A near-infrared-II compound, a preparation method thereof and application thereof in a near-infrared-II photoacoustic imaging contrast agent

Abstract

This invention relates to the field of nanobiomedical imaging technology, and in particular to a near-infrared-II compound, its preparation method, and its application in near-infrared-II photoacoustic imaging contrast agents. The near-infrared-II compound uses triphenylamine and piperazine groups as electron acceptors, and an electron-rich phenothiazine group as the hypochlorous acid recognition response site and electron acceptor precursor. The near-infrared-II compound of this invention, after activation with hypochlorous acid, exhibits near-infrared-II absorption and intramolecular charge transfer properties. It is a typical D-A-D type organic small molecule, enabling better photoacoustic imaging effects and providing a highly sensitive imaging method for disease diagnosis.

Description

Technical Field

[0001] This invention relates to the field of nanobiomedical imaging technology, and in particular to a near-infrared-II compound, its preparation method, and its application in near-infrared-II photoacoustic imaging contrast agents. Background Technology

[0002] Photoacoustic imaging is an emerging imaging technique that combines the advantages of optics and acoustics to achieve real-time, non-invasive, and radiation-free measurements of optical tissue properties. In biological tissues, due to the extremely low scattering of acoustic signals, photoacoustic imaging receives acoustic signals that penetrate deeper into biological tissues compared to the fluorescence signals received by conventional fluorescence imaging. Simultaneously, photoexcitation provides higher tissue contrast than ultrasound imaging. Therefore, photoacoustic imaging can achieve high tissue contrast, deeper tissue penetration, and higher resolution biological imaging.

[0003] Existing research has shown that photoacoustic imaging in the near-infrared-II region has significant advantages over photoacoustic imaging in the near-infrared-I region, such as deeper tissue penetration and higher imaging resolution. Based on these advantages, photoacoustic imaging has been widely used in medical diagnostics, such as early diagnosis of various cancers, tracking of tumor metastases, gastrointestinal endoscopic imaging, and monitoring of treatment effectiveness.

[0004] Currently, various inorganic / organic contrast agents have been developed for near-infrared-II photoacoustic imaging. Among them, organic molecules without heavy metal toxicity, including conjugated polymers and some small molecules, show greater potential for clinical translation. However, conjugated polymers suffer from poor biodegradability and low synthetic reproducibility; traditional small molecules, such as polymethystine cyanine dyes, are limited by their poor photostability, restricting their further application.

[0005] While donor-acceptor-donor (DAD) conjugated small molecules hold great promise for constructing near-infrared-II photoacoustic contrast agents due to their well-defined chemical structures, reliable biodegradability / biocompatibility, and flexible optical properties, and various strategies exist to shift absorption wavelengths to the near-infrared II window, most current near-infrared-II photoacoustic imaging contrast agents are always on, making them susceptible to background signals and exhibiting poor sensitivity, thus failing to meet practical photoacoustic imaging requirements. Therefore, the development of near-infrared-II organic dyes with excellent optical properties and near-infrared II absorption is urgently needed. Summary of the Invention

[0006] The purpose of this invention is to provide a near-infrared-II compound, its preparation method, and its application in near-infrared-II photoacoustic imaging contrast agents to overcome the shortcomings and defects of the prior art.

[0007] To achieve the above objectives, the present invention provides a near-infrared-II compound, wherein the near-infrared-II compound uses a triphenylamine group and a piperazine group as electron acceptors, and an electron-rich phenothiazine group as a hypochlorous acid recognition response site and electron acceptor precursor, with the following structural formula.

[0008]

[0009] This invention also provides a method for preparing the above-mentioned near-infrared-II compound, comprising the following steps:

[0010] S1. Under light-protected conditions, phenothiazine derivatives, triphenylamine derivatives and catalysts are added to an organic solvent, and a Suzuki coupling reaction is carried out under a protective atmosphere to obtain compound I.

[0011] The structural formula of compound I is as follows:

[0012]

[0013] S2. Under light-protected conditions, compound I, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine and a catalyst were added to an organic solvent, and a Suzuki coupling reaction was carried out under a protective atmosphere to prepare compound II, i.e., near-infrared-II compound.

