WO2021036022A1 - Pet/ct tracer having selectivity for different lung cancer cells, preparation method therefor and use thereof - Google Patents

Abstract

A PET/CT tracer having selectivity for different lung cancer cells, a preparation method therefor and use thereof. The PET/CT tracer is a compound represented by formula I, or a salt or stereoisomer thereof, wherein R₁ and R₂ are each independently selected from H or C₁-C₅ alkyl, and X is independently selected from ¹¹C, ¹⁸F, ¹⁹F, ¹⁵O, or ¹³N. The prepared ¹⁸F-PET/CT tracer can be selectively taken in by different carcinogenic driver gene mutant lung cancer cells. Test results show that the ¹⁸F-PET/CT tracer is expected to achieve high quality imaging in an NRas Q61K tumor model, and has certain selectivity for different carcinogenic driver gene mutant lung cancers. The tracer is different from ¹⁸F-FDG that may lead to high-concentration imaging in any lesion due to increased glucose metabolism, and is expected to make up for the deficiency of imaging by using ¹⁸F-FDG alone. Therefore, the ¹⁸F-PET/CT tracer is expected to be applied to PET/CT iconography and change the situation of lack of tracers on lung cancers.

Description

PET/CT tracer with selectivity to different lung cancer cells and preparation method and application thereof Technical field

The invention belongs to the field of organic chemistry, and specifically relates to a PET/CT tracer with selectivity to different lung cancer cells, and a preparation method and application thereof.

Background technique

PET/CT is an advanced diagnostic and treatment equipment for functional imaging. Although its application in lung cancer is increasingly popularized, it still has great limitations. This limitation mainly comes from the core component of functional imaging: PET/CT tracer. The current PET/CT tracer for lung cancer is mainly ¹⁸ F-FDG. Because ¹⁸ F-FDG lacks specificity at other molecular levels except for glucose metabolism, on the one hand, there are false positive and false negative defects, and on the other hand, it cannot The functional imaging level reflects the molecular classification of lung cancer or the information of other specific molecular targets. At the same time, ¹⁸ F-FDG has no specific choice for lung cancer. Therefore, it has become a major technical bottleneck for accurate diagnosis and treatment of lung cancer.

Currently, the types and effects of tracers that can be used for lung cancer diagnosis are very limited. Therefore, there is an urgent need to develop new functional imaging tracers and precursor reagents for accurate diagnosis of lung cancer.

Summary of the invention

The purpose of the present invention is to provide a PET/CT tracer with selectivity to different lung cancer cells and its preparation method and application.

The present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof:

Wherein, R ₁ and R ₂ are each independently selected from H or C ₁ -C ₅ alkyl groups;

X is independently selected from ¹¹ C, ¹⁸ F, ¹⁹ F, ¹⁵ O or ¹³ N.

Further, the compound is the following compound formula II:

Wherein, R _{2 is} selected from H or C ₁ -C ₅ alkyl group;

X is independently selected from ¹¹ C, ¹⁸ F, ¹⁹ F, ¹⁵ O or ¹³ N.

Further, the compound is the following compound formula III:

Wherein, R _{2 is} selected from H or C ₁ -C ₅ alkyl.

Further, the compound is the following compound ¹⁸ F-HX:

The present invention also provides a method for preparing the aforementioned compound ¹⁸ F-HX, or a salt thereof, or a stereoisomer thereof, which comprises the following steps:

Step a: Synthesis of compound 1 with tert-butylhydrazine hydrochloride, triethylamine and ethoxymethylenemalononitrile using absolute ethanol as a solvent;

Step b: Compound 1 is reacted with formamide to obtain compound 2;

Step c: Compound 2 and bromine undergo bromination reaction with water as a solvent to obtain compound 3;

Step d: Compound 3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and potassium carbonate with 1,4-dioxyl The mixed solution of alkane and water is used as a solvent and reacted under a catalytic amount of catalyst to obtain compound 4;

Step e: Compound 4, tetraethylene glycol bis(p-toluene hydrochloride) and anhydrous potassium carbonate are reacted in benzene solution to obtain compound 5;

Step f: After the compound 5 is dissolved in DMF, it is placed in a PET single-shot module, the target is hit, the water is removed, and the nucleophilic substitution reaction is followed by purification and elution to obtain ¹⁸ F-HX.

