An alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe, its preparation method and application

Abstract

This invention discloses an alendronate-based chemical exchange saturation transfer magnetic resonance imaging (CELTMRI) probe, its preparation method, and its applications. It relates to the field of CELTMRI technology, and its key technical features are: the probe (Alen-FF-SSZ) is composed of an alendronate group (Alen), a phenylalanine-phenylalanine (FF) self-assembled group, and a sulfasalazine (SSZ) CEST MRI imaging unit. The specific molecular probe structure is shown below. This invention successfully developed an alendronate-based CEST MRI molecular probe, which has achieved CEST MRI imaging and treatment of osteosarcoma. This structure also has broad prospects for clinical translation.

Description

Technical Field

[0001] This invention relates to the field of chemical exchange saturation transfer magnetic resonance imaging (CELTMRI) technology, and more specifically, to an alendronate-based CELTMRI probe, its preparation method, and its application. Background Technology

[0002] Currently, chemical exchange saturation transfer magnetic resonance imaging (CELTMRI), as a label-free, highly biocompatible, non-invasive imaging technique with deep tissue penetration capabilities, has become a hot research area in tumor diagnosis and treatment. Related studies have also verified that this imaging method has certain clinical translational potential; for example, amide proton-based CELTMRI has become an important detection method for brain tumors, inflammation, and neurodegenerative diseases. Simultaneously, the signal intensity in CELTMRI is affected by physiological environmental factors such as temperature and pH, and to a certain extent, its signal intensity reflects relevant physiological information. Some articles have already applied this characteristic to the detection of cell transplantation. Therefore, research on contrast agents for CELTMRI holds great promise for achieving precise diagnosis and building integrated diagnostic and therapeutic platforms.

[0003] Bisphosphonates have been commonly used as bone protectants in clinical practice since the 1940s due to their excellent bone-targeting and bone-adsorption capabilities. Today, their strong adsorption to hydroxyapatite in bone is widely utilized in the design of various bone-targeting bioprobes. Once adsorbed by bone, bisphosphonates remain there for a long time. In bone-related diseases (bone defects, osteosarcoma), specifically activated osteoclasts form acidic chambers that erode bone. During this process, the bisphosphonates adsorbed in the bone are released and accumulate in the acidic chambers. High concentrations of bisphosphonates inhibit osteoclast function, preventing further bone destruction. Summary of the Invention

[0004] The purpose of this invention is to provide an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe, its preparation method, and its application for imaging osteosarcoma.

[0005] The above-mentioned technical objective of this invention is achieved through the following technical solution: a chemical exchange saturation transfer magnetic resonance imaging probe based on alendronate, wherein the probe (Alen-FF-SSZ) is composed of an alendronate group (Alen), a phenylalanine-phenylalanine (FF) self-assembled group, and a sulfasalazine (SSZ) CEST MRI imaging unit, and its specific structure is shown below:

[0006]

[0007] By employing the above technical solution, the probe achieves adsorption to bone through the specific adsorption of the alendronate group and bone, and then releases the sulfasalazine group through cleavage by an esterase overexpressed in tumor tissue. The released sulfasalazine can exchange protons to expose and activate the CEST MRI signal.

[0008] This invention further provides a method for preparing the above-mentioned alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe, comprising the following five steps:

[0009] S1. Preparation of SSZ-COOH;

[0010] S2. Preparation of Trt-SH-FF-SSZ;

[0011] S3. Preparation of SH-FF-SSZ;

[0012] S4. Preparation of Alen-Male;

[0013] S5. Synthesize Alen-FF-SSZ.

[0014] The present invention is further configured such that the specific steps for synthesizing SSZ-COOH in S1 are as follows:

[0015] (1) Dissolve sulfasalazine in tetrahydrofuran and add excess thionyl chloride to it. After stirring the reaction for one hour, evaporate the tetrahydrofuran and excess thionyl chloride in the reaction vessel.

[0016] (2) Dissolve glycolic acid in dichloromethane and add a small amount of triethylamine to mix and dissolve. Add the mixture dropwise to the product from the previous step after rotary drying. After stirring for three hours, separate and purify the product by column chromatography to obtain SSZ-COOH.

[0017] The present invention is further configured such that the specific steps for preparing Trt-SH-FF-SSZ in step S2 are as follows:

[0018] (1) FF-SSZ was synthesized using the standard scheme of solid-phase synthesis (SPPS) and the product was purified by high performance liquid chromatography;

[0019] (2) Dissolve the product from the previous step with triethylmethylthiol, N-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurene hexafluorophosphate (HBTU), and N-hydroxybenzotriazole in dimethylformamide, then dissolve in N,N-diethylethylamine, and add N,N-diethylethylamine.