[0014] Preferably, the molar ratio of the phenothiazine derivative to the triphenylamine derivative in S1 is 0.8–1.2:0.8–1.2.

[0015] Preferably, the molar ratio of compound I in S2 to 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine is 0.8-1.2:0.8-1.2.

[0016] Preferably, the Suzuki coupling reaction temperature in both S1 and S2 is 90–110°C, and the reaction time is 12–24 h.

[0017] All catalysts were palladium catalysts, and all organic solvents were anhydrous toluene.

[0018] This invention also provides the application of the above-mentioned near-infrared-II compound in near-infrared-II photoacoustic imaging contrast agents. The organic solution of the near-infrared-II compound and the aqueous solution of the amphiphilic block copolymer are mixed under ultrasonic conditions to complete the nano-co-precipitation of the near-infrared-II compound and the amphiphilic block copolymer. After removing the organic solvent from the organic solution, a water-soluble and activatable near-infrared-II photoacoustic imaging contrast agent is obtained.

[0019] Preferably, the concentration of the near-infrared II compound in the organic solution is 0.1–1 mg / mL, and the concentration of the aqueous solution of the amphiphilic block polymer is 1–20 mg / mL.

[0020] Preferably, the volume ratio of the organic solution to the aqueous solution of the amphiphilic front polymer is less than or equal to 1:5.

[0021] Preferably, the mass ratio of the near-infrared-II compound to the amphiphilic block copolymer is 1:5 to 100.

[0022] Preferably, the organic solvent of the organic solution is tetrahydrofuran, and the amphiphilic block copolymer is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer.

[0023] The beneficial effects of this invention are:

[0024] (1) The near-infrared-II compound of the present invention has near-infrared-II absorption and intramolecular charge transfer characteristics after activation by hypochlorous acid. It is a typical DAD type organic small molecule, which can achieve better photoacoustic imaging effect and provide a highly sensitive imaging means for disease diagnosis.

[0025] (2) The preparation method of the near-infrared-II compound of the present invention is simple, the reaction conditions are mild, and it is easy to operate and control, which is beneficial to improving the reproducibility and yield of the reaction;

[0026] (3) The method for preparing the near-infrared-II photoacoustic imaging contrast agent of the present invention involves self-assembly of a near-infrared-II compound (photoacoustic imaging small molecule) and combining it with an amphiphilic polymer. The resulting contrast agent has activated near-infrared II absorption and can achieve photoacoustic imaging in the near-infrared-II window, which greatly improves the imaging quality of live tumors. The embodiments of the present invention demonstrate that it can achieve NIR-II photoacoustic imaging of live tumors in mice.

[0027] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0028] Figure 1 The 1H NMR spectrum of the compound of formula I obtained in Example 1 of this invention;

[0029] Figure 2 The above is the proton NMR spectrum of the near-infrared-II compound prepared in Example 1 of this invention;

[0030] Figure 3 This is the mass spectrum of the near-infrared-II compound obtained in Example 1 of the present invention;

[0031] Figure 4This is a schematic diagram of the hydrodynamic diameter measured by dynamic light scattering of the near-infrared-II photoacoustic imaging contrast agent prepared in Example 4 of the present invention.

[0032] Figure 5 The absorption spectrum of the contrast agent aqueous solution prepared with the near-infrared-II photoacoustic imaging contrast agent obtained in Example 4 of this invention. Detailed Implementation

[0033] The present invention will be further described below with reference to the accompanying drawings and embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0034] This invention provides a near-infrared-II compound, which uses a triphenylamine group and a piperazine group as electron acceptors, and an electron-rich phenothiazine group as a hypochlorous acid recognition response site and electron acceptor precursor. The structural formula is as follows.

[0035]

[0036] The aforementioned near-infrared-II compound exhibits intramolecular charge transfer (ICT) properties after activation with hypochlorous acid. It is a typical DAD-type small organic molecule and has near-infrared-II absorption, thus achieving better photoacoustic imaging effects.