further,

In step a, the molar ratio of the tert-butylhydrazine hydrochloride, triethylamine and ethoxymethylene malononitrile is 1:1:1; the volume ratio of the triethylamine to absolute ethanol is 9.7:460;

And/or, in step b, the mass-volume ratio of compound 1 and formamide is 1.1:15 (w/v);

And/or, in step c, the molar ratio of compound 2 to bromine is 1:2; the volume ratio of bromine to water is 0.52:25;

And/or, in step d, the compound 3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and potassium carbonate mole The ratio is 0.56:3:3; the mass-volume ratio of the compound 3 to the mixed solution of 1,4-dioxane and water is 0.05:10 (w/v); the 1,4-dioxane and In the mixed solution of water, the volume ratio of 1,4-dioxane to water is 5:1;

And/or, in step e, the molar ratio of compound 4, tetraethylene glycol bis(p-toluene hydrochloride) and anhydrous potassium carbonate is 1:1:2; the mass volume ratio of compound 4 to the benzene solution is 0.1 :50(w/v).

further,

In step a, the synthesis conditions are heating and refluxing for 3 hours;

And/or, in step b, the reaction conditions are heating to reflux for 6 hours;

And/or, in step c, the bromination reaction conditions are stirring at room temperature for 1 hour, and then heating at 100°C for 2 hours;

And/or, in step d, the reaction conditions are heating in an oil bath at 90°C for 2 hours;

And/or, in step d, the catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

And/or, in step e, the reaction conditions are reflux heating for 4 hours;

And/or, in step f, in the PET single module, ethanol activates the C18 column, and sodium bicarbonate activates the QMA column;

And/or, in step f, the shooting time is 30-60 min;

And/or, in step f, the water scavenger is anhydrous acetonitrile;

And/or, in step f, the nucleophilic substitution reaction temperature is 125°C, and the time is 12 min;

And/or, in step f, the purification uses a C18 column for separation and purification;

And/or, in step f, absolute ethanol is used for the elution.

further,

In step a, the obtained compound 1 is purified, and the specific method is as follows: the reaction solution is extracted with a mixture of ethyl acetate and water in a volume ratio of 2:1, the organic layer is dried with anhydrous magnesium sulfate, and the organic layer is evaporated to obtain a solid. Wash with 10% ethyl acetate-containing cyclohexane solution, and then filter with suction;

And/or, in step b, the obtained compound 2 is purified. The specific method is: extracting the reaction solution with ethyl acetate three times, drying the organic layer with anhydrous magnesium sulfate, filtering and evaporating the solvent under reduced pressure to obtain a solid;

And/or, in step c, the obtained compound 3 is purified, the specific method is: the reaction solution is extracted 3 times with ethyl acetate, then washed with 5% sodium hydrogen sulfate and 5% sodium chloride solution in turn, and dried with anhydrous magnesium sulfate The organic layer is filtered and concentrated, and the solvent is evaporated under reduced pressure to obtain a solid.

And/or, in step d, the obtained compound 4 is purified, the specific method is: the reaction solution is extracted with ethyl acetate and water in a volume ratio of 2:1, the organic layer is dried with anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain a solid, namely can;

And/or, in step e, the obtained compound 5 is purified. The specific method is: after the reaction solution is neutralized with 1N HCl, it is extracted with dichloromethane, and then the organic layer solution is dried under reduced pressure and separated by chromatography.

The present invention also provides the application of the aforementioned compound in the preparation of a tracer; preferably, the tracer is a PET/CT tracer.

Further, the PET/CT tracer is a tracer used in tumor diagnosis; preferably, the tumor is lung cancer.

The present invention also provides a tracer, which is prepared by using the aforementioned compound, or its salt, or its stereoisomer as the active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients.

In the present invention, w/v is the mass-to-volume ratio, and the unit is g/mL.