[0020] (3) Stir the reaction overnight and detect the reaction using an analytical high-performance liquid chromatograph;

[0021] (4) After the raw materials have reacted completely, the product Trt-SH-FF-SSZ is separated using a preparative high performance liquid chromatograph.

[0022] The present invention is further configured as follows: the specific steps for preparing SH-FF-SSZ in S3 are as follows: the product obtained in S2 is dissolved in a dichloromethane solution containing 95% trifluoroacetic acid, the triphenylmethyl group in the product of the previous step is removed, and the compound SH-FF-SSZ is obtained. Excess trifluoroacetic acid and dichloromethane are removed by rotary evaporation to obtain the orange-yellow solid product SH-FF-SSZ.

[0023] The present invention is further configured such that the specific steps for preparing Alen-Male in step S4 are as follows:

[0024] (1) Dissolve sodium alendronate in water and adjust the pH to 9 so that alendronate is completely dissolved in water;

[0025] (2) Then 3-maleimide propionic acid hydroxysuccinimide ester is suspended in 1,4-dioxane, and the suspension of 3-maleimide propionic acid hydroxysuccinimide ester is slowly added dropwise to alendronate sodium aqueous solution. During the dropwise addition, the pH of the mixed solution is adjusted to between 9 and 10 using 1mM NaOH solution. After the dropwise addition is completed, the solution is placed on a shaker and shaken for 15 minutes.

[0026] (3) After shaking, adjust the pH to 7 using 1mM hydrochloric acid solution;

[0027] (4) Extract the pH-adjusted reaction solution with dichloromethane to remove the remaining 3-maleimide propionic acid hydroxysuccinimide ester in the reaction, and collect the aqueous phase after extraction, which contains Alen-Male.

[0028] The present invention is further configured such that the specific steps for synthesizing Alen-FF-SSZ in step S5 are as follows:

[0029] (1) Dissolve SH-FF-SSZ solid in pyridine solution and slowly add aqueous solution containing Alen-Male to it in multiple batches;

[0030] (2) After the addition is complete, place the mixture on a shaker and react for 1 hour, and use high performance liquid chromatography to detect the formation of the product;

[0031] (3) After the amount of the final product stops increasing, the final product Alen-FF-SSZ is separated by high performance liquid chromatography.

[0032] The present invention further provides the application of an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe in the preparation of drugs that inhibit osteosarcoma growth.

[0033] The present invention further provides the application of an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe in the preparation of drugs for treating osteosarcoma.

[0034] The present invention further provides an application of an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe in CEST MRI imaging of osteosarcoma tissue.

[0035] In summary, the present invention has the following beneficial effects:

[0036] 1. This invention provides a synthetic route for a chemical exchange saturation transfer magnetic resonance imaging probe that can be cleaved by esterases in vivo. The raw materials for synthesizing this probe are readily available, have low cost, and are easy to synthesize.

[0037] 2. This product provides a novel synthetic route for linking bisphosphonates to peptide chains, which greatly improves the synthetic yield.

[0038] 3. This invention provides the use of a chemical exchange saturated transfer magnetic resonance imaging probe, which can perform magnetic resonance imaging on osteosarcoma cells in situ, and has significant advantages compared with small molecules.

[0039] 4. The compound structure of the present invention achieves bone adsorption through the bisphosphonate structure, thereby increasing the retention time of the compound in tumor tissue, thus improving the signal intensity of imaging and the therapeutic effect. Attached Figure Description

[0040] Figure 1 It is the synthetic route of Alen-FF-SSZ;

[0041] Figure 2 This is a high-resolution mass spectrum of Alen-FF-SSZ;

[0042] Figure 3 This is the hydrogen NMR spectrum of Alen-FF-SSZ;

[0043] Figure 4 This is the Z-spectrum of Alen-FF-SSZ in vitro CEST MRI signal activation in Example 2;

[0044] Figure 5 This is a statistical graph showing the signal activation of Alen-FF-SSZ on in vitro CEST MRI in Example 2;

[0045] Figure 6 This is the synthetic route for FF-SSZ;

[0046] Figure 7 This is a high-resolution mass spectrum of the FF-SSZ compound;

[0047] Figure 8 This is the 1H NMR spectrum of FF-SSZ;

[0048] Figure 9 This is the flowchart of the animal CEST MRI imaging experiment in Example 3;

[0049] Figure 10 This is a pseudo-color image of an animal's CEST MRI imaging in Example 3;

[0050] Figure 11 This is a CEST MRI signal statistics chart of Alen-FF-SSZ animal imaging in Example 3;

[0051] Figure 12 This is a CEST MRI signal statistics chart of FF-SSZ animal imaging in Example 3;

[0052] Figure 13 This is a CEST MRI signal statistics graph of the SSZ animal in Example 3;

[0053] Figure 14 This is a statistical graph of CEST MRI signals of the three compounds in Example 3 at 2 hours.