[0037] This invention also provides a method for preparing the above-mentioned near-infrared-II compound, comprising the following steps:

[0038] S1. Under light-protected conditions, phenothiazine derivatives, triphenylamine derivatives and catalysts are added to an organic solvent, and a Suzuki coupling reaction is carried out under a protective atmosphere to obtain compound I.

[0039] The structural formula of compound I is as follows:

[0040]

[0041] S2. Under light-protected conditions, compound I, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine and a catalyst were added to an organic solvent, and a Suzuki coupling reaction was carried out under a protective atmosphere to prepare compound II, i.e., near-infrared-II compound.

[0042] Preferably, the molar ratio of the phenothiazine derivative to the triphenylamine derivative is 0.8–1.2:0.8–1.2.

[0043] In some embodiments of the present invention, the molar ratio of the phenothiazine derivative to the triphenylamine derivative is 1:1. Controlling the molar ratio within this range in the present invention helps to reduce the generation of byproducts, lower reaction costs, and increase product yield.

[0044] In some embodiments of the present invention, the phenothiazine derivative is 3,7-dibromo-10H-phenothiazine, and the triphenylamine derivative is 4-boronate-4',4'-dimethoxytriphenylamine.

[0045] In some embodiments of the present invention, the synthetic route of step S1 is as follows:

[0046]

[0047] In some embodiments of the present invention, the synthesis route for step S2 is as follows:

[0048]

[0049] Preferably, the molar ratio of compound I in S2 to 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine is 0.8-1.2:0.8-1.2.

[0050] In some embodiments of the present invention, the molar ratio of compound I to 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine is 1:1. Controlling the molar ratio within the above range in the present invention is beneficial for reducing the generation of byproducts, lowering reaction costs, and increasing product yield.

[0051] Preferably, the Suzuki coupling reaction temperature in both S1 and S2 is 90–110°C, and the reaction time is 12–24 h.

[0052] All catalysts were palladium catalysts, and all organic solvents were anhydrous toluene.

[0053] In some embodiments of the present invention, the palladium catalysts in S1 and S2 each independently include tetra(triphenylphosphine)palladium. The tetra(triphenylphosphine)palladium is only used for catalytic reaction and is not used as a reactant. Therefore, its amount is not further limited and can be the amount known to those skilled in the art.

[0054] In some embodiments of the present invention, the Suzuki coupling reaction temperature in both S1 and S2 is 100°C and the reaction time is 24h.

[0055] In some embodiments of the present invention, the protective atmosphere in S1 and S2 each independently includes nitrogen.

[0056] In some embodiments of the present invention, the organic solvent is subjected to dehydration and / or deoxygenation treatment before use.

[0057] In some embodiments of the present invention, anhydrous toluene is bubbled with nitrogen or argon before use to remove oxygen.

[0058] In some embodiments of the present invention, after the Suzuki coupling reaction of S1 and S2 is completed, organic solvents are added to the system separately to dissolve the reaction products, and solid-liquid separation is performed. After adding silica gel powder to the obtained liquid to adsorb the reaction products, the silica gel powder is packed into a column and eluted with a silica gel column chromatography method. The reaction product solution is collected and the solvent is removed.

[0059] In some embodiments of the present invention, the organic solvent for dissolving the reaction product is dichloromethane. Dichloromethane is used only as a solvent and not as a reactant; therefore, its amount is not further limited and can be any amount known to those skilled in the art.

[0060] In some embodiments of the present invention, the silica gel powder has a particle size of 200 mesh, the organic solvent added to the system is dichloromethane, and the eluent is a mixture of dichloromethane and methanol. The present invention does not impose any special restrictions on the ratio of dichloromethane to methanol in the eluent; any amount known to those skilled in the art can be used.

[0061] This invention also provides the application of the above-mentioned near-infrared-II compound in near-infrared-II photoacoustic imaging contrast agents. The organic solution of the near-infrared-II compound and the aqueous solution of the amphiphilic block copolymer are mixed under ultrasonic conditions to complete the nano-co-precipitation of the near-infrared-II compound and the amphiphilic block copolymer. After removing the organic solvent from the organic solution, a water-soluble and activatable near-infrared-II photoacoustic imaging contrast agent is obtained.