The invention successfully prepares an ¹⁸ F-PET/CT tracer. ^{The 18} F-PET/CT tracer prepared in the present invention can be selectively taken up by different oncogenic driver gene mutant lung cancer cells, and the H1299 (NRas Q61K) tumor model is in the ¹⁸ F-PET/CT tracer prepared in the present invention. The imaging sensitivity in PET is ^{similar to that of 18} F-FDG and is the clearest. H460 (KRas Q61H) followed by HCC827 (EGFR A746-750del), PC-9 (EGFR A746-750del), H1975 (EGFR L858R/T790M) tumor models have no effect on the ¹⁸ F-PET/CT tracer prepared by the present invention. Obviously ingested. This shows that the ¹⁸ F-PET/CT tracer of the present invention is expected to be high-quality imaging in the NRas Q61K tumor model, and has a certain selectivity for different oncogenic driver gene mutant lung cancers. This and any lesions with increased glucose metabolism can cause high concentrations different imaging nonspecific ¹⁸ F-FDG, is expected to make up for the lack of a single use of ¹⁸ F-FDG imaging. Therefore, the ¹⁸ F-PET/CT tracer of the present invention is expected to be applied to PET/CT imaging to change the lack of tracers on lung cancer.

Obviously, according to the above-mentioned content of the present invention, according to common technical knowledge and conventional means in the field, various other modifications, substitutions or alterations can be made without departing from the above-mentioned basic technical idea of the present invention.

Hereinafter, the above-mentioned content of the present invention will be further described in detail through specific implementations in the form of examples. However, it should not be understood that the scope of the above-mentioned subject of the present invention is limited to the following examples. All technologies implemented based on the foregoing content of the present invention belong to the scope of the present invention.

Description of the drawings

Figure 1 is the HPLC spectrum of the non-radioactive standard; A: no signal under the radioactivity detector, B: signal under the UV detector.

Figure 2 is the HPLC chart of the PET/CT tracer ¹⁸ F-HX of the present invention; A: there is a signal under the radioactivity detector, B: there is no signal under the ultraviolet detector.

Fig. 3 HPLC spectrum of non-radioactive standard substance and PET/CT tracer ¹⁸ F-HX of the present invention after mixed injection; A: signal under the radioactivity detector, B: signal under the ultraviolet detector.

Figure 4 is a ^{comparison of imaging effects of the PET/CT tracer 18} F-HX and the PET/CT tracer ¹⁸ F-FDG on H1299 lung cancer cells.

Figure 5 is a comparison of imaging effects of the PET/CT tracer ^{18 F-HX of the present invention on different NSCLC cell lines.}

detailed description

The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

Example 1. Preparation of PET/CT tracer ¹⁸ F-HX of the present invention

1. Preparation of 5-amino-1-tert-butyl-1hydro-pyrazole-4-cyano

After adding triethylamine (9.7mL, 69.6mmol) to tert-butylhydrazine hydrochloride (8.67g, 69.6mmol), add absolute ethanol (460mL) and stir to dissolve at room temperature, then add ethoxy groups in small amounts Methylene malononitrile (8.5 g, 69.6 mmol), the solution was heated to reflux for 3 hours, and then the solvent was rotary evaporated in vacuo to obtain an orange crude product. Then, it was extracted with a mixed solution of ethyl acetate (0.5L) and water (0.25L). After adding anhydrous magnesium sulfate to dry, the organic layer was evaporated to obtain an orange solid. Continue to wash the obtained solid with a cyclohexane solution containing 10% ethyl acetate and extract to obtain a crystalline solid 5-amino-1-tert-butyl 1 hydrogen-pyrazole-4-cyano 9.54g (yield 83% ).

¹ H NMR (400 MHz, DMSO-d6): δ 7.45 (s, 1H), 6.29 (br s, 2H), 1.51 (s, 9H). HRMS(ESI-TOF):for C ₈ H ₁₂ N ₄ [M+H]:calcd 164.1062; found 164.1080.

2. Preparation of 1-tert-butyl-1hydro-pyrazole[3,4-d]pyrimidine-4-amino

Formamide (15 mL) was added to 5-amino-1-tert-butyl 1-hydro-pyrazole-4-cyano (1.1 g, 6.75 mmol), and heated to reflux for 6 hours to obtain a reaction solution. The reaction solution was mixed with ethyl acetate. The ester (3×30 mL) was extracted, and the obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a brown solid (0.97 g, 5.1 mmol) (yield 76%).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.08(s,1H),7.97(s,1H),7.51(s,2H),1.63(s,9H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ158.12,154.66,152.69,130.00,101.39,59.19,28.75. HRMS(ESI-TOF): for C ₉ H ₁₄ N ₅ [M+H]: calcd 192.1250; found 192.1250.