[0054] Figure 15 This is the flowchart of the animal treatment experiment in Example 4;

[0055] Figure 16 These are anatomical diagrams of the tumors in each group in Example 4;

[0056] Figure 17 This is a statistical chart of tumor size measurements in each group in Example 4;

[0057] Figure 18 This is a statistical chart of tumor weight in Example 4;

[0058] Figure 19 This is a Micro-CT scan of the mouse leg bone in Example 4;

[0059] Figure 20 This is a statistical chart of the bone volume of the mouse leg bone in Example 4;

[0060] Figure 21 This is a statistical chart showing the ratio of bone volume to tissue volume in the mouse leg bone in Example 4;

[0061] Figure 22 This is a chart showing the weight statistics of mice in Example 4;

[0062] Figure 23 This is a graph showing the blood biochemistry measurements of mice in Example 4. Detailed Implementation

[0063] The following is in conjunction with the appendix Figure 1-23 The present invention will be described in further detail below.

[0064] Example 1. Specific synthesis process of the probe

[0065] 1. Dissolve 500 mg of sulfasalazine in a round-bottom flask, add 5 mL of tetrahydrofuran until completely dissolved, and then add 2 mL of thionyl chloride solution. Stir and react for 1 h. After the reaction is complete, remove the tetrahydrofuran liquid and excess thionyl chloride from the flask using a rotary evaporator. Further, dissolve 200 mg of glycolic acid in dichloromethane solution, add 500 μL of triethylamine, and then repeatedly add this mixture dropwise to the round-bottom flask until the solid in the flask is completely dissolved. Stir and react for 3 h. Monitor the reaction until the reactants have completely reacted using thin-layer chromatography. Separate the product using column chromatography (methanol:dichloromethane = 1:10) to obtain SSZ-COOH.

[0066] 2. Compound FF-SSZ was synthesized using a standard solid-phase peptide synthesis (SPPS) protocol (Solid phase peptide synthesis. I. The synthesis of a tetrapeptide; J. Am. Chem. Soc. 1963, 85(14), 2149–2154, DOI: 10.1021 / ja00897a025). The product obtained from the solid-phase synthesis was dissolved in dimethylformamide with triethylmethylthiol, N-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurene hexafluorophosphate (HBTU), and N-hydroxybenzotriazole, and N,N-diethylethylamine was added. The reaction was stirred overnight, and the reaction was detected using analytical high-performance liquid chromatography (HPLC). After the starting materials had completely reacted, the product Trt-SH-FF-SSZ was separated using preparative HPLC.

[0067] 3. Dissolve the Trt-SH-FF-SSZ obtained in the previous step in a dichloromethane solution containing 95% trifluoroacetic acid, stir the reaction for 3 hours, and then remove the trifluoroacetic acid and dichloromethane using a rotary evaporator to obtain the compound SH-FF-SSZ.

[0068] 4. For the alendronate fraction, first dissolve sodium alendronate in water and adjust the pH to 9 to ensure complete dissolution of alendronate. Then, suspend 3-maleimide propionate hydroxysuccinimide ester in 1,4-dioxane. Slowly add the 3-maleimide propionate hydroxysuccinimide ester suspension dropwise to the sodium alendronate aqueous solution. During the addition, adjust the pH of the mixed solution to between 9 and 10 using 1 mM NaOH solution. After the addition is complete, place the solution on a shaker and shake for 15 minutes. After shaking, adjust the pH to 7 using 1 mM hydrochloric acid solution. Extract the pH-adjusted reaction solution with dichloromethane to remove any remaining 3-maleimide propionate hydroxysuccinimide ester. Collect the aqueous phase after extraction, which contains alendronate.