[0062] In some embodiments of the present invention, near-infrared-II photoacoustic imaging contrast agents are used for high-sensitivity near-infrared-II photoacoustic imaging for disease diagnosis purposes.

[0063] In some embodiments of the present invention, the near-infrared-II compound and the amphiphilic block copolymer self-assemble in solution, which can achieve the water solubility of the near-infrared-II compound and the resulting nanostructure has good biocompatibility.

[0064] Preferably, the concentration of the near-infrared II compound in the organic solution is 0.1–1 mg / mL, and the concentration of the aqueous solution of the amphiphilic block polymer is 1–20 mg / mL.

[0065] In some embodiments of the present invention, the concentration of the near-infrared-II compound in the organic solution is 0.1 to 0.5 mg / mL, and the concentration of the aqueous solution of the amphiphilic block polymer is 1 to 2 mg / mL.

[0066] Preferably, the volume ratio of the organic solution to the aqueous solution of the amphiphilic front polymer is less than or equal to 1:5.

[0067] Preferably, the mass ratio of the near-infrared-II compound to the amphiphilic block copolymer is 1:5 to 100.

[0068] In some embodiments of the present invention, the mass ratio of the near-infrared-II compound to the amphiphilic block copolymer is 1:20. Controlling the mass ratio within this range facilitates the encapsulation of the near-infrared-II compound within the amphiphilic block copolymer shell, forming uniformly sized, spherical, and highly water-soluble nanoparticles. Furthermore, it avoids leakage of the near-infrared-II compound, thus exhibiting high biocompatibility.

[0069] Preferably, the organic solvent of the organic solution is tetrahydrofuran, and the amphiphilic block copolymer is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer (F-127).

[0070] In some embodiments of the present invention, the removal of organic solvents from organic solutions can be achieved by blowing and evaporation.

[0071] Example 1

[0072] A method for preparing a near-infrared-II compound includes the following steps:

[0073] S1. Under light-protected conditions, 0.1 mmol of 3,7-dibromo-10H-phenthiazide, 0.1 mmol of 4-boronate-4',4'-dimethoxytriphenylamine, and 0.0006 mmol of tetra(triphenylphosphine)palladium catalyst were added to a 50 mL flask. A reflux reflux tube was connected, and the entire system was evacuated and purged with nitrogen. Then, anhydrous toluene, after being bubbled (using nitrogen as the gas), was added to the flask, and the mixture was stirred at 100 °C for 24 h to carry out a Suzuki coupling reaction. After the reaction was complete, dichloromethane was added to dissolve the reaction product, and the insoluble substances were removed by filtration to obtain a crude product solution. 50 g of silica gel powder (200 mesh) was added, and all solvent was removed by rotary evaporation to allow the silica gel powder to fully adsorb the crude product. The silica gel powder adsorbed with the crude product was packed into a column and separated by silica gel column chromatography, eluting with a dichloromethane / methanol mixed solution to obtain a pure product solution. After removing the solvent by rotary evaporation, the product was dried under vacuum to obtain compound I.

[0074] S2. Under light-protected conditions, 0.1 mmol of compound I, 0.1 mmol of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine, and 0.0006 mmol of tetra(triphenylphosphine)palladium catalyst were added to a 50 mL flask. A reflux reflux tube was connected, and the entire system was evacuated and purged with nitrogen. Then, anhydrous toluene, which had been bubbled (using nitrogen as the gas), was added to the flask, and the mixture was stirred at 100 °C for 24 h to carry out the Suzuki coupling reaction. After the reaction was complete, dichloromethane was added to dissolve the reaction product, and the insoluble substances were removed by filtration to obtain a crude product solution. 50 g of silica gel powder (200 mesh) was added, and all solvents were removed by rotary evaporation to allow the silica gel powder to fully adsorb the crude product. The silica gel powder adsorbed with the crude product was packed into a column and separated by silica gel column chromatography, eluting with a dichloromethane / methanol mixed solution to obtain a pure product solution. After removing the solvent by rotary evaporation, the compound of formula II, namely the near-infrared-II compound, was prepared by vacuum drying.