3. Preparation of 3-bromo-1-tert-butyl-1hydro-pyrazole[3,4-d]pyrimidine-4-amino

After adding 25mL of water to 1-tert-butyl-1hydro-pyrazole[3,4-d]pyrimidine-4-amino (0.97g, 5.1mmol), then adding bromine (0.52mL, 10.2mmol) at room temperature Stir for 1 hour, then heat at 100°C for 2 hours to obtain the reaction solution. The reaction solution is extracted with ethyl acetate (3x 25mL), and then washed with 5% sodium bisulfate solution (25mL) and 5% sodium chloride solution (25mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated, and 1.2 g of a pink solid was obtained by evaporating the solvent under reduced pressure (yield 84%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.21 (s, 1H), 6.42 (s, 2H), 1.68 (s, 9H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 157.47, 155.59, 153.48 ,115.25,100.43,60.57,28.58.HRMS(ESI-TOF):for C ₉ H ₁₃ BrN ₅ [M+H]:calcd 270.0355;found 270.0388.

4. Preparation of 4-(4-amino-1-tert-butyl-1hydro-pyrazole[3,4-d]pyrimidine-3-)phenol

Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (660mg, 3.0mmol) to 3-bromo-1-tert-butyl 1-hydro-pyrazole[3,4-d]pyrimidine-4-amino (150mg, 0.56mmol) in 1,4-dioxane/water (volume ratio 5:1, that is, 25mL:5mL) solution After that, potassium carbonate (41.4mg, 3.0mmol) and pdcl2dppf ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) (4mg, 0.05mmol) were continuously added. Then it was heated in an oil bath at 90°C for 2 hours to obtain a reaction solution. A mixed solution of water (0.25 L) and ethyl acetate (0.5 L) was added to the reaction solution for extraction, the organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 100 mg of white solid (yield 75%).

¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.83 (s, 1H), 8.28 (s, 1H), 7.54-7.49 (m, 2H), 7.04-6.96 (m, 2H), 1.80 (s, 9H) ). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ158.19,157.77,154.47,153.66,141.82,129.62,123.90,115.81,115.60,98.55,59.38,28.74.HRMS(ESI-TOF):for C ₁₅ H ₁₈ N ₅ O[M+H]:calcd 284.1512; found 284.1513.

5. 2-(2-(2-(2-(4-(4-Amino-1-tert-butyl-1H-pyrazole[3,4-d]pyrimidine-3-)phenoxy)ethoxy )Ethoxy)ethoxy)ethyl 4-methylbenzenesulfonic acid preparation

Tetraethylene glycol bis(p-toluene hydrochloride) (164mg, 3.46mmol), 4-(4-amino-1-tert-butyl-1hydro-pyrazole[3,4-d]pyrimidine-3-)phenol ( 100 mg, 3.46 mmol), and anhydrous potassium carbonate (96 mg, 6.92 mol) were heated at reflux in 50 mL of benzene solution for 4 hours to obtain a reaction solution. After the reaction solution was neutralized with 1N HCl, it was extracted with dichloromethane. Then the organic layer solution was dried under reduced pressure to obtain a solid and subjected to column chromatography to obtain 160 mg of a brown-yellow syrupy product (yield 76%).

¹ H NMR(600MHz,DMSO-d ₆ )δ8.23(s,1H), 7.81–7.76(m,2H), 7.60–7.53(m,2H), 7.46(d,J=8.0Hz,2H), 7.13–7.07(m,2H), 5.76(s,1H), 4.18–4.13(m,2H), 4.13–4.08(m,2H), 3.80–3.75(m,2H), 3.58(ddd,J=10.7 ,5.4,3.4Hz,4H),3.52(dd,J=5.8,3.6Hz,2H),3.49–3.43(m,4H),2.40(s,3H),1.74(s,9H). ¹³ C NMR( 151MHz, DMSO-d ₆ )δ159.15,158.69,155.01,154.22,145.33,141.92,132.84,130.57,130.09,128.07,126.09,115.47,99.07,70.44,70.37,70.27,70.17,70.13,69.35,68.34,67.72,59.35,68.34,67.72,59.35 ,55.37,29.22,21.54. HRMS(ESI-TOF):for C ₃₀ H ₄₀ N ₅ O ₇ S[M+H]:calcd 614.2649;found 614.2469.