[0069] 5. Dissolve the obtained SH-FF-SSZ in pyridine solution, and slowly add the aqueous solution containing Alen-Male to it in multiple batches. After the addition is complete, place the mixture on a shaker and react for 1 hour, detecting the product formation using high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS). Once the amount of the final product stops increasing, separate the final product Alen-FF-SSZ using HPLC. (M+Na=1232.1313) 1 HNMR(400MHz,DMSO)δ11.14(s,1H),8.49–8.37(m,3H),8.28–8.00(m,8H),7.88–7.82(m,1H), 7.48–7.16(m,12H),6.94(t,J=6.4Hz,1H),4.81(s,2H),4.67(td,J=8.9,4.5Hz,1H),4.55(q, J=7.9Hz,1H),4.05(q,J=4.3Hz,1H),3.64(t,J=7.7Hz,4H),3.08(p,J=6.7Hz,4H),2.87(m,5H ), 2.38 (t, J = 7.7Hz, 2H), 2.28 (t, J = 7.4Hz, 2H), 1.67 (p, J = 7.3Hz, 2H), 1.33 (q, J = 6.1Hz, 2H).

[0070] The synthetic route of the compound is as follows Figure 1 As shown, Figure 2 This is a high-resolution mass spectrum of the final product. Figure 3 This is the hydrogen NMR spectrum of Alen-FF-SSZ.

[0071] Example 2. In vitro signal activation test case of this probe

[0072] 10 mM MAlen-FF-SSZ and 500 U / mL esterase were dissolved in phosphate-buffered saline (PBS, 10 mM, pH 7.4) containing 5% DMSO (v / v). After overnight incubation, the CEST MRI signal of this mixture was measured. Figure 4-5 As shown in the figure, the results indicate that Alen-FF-SSZ showed a significant activation of CEST MRI signal after incubation with esterase.

[0073] Example 3. This probe is used in chemical exchange saturation transfer magnetic resonance imaging.

[0074] To demonstrate the advantages of the Alen group in Alen-FF-SSZ, a control compound, FF-SSZ, was synthesized, with the structure shown below:

[0075]

[0076] Figure 6 The synthetic route for FF-SSZ, Figure 7 This is a high-resolution mass spectrum of FF-SSZ. Figure 8 The image shows the proton NMR spectrum of FF-SSZ.

[0077] Will contain 1×10 6 A suspension derived from human osteosarcoma cells 143B was injected into the tibial medullary cavity of 4-week-old Balb / c nude mice (each mouse weighing approximately 18-20g) to establish an orthotopic osteosarcoma model in nude mice. Fourteen days after modeling (tumor volume approximately 150mm²), [the tumor was observed]. 3 Chemical exchange saturation transfer magnetic resonance imaging (CEST MRI, n=4) was performed on mice. After anesthesia, mice underwent a pre-scan before drug injection; subsequently, Alen-FF-SSZ (121 mg / kg) was injected orally into the tumor tissue, and dynamic imaging continued. The total scanning time was 8 hours. The experimental procedure is as follows: Figure 9 As shown. After the scan, the obtained signal data were processed using the PLOF method and subjected to graphical analysis. Using the same method, FF-SSZ (75 mg / kg) and sulfasalazine solution (39.9 mg / kg) were injected intratumorally into mice with orthotopic osteosarcoma, and scans were performed and data processing was completed.

[0078] The results are as follows Figure 10-14As shown in the data, the CEST signal in the Alen-FF-SSZ and FF-SSZ groups continuously increased within 0-2 hours (Alen-FF-SSZ: 1.02%; FF-SSZ: 0.6%), reaching a peak at 2 hours; while the sulfasalazine group showed the highest signal intensity (1.49%) at the beginning of the experiment. This result verifies that the Alen-FF-SSZ and FF-SSZ groups trigger the CEST signal activation mechanism in vivo through esterase-mediated SSZ cleavage and release.

[0079] Furthermore, compared to the sulfasalazine group, the Alen-FF-SSZ and FF-SSZ groups showed longer signal durations, indicating that smaller molecules in the nanostructures have superior retention capabilities. Among the two nanostructure probe groups, the Alen-FF-SSZ group exhibited a higher signal intensity at 2 hours, demonstrating that the bone-targeting adsorption of the Alen group allows for the retention of more compounds in the tumor region.

[0080] In summary, the experimental results demonstrate that Alen-FF-SSZ can achieve targeted diagnosis of osteosarcoma tissue through precise CEST imaging, showcasing its great potential in tumor imaging.

[0081] Example 4. An instance of this probe being used in the treatment of osteosarcoma.