[0075] Example 2

[0076] A method for preparing a near-infrared-II compound includes the following steps:

[0077] S1. Under light-protected conditions, 0.08 mmol of 3,7-dibromo-10H-phenthiazide, 0.1 mmol of 4-boronate-4',4'-dimethoxytriphenylamine, and 0.0006 mmol of tetra(triphenylphosphine)palladium catalyst were added to a 50 mL flask. A reflux reflux tube was connected, and the entire system was evacuated and purged with nitrogen. Then, anhydrous toluene, after being bubbled (using nitrogen as the gas), was added to the flask, and the mixture was stirred at 100 °C for 24 h to carry out a Suzuki coupling reaction. After the reaction was complete, dichloromethane was added to dissolve the reaction product, and the insoluble substances were removed by filtration to obtain a crude product solution. 50 g of silica gel powder (200 mesh) was added, and all solvent was removed by rotary evaporation to allow the silica gel powder to fully adsorb the crude product. The silica gel powder adsorbed with the crude product was packed into a column and separated by silica gel column chromatography, eluting with a dichloromethane / methanol mixed solution to obtain a pure product solution. After removing the solvent by rotary evaporation, the product was dried under vacuum to obtain compound I.

[0078] S2. Under light-protected conditions, 0.08 mmol of compound I, 0.1 mmol of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine, and 0.0006 mmol of tetra(triphenylphosphine)palladium catalyst were added to a 50 mL flask. A reflux duct was connected, and the entire system was evacuated and purged with nitrogen. Then, anhydrous toluene, treated with bubbling (using nitrogen as the gas), was added to the flask, and the mixture was stirred at 100 °C for 24 h to carry out the Suzuki coupling reaction. After the reaction was complete, dichloromethane was added to dissolve the reaction product. The insoluble substances were removed by filtration to obtain a crude product solution. 50 g of silica gel powder (200 mesh) was added, and all solvents were removed by rotary evaporation to allow the silica gel powder to fully adsorb the crude product. The silica gel powder adsorbed with the crude product was packed into a column and separated by silica gel column chromatography, eluting with a dichloromethane / methanol mixed solution to obtain a pure product solution. After removing the solvent by rotary evaporation, the compound of formula II, namely the near-infrared-II compound, was prepared by vacuum drying.

[0079] Example 3

[0080] A method for preparing a near-infrared-II compound includes the following steps:

[0081] S1. Under light-protected conditions, 0.1 mmol of 3,7-dibromo-10H-phenthiazide, 0.12 mmol of 4-boronate-4',4'-dimethoxytriphenylamine, and 0.0006 mmol of tetra(triphenylphosphine)palladium catalyst were added to a 50 mL flask. A reflux reflux tube was connected, and the entire system was evacuated and purged with nitrogen. Then, anhydrous toluene, after being bubbled (using nitrogen as the gas), was added to the flask, and the mixture was stirred at 100 °C for 24 h to carry out a Suzuki coupling reaction. After the reaction was complete, dichloromethane was added to dissolve the reaction product. The insoluble substances were removed by filtration to obtain a crude product solution. 50 g of silica gel powder (200 mesh) was added, and all solvent was removed by rotary evaporation to allow the silica gel powder to fully adsorb the crude product. The silica gel powder adsorbed with the crude product was packed into a column and separated by silica gel column chromatography, eluting with a dichloromethane / methanol mixed solution to obtain a pure product solution. After removing the solvent by rotary evaporation, the product was dried under vacuum to obtain compound I.