6. ^{Preparation of tracer 18} F-HX

1) Weigh 1 mg of compound 5 and dissolve it in 0.8 mL DMF;

2) PET single module preparation:

a. Take 10mL of 0.5M sodium bicarbonate to rinse the QMA column, and then rinse with 10mL of high-purity water to activate the QMA column;

b. Rinse the C-18 column with 5 mL of ethanol, and then rinse with 10 mL of high-purity water to purify the C-18 column;

c. Set up the following procedures:

B1: 1.5mL of K22 acetonitrile eluent eluted the QMA column to elute the 18F ⁺ on the QMA column to the reaction tube;

B2: Add 2 mL of anhydrous acetonitrile to the reaction tube to remove water;

B3: After cooling the reaction tube, add 0.8mL compound 5, and carry out the nucleophilic reaction at 125°C, the reaction time is 12min;

B4: Add water to transfer the product to the C-18 column for separation and purification, and continue to wash with water to remove the remaining 18F ⁺ ion and acetonitrile on the QMA column;

^{B5: 18} F-HX was eluted with 5 mL of absolute ethanol.

3) Preparation and analysis:

A. ^{Target shooting 30-60min, about 600mCi of 18} F ion is transferred to the synthesis module;

B. Follow the procedures B1～B5 set in 2) to ^{synthesize 18} F-HX;

After the separation of C product, about 300-360mCi residue was monitored on the C-18 column, which is an unlabeled ¹⁸ F ion;

D. The radioactivity of the final product is about 10mCi, and the volume is about 5mL;

E. 85% acetonitrile mobile phase, HPLC detection, analysis of the proportion of F ion peak and product peak.

The lower edge of the thin-layer plate is immersed in the mobile phase. After the plate is spotted, the radioactive detector detects the peak position and kurtosis of the radioactive-labeled nuclide probe. According to the experimental results, the free F ion Rf=0.263, ^{the Rf of 18} F-HX=0.593, and the product kurtosis is about 88.93%. Throughout the ¹⁸ F labeling rate was about 15.9%, by HPLC purification of the labeled compound and identification, the ¹⁸ F-HX to give the compound ⁽¹⁸ F-HX and the compound of the present invention is non-radioactive radiochemical purity greater than 95% The HPLC spectra of the standard products are shown in Figures 1 to 3, respectively, indicating that the ¹⁸ F-HX compound of the present invention was successfully synthesized).

Hereinafter, the beneficial effects of the present invention are explained by way of test examples.

The tumor-bearing mouse in the test example of the present invention is a mouse that has been inoculated with lung adenocarcinoma epithelial cells A549 and a tumor model has been successfully created.

Test Example 1. Study on the imaging effect of human lung cancer tumor-bearing mice ^{with the tracer 18 F-HX of the present invention}

1. Experimental materials and instruments:

Materials: Streptomycin, Penicillin, Fetal Bovine Serum, 1640 Medium, Trypsin (ThermoFisher Company);

Equipment: cell incubator (ThermoFisher company), PET/CT (Siemens Biograph 16HR).

2. Experimental animals

BALB/c-nu/nu nude mice, male (SPF grade 4 weeks old).

3. Experimental method

Non-small cell lung cancer (NSCLC) cell lines (respectively H1299 cells, HCC827 cells, PC-9 cells, H460 cells and H1975 cells) were cultured in 10cm culture flasks, showing adherent growth, until the cell growth confluence is close to 80% Around, after trypsinization, the cells were collected by centrifugation at 800 rpm for 3 min, the supernatant was discarded, the cells were resuspended in PBS, and the cells were counted, and the cells were collected by centrifugation again in PBS. Each nude mouse was inoculated subcutaneously with 3×10 ⁶ cells/100 μL. From the day of inoculation, the tumor growth was observed every two days, and the maximum diameter of the subcutaneous transplanted tumor was measured and recorded with a vernier caliper. When the subcutaneous transplanted tumor grows to a maximum diameter of 1 cm or more, PET-CT imaging is performed. Before imaging, the animals are fasted for more than 6 hours in advance and can drink water; the nude mice are anesthetized in a box full of isoflurane, and after the nude mice lose consciousness, they are fixed on the detection table with the padding material, and the present invention is shown. ^{Tracer 18} F-HX or ¹⁸ F-FDG, each nude mouse is injected with 3.7MBq, the total volume does not exceed 100μL. The nude mouse was fixed on a small animal PET/CT instrument in a prone position, and two tomographic scans of PET and CT were taken continuously 1 hour after injection, and images were collected.

