroaniline quinazoline compound of F-18 label according to claim 1, is characterized in that, realizes by the following steps: application cyclotron application bombards ¹⁸ O water, by ¹⁸ O(p n ) ¹⁸ F nuclear reaction to produce ¹⁸ F ions, rinse ¹⁸ F into the reaction tube with 1mL solution, evaporate to dryness, add 2mL of acetonitrile, evaporate to dryness again, add 5mg of 4-N-tert-butylcarbonyl 2-position halogen to replace Organic solution of 4-aniline quinazoline precursor, react at 100-140°C for 10 minutes, add hydrochloric acid, remove the protection, and obtain 2-fluorine-18 substituted 4-aniline quinazoline compounds; through C-18 small column and The product is separated by HPLC. The separation column is a preparative or semi-preparative C-18 column. The mobile phase is the eluent of acetonitrile and water or the eluent of ethanol and water. The reaction formula: . 4. The preparation method of the F-18 labeled 2-fluoroaniline quinazoline compound according to claim 2 or 3, wherein said halogen is chlorine, bromine or iodine. 5. according to the preparation method of the 2-fluoroaniline quinazoline compound of F-18 mark described in claim 2 or 3, it is characterized in that, organic solution selects dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile. 6. The preparation method of F-18-labeled 2-fluoroaniline quinazoline compound according to claim 2 or 3, characterized in that ¹⁸ F is produced by cyclotron through ¹⁸ O(p n) ¹⁸ F nuclear reaction. 7. The application of a kind of F-18 labeled 2-fluoroaniline quinazoline compound according to claim 1 in the preparation of PET imaging agent.