[0082] S2. Under light-protected conditions, 0.1 mmol of compound I, 0.12 mmol of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine, and 0.0006 mmol of tetra(triphenylphosphine)palladium catalyst were added to a 50 mL flask. A reflux reflux tube was connected, and the entire system was evacuated and purged with nitrogen. Then, anhydrous toluene, which had been bubbled (using nitrogen as the gas), was added to the flask, and the mixture was stirred at 100 °C for 24 h to carry out the Suzuki coupling reaction. After the reaction was complete, dichloromethane was added to dissolve the reaction product, and the insoluble substances were removed by filtration to obtain a crude product solution. 50 g of silica gel powder (200 mesh) was added, and all solvents were removed by rotary evaporation to allow the silica gel powder to fully adsorb the crude product. The silica gel powder adsorbed with the crude product was packed into a column and separated by silica gel column chromatography, eluting with a dichloromethane / methanol mixed solution to obtain a pure product solution. After removing the solvent by rotary evaporation, the compound of formula II, namely the near-infrared-II compound, was prepared by vacuum drying.

[0083] Example 4

[0084] The near-infrared-II compound prepared in Example 1 was used to prepare a tetrahydrofuran solution (denoted as solution A) with a concentration of 1 mg / mL. Under intense ultrasonic conditions, the specific parameters were set as follows: continuous ultrasonic time of 2 minutes, ultrasonic power ratio of 50%, and time interval of 8 seconds of ultrasonication followed by 2 seconds of pause. The solution was directly added to an aqueous solution of amphiphilic triblock polymer F-127 with a concentration of 2 mg / mL (denoted as solution B) for mixing. After self-assembly under ultrasonic conditions, the excess tetrahydrofuran organic solvent was removed by evaporation by blowing air to obtain the near-infrared-II photoacoustic imaging contrast agent. The volume ratio of solution A to solution B was 1:10.

[0085] Example 5

[0086] The near-infrared-II compound prepared in Example 1 was used to prepare a tetrahydrofuran solution (denoted as solution A) with a concentration of 1 mg / mL. Under intense ultrasonic conditions, the specific parameters were set as follows: continuous ultrasonic time of 2 minutes, ultrasonic power ratio of 50%, and time interval of 8 seconds of ultrasonication followed by 2 seconds of pause. The solution was directly added to an aqueous solution of amphiphilic triblock polymer F-127 with a concentration of 0.5 mg / mL (denoted as solution B) for mixing. After self-assembly under ultrasonic conditions, the excess tetrahydrofuran organic solvent was removed by blowing air to evaporate, thus obtaining the near-infrared-II photoacoustic imaging contrast agent. The volume ratio of solution A to solution B was 1:5.

[0087] Example 6

[0088] The near-infrared-II compound prepared in Example 1 was used to prepare a tetrahydrofuran solution (denoted as solution A) with a concentration of 1 mg / mL. Under intense ultrasonic conditions, the specific parameters were set as follows: continuous ultrasonic time of 2 minutes, ultrasonic power ratio of 50%, and time interval of 8 seconds of ultrasonication followed by 2 seconds of pause. The solution was directly added to an aqueous solution of amphiphilic triblock polymer F-127 with a concentration of 10 mg / mL (denoted as solution B) for mixing. After self-assembly under ultrasonic conditions, the excess tetrahydrofuran organic solvent was removed by blowing air to evaporate, thus obtaining the near-infrared-II photoacoustic imaging contrast agent. The volume ratio of solution A to solution B was 1:10.

[0089] Characterization detection

[0090] The compound of formula I obtained in step S1 of Example 1 was subjected to nuclear magnetic resonance detection, and the results are as follows: Figure 1 As shown, from Figure 1 The proton NMR spectrum shows the same characteristic proton signal as the compound of formula I, indicating that the compound of formula I was successfully prepared in Example 1.

[0091] The near-infrared-II compound obtained in step S2 of Example 1 was subjected to nuclear magnetic resonance detection and mass spectrometry analysis, and the results are as follows: Figure 2 and Figure 3 As shown, from Figure 2 The proton NMR spectrum shows characteristic proton signals identical to those of the near-infrared-II compound. Figure 3 The mass spectrum shows a molecular weight of 661.990, consistent with the theoretical molecular weight of 662.27 for the near-infrared-II compound. Therefore, Example 1 successfully prepared the near-infrared-II compound. The near-infrared-II photoacoustic imaging contrast agent obtained in Example 4 was prepared into an aqueous solution with a near-infrared-II compound concentration of 0.01 mg / mL. The hydrodynamic radius of the aqueous contrast agent solution was determined by dynamic light scattering, and the absorption spectrum of the aqueous contrast agent solution was measured. The results are as follows: Figure 4 and Figure 5 As shown.