4. Experimental results

As shown in Figure 4, compared with ¹⁸ F-FDG, the tracer ¹⁸ F-HX of the present invention can be specifically and effectively taken up by H1299 lung cancer cells, and the sensitivity is similar to that of ¹⁸ F-FDG; as shown in Figure 5, the present invention It is clear that the tracer ¹⁸ F-HX can be taken up by 5 types of lung cancer cells to varying degrees. Among them, H1299 tumor-bearing mice have the ^{most obvious uptake of the tracer 18} F-HX of the present invention, followed by H460, and HCC827, PC-9 and H1975 cells. Not obvious. It shows that the tracer ¹⁸ F-HX of the present invention can be used as a PET/CT tracer for selectively detecting different lung cancer cell types.

In summary, the present invention successfully prepared an ¹⁸ F-PET/CT tracer. ^{The 18} F-PET/CT tracer prepared in the present invention can be selectively taken up by different oncogenic driver gene mutant lung cancer cells, and the H1299 (NRas Q61K) tumor model is in the ¹⁸ F-PET/CT tracer prepared in the present invention. The imaging sensitivity in PET is ^{similar to that of 18} F-FDG and is the clearest. H460 (KRas Q61H) followed by HCC827 (EGFR A746-750del), PC-9 (EGFR A746-750del), H1975 (EGFR L858R/T790M) tumor models have no effect on the ¹⁸ F-PET/CT tracer prepared by the present invention. Obviously ingested. This shows that the ¹⁸ F-PET/CT tracer of the present invention is expected to be high-quality imaging in the NRas Q61K tumor model, and has a certain selectivity for different oncogenic driver gene mutant lung cancers. This and any lesions with increased glucose metabolism can cause high concentrations different imaging nonspecific ¹⁸ F-FDG, is expected to make up for the lack of a single use of ¹⁸ F-FDG imaging. Therefore, the ¹⁸ F-PET/CT tracer of the present invention is expected to be applied to PET/CT imaging to change the lack of tracers on lung cancer.

Claims (11)

1. The compound represented by formula I, or its salt, or its stereoisomer:

   

   Wherein, R ₁ and R ₂ are each independently selected from H or C ₁ -C ₅ alkyl groups;

   X is independently selected from ¹¹ C, ¹⁸ F, ¹⁹ F, ¹⁵ O or ¹³ N.
2. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, wherein the compound is the following compound of formula II:

   

   Wherein, R _{2 is} selected from H or a C ₁ -C ₅ alkyl group;

   X is independently selected from ¹¹ C, ¹⁸ F, ¹⁹ F, ¹⁵ O or ¹³ N.
3. The compound according to claim 2, or a salt thereof, or a stereoisomer thereof, wherein the compound is the following compound of formula III:

   

   Wherein, R _{2 is} selected from H or C ₁ -C ₅ alkyl.
4. The compound of claim 3, or a salt thereof, or a stereoisomer thereof, wherein the compound is the following compound ¹⁸ F-HX:

   
5. A method for preparing compound ¹⁸ F-HX, or a salt thereof, or a stereoisomer thereof according to claim 4, characterized in that it comprises the following steps:

   

   Step a: Synthesis of compound 1 with tert-butylhydrazine hydrochloride, triethylamine and ethoxymethylenemalononitrile using absolute ethanol as a solvent;

   Step b: Compound 1 is reacted with formamide to obtain compound 2;

   Step c: Compound 2 and bromine undergo bromination reaction with water as a solvent to obtain compound 3;

   Step d: Compound 3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and potassium carbonate with 1,4-dioxyl The mixed solution of alkane and water is used as a solvent and reacted under a catalytic amount of catalyst to obtain compound 4;

   Step e: Compound 4, tetraethylene glycol bis(p-toluene hydrochloride) and anhydrous potassium carbonate are reacted in benzene solution to obtain compound 5;