[0092] Depend on Figure 4 The hydrodynamic diameter diagram shows that the near-infrared-II photoacoustic imaging contrast agent prepared in Example 4 has a hydrodynamic radius of 85 nm. Nanoparticles of this size exhibit excellent long-term blood circulation and accumulation effects in in vivo applications. Figure 5 The absorption spectrum shows that the near-infrared-II photoacoustic imaging contrast agent prepared in Example 4 has a maximum near-infrared absorption peak at around 860 nm, and still has good absorption at 1064 nm, which is obviously a near-infrared-II absorbing material.

[0093] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A near-infrared-II compound, characterized in that: The near-infrared-II compound uses triphenylamine and piperazine groups as electron acceptors, and an electron-rich phenothiazine group as the hypochlorous acid recognition response site and electron acceptor precursor. Its structural formula is as follows.

2. A method for preparing the near-infrared-II compound as described in claim 1, characterized in that: Includes the following steps, S1. Under light-protected conditions, phenothiazine derivatives, triphenylamine derivatives and catalysts are added to an organic solvent, and a Suzuki coupling reaction is carried out under a protective atmosphere to obtain compound I. The structural formula of compound I is as follows: S2. Under light-protected conditions, compound I, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine and a catalyst were added to an organic solvent, and a Suzuki coupling reaction was carried out under a protective atmosphere to prepare compound II, i.e., near-infrared-II compound.

3. The method for preparing a near-infrared-II compound according to claim 2, characterized in that: The molar ratio of phenothiazine derivative to triphenylamine derivative in S1 is 0.8–1.2:0.8–1.

2.

4. The method for preparing a near-infrared-II compound according to claim 2, characterized in that: The molar ratio of compound I in S2 to 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine is 0.8–1.2:0.8–1.

2.

5. The method for preparing a near-infrared-II compound according to claim 2, characterized in that: The Suzuki coupling reaction temperature in both S1 and S2 is 90–110 °C, and the reaction time is 12–24 h. All catalysts were palladium catalysts, and all organic solvents were anhydrous toluene.

6. The application of the near-infrared-II compound as described in claim 1 in a near-infrared-II photoacoustic imaging contrast agent, characterized in that: An organic solution of a near-infrared-II compound and an aqueous solution of an amphiphilic block copolymer were mixed under ultrasonic conditions to complete the nano-coprecipitation of the near-infrared-II compound and the amphiphilic block copolymer. The organic solvent from the organic solution was then removed to prepare a water-soluble, activatable near-infrared-II photoacoustic imaging contrast agent.

7. The application of a near-infrared-II compound according to claim 6 in a near-infrared-II photoacoustic imaging contrast agent, characterized in that: The concentration of near-infrared II compounds in organic solutions ranges from 0.1 to 1 mg / mL, and the concentration of aqueous solutions of amphiphilic block polymers ranges from 1 to 20 mg / mL.

8. The application of a near-infrared-II compound according to claim 6 in a near-infrared-II photoacoustic imaging contrast agent, characterized in that: The volume ratio of the organic solution to the aqueous solution of the amphiphilic front polymer is less than or equal to 1:

5.

9. The application of a near-infrared-II compound according to claim 6 in a near-infrared-II photoacoustic imaging contrast agent, characterized in that: The mass ratio of the near-infrared-II compound to the amphiphilic block copolymer is 1:5 to 100.

10. The application of a near-infrared-II compound according to claim 6 in a near-infrared-II photoacoustic imaging contrast agent, characterized in that: The organic solvent in the organic solution is tetrahydrofuran, and the amphiphilic block copolymer is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer.

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