   Step f: After the compound 5 is dissolved in DMF, it is placed in a PET single-shot module, the target is hit, the water is removed, and the nucleophilic substitution reaction is followed by purification and elution to obtain ¹⁸ F-HX.
6. The preparation method according to claim 5, characterized in that:

   In step a, the molar ratio of the tert-butylhydrazine hydrochloride, triethylamine and ethoxymethylene malononitrile is 1:1:1; the volume ratio of the triethylamine to absolute ethanol is 9.7:460;

   And/or, in step b, the mass-volume ratio of compound 1 and formamide is 1.1:15 (w/v);

   And/or, in step c, the molar ratio of compound 2 to bromine is 1:2; the volume ratio of bromine to water is 0.52:25;

   And/or, in step d, the compound 3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and potassium carbonate mole The ratio is 0.56:3:3; the mass-volume ratio of the compound 3 to the mixed solution of 1,4-dioxane and water is 0.05:10 (w/v); the 1,4-dioxane and In the mixed solution of water, the volume ratio of 1,4-dioxane to water is 5:1;

   And/or, in step e, the molar ratio of compound 4, tetraethylene glycol bis(p-toluene hydrochloride) and anhydrous potassium carbonate is 1:1:2; the mass volume ratio of compound 4 to the benzene solution is 0.1 :50(w/v).
7. The preparation method according to claim 5, characterized in that:

   In step a, the synthesis conditions are heating and refluxing for 3 hours;

   And/or, in step b, the reaction conditions are heating to reflux for 6 hours;

   And/or, in step c, the bromination reaction conditions are stirring at room temperature for 1 hour, and then heating at 100°C for 2 hours;

   And/or, in step d, the reaction conditions are heating in an oil bath at 90°C for 2 hours;

   And/or, in step d, the catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

   And/or, in step e, the reaction conditions are reflux heating for 4 hours;

   And/or, in step f, in the PET single module, ethanol activates the C18 column, and sodium bicarbonate activates the QMA column;

   And/or, in step f, the shooting time is 30-60 min;

   And/or, in step f, the water scavenger is anhydrous acetonitrile;

   And/or, in step f, the nucleophilic substitution reaction temperature is 125°C, and the time is 12 min;

   And/or, in step f, the purification uses a C18 column for separation and purification;

   And/or, in step f, absolute ethanol is used for the elution.
8. The preparation method according to claim 5, characterized in that:

   In step a, the obtained compound 1 is purified, and the specific method is as follows: the reaction solution is extracted with a mixture of ethyl acetate and water in a volume ratio of 2:1, the organic layer is dried with anhydrous magnesium sulfate, and the organic layer is evaporated to obtain a solid. Wash with 10% ethyl acetate-containing cyclohexane solution, filter with suction, and then;

   And/or, in step b, the obtained compound 2 is purified. The specific method is: extracting the reaction solution with ethyl acetate three times, drying the organic layer with anhydrous magnesium sulfate, filtering and evaporating the solvent under reduced pressure to obtain a solid;

   And/or, in step c, the obtained compound 3 is purified, the specific method is: the reaction solution is extracted with ethyl acetate 3 times, and then washed with 5% sodium hydrogen sulfate and 5% sodium chloride solution in turn, and dried with anhydrous magnesium sulfate The organic layer is filtered and concentrated, and the solvent is evaporated under reduced pressure to obtain a solid.

   And/or, in step d, the obtained compound 4 is purified, the specific method is: the reaction solution is extracted with ethyl acetate and water in a volume ratio of 2:1, the organic layer is dried with anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain a solid, namely can;

   And/or, in step e, the obtained compound 5 is purified. The specific method is: after the reaction solution is neutralized with 1N HCl, it is extracted with dichloromethane, and then the organic layer solution is dried under reduced pressure and separated by chromatography.
9. The use of the compound according to any one of claims 1 to 4 in the preparation of a tracer; preferably, the tracer is a PET/CT tracer.
10. The application according to claim 9, wherein the PET/CT tracer is a tracer used in tumor diagnosis; preferably, the tumor is lung cancer.
11. A tracer, which is prepared by using the compound described in any one of claims 1 to 4, or a salt thereof, or a stereoisomer thereof as an active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients. Into.

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