[0082] Will contain 1×10 6 Personally derived osteosarcoma cell suspension 143B was injected intramuscularly into the tibial medullary cavity of 4-week-old Balb / c nude mice (approximately 18-20 g per mouse) to establish an orthotopic osteosarcoma model in nude mice. Fourteen days after modeling (tumor volume approximately 120 mm²), the tumor was observed. 3 Mice were randomly divided into 4 groups (n=5 per group) for a treatment experiment. The treatment procedure was as follows: Figure 15 As shown in the figure. Mice in each group received intratumoral injections every two days with the following doses: 18.15 mg / kg Alen-FF-SSZ, 11.25 mg / kg FF-SSZ, 5.98 mg / kg SSZ, and PBS, for 14 consecutive days. Tumor size and mouse weight were monitored during this period. On day 14, mice were euthanized, dissected, and tumors and major organs (heart, liver, spleen, lungs, and kidneys) were collected, along with blood samples. After dissection, the tumors were weighed and photographed. The experimental results are shown in the figure. Figure 16-18 As shown in the figure. The results showed that the Alen-FF-SSZ group had the most significant therapeutic effect, with tumor size significantly smaller than the other three groups. The FF-SSZ group also showed some therapeutic effect, but it was lower than that of the Alen-FF-SSZ group. This may be due to the bone adsorption effect brought about by the Alen group and the nanoparticle size characteristics, which caused more compounds to remain in the tumor tissue, thus leading to the difference in therapeutic effect.

[0083] Subsequently, a Micro-CT scan was performed on the legs of the dissected mice to examine their bone condition. The experimental results are as follows: Figure 19-21 As shown in the figure. The results showed that the Alen-FF-SSZ group mice had the highest bone volume in the tibia and the highest ratio of bone volume to tissue volume, indicating that the leg bones of these mice were well preserved. This further proves that Alen-FF-SSZ can not only inhibit osteosarcoma growth but also effectively prevent cancer cells from eroding the bone. In addition, Figure 22-23 The experimental results show that the body weight of mice in the Alen-FF-SSZ group did not change significantly during treatment, and no abnormalities were observed in blood biochemical indicators after treatment, proving that Alen-FF-SSZ has no obvious side effects on mice. In conclusion, the experimental results indicate that Alen-FF-SSZ can effectively treat osteosarcoma and protect bone.

[0084] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. A chemical exchange saturation transfer magnetic resonance imaging probe based on alendronate, characterized in that: The probe's structure consists of an alendronate group, a phenylalanine-phenylalanine self-assembly group, and a sulfasalazine CEST MRI imaging unit, as shown below: 。 2. The method for preparing an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 1, characterized in that: The preparation method is as follows: ； It specifically includes the following five steps: S1. Preparation of compound I: SSZ-COOH; S2. Preparation of compound II: Trt-SH-FF-SSZ; S3. Preparation of compound III: SH-FF-SSZ; S4. Preparation of compound IV: Alen-Male; S5. Synthesize compound V: Alen-FF-SSZ.

3. The method for preparing an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 2, characterized in that: The specific steps for synthesizing SSZ-COOH in S1 are as follows: (1) Dissolve sulfasalazine in tetrahydrofuran and add excess thionyl chloride to it. After stirring for one hour, evaporate the tetrahydrofuran and excess thionyl chloride in the reaction vessel. (2) Dissolve glycolic acid in dichloromethane and add a small amount of triethylamine to mix and dissolve. Add the mixture dropwise to the product from the previous step after rotary drying. Stir the reaction for three hours and then separate and purify the product by column chromatography to obtain SSZ-COOH.

4. The method for preparing an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 3, characterized in that: The specific steps for preparing Trt-SH-FF-SSZ in S2 are as follows: (1) FF-SSZ was synthesized using the SPPS standard method of solid-state synthesis and the product was purified by high performance liquid chromatography; (2) Dissolve the product from the previous step with triethylmethylthiol, N-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurene hexafluorophosphate, and N-hydroxybenzotriazole in dimethylformamide and N,N-diethylethylamine, and add N,N-diethylethylamine. (3) Stir the reaction overnight and detect the reaction using an analytical high-performance liquid chromatograph; (4) After the raw materials have reacted completely, the product Trt-SH-FF-SSZ is separated using a preparative high performance liquid chromatograph.

5. The method for preparing an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 4, characterized in that: The specific steps for preparing SH-FF-SSZ in S3 are as follows: the product obtained in S2 is dissolved in a dichloromethane solution containing 95% trifluoroacetic acid, the triphenylmethyl group in the previous product is removed, and the compound SH-FF-SSZ is obtained. Excess trifluoroacetic acid and dichloromethane are removed by rotary evaporation to obtain the orange-yellow solid product SH-FF-SSZ.

6. The method for preparing an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 5, characterized in that: The specific steps for preparing Alen-Male in S4 are as follows: (1) Dissolve sodium alendronate in water and adjust the pH to 9 so that alendronate is completely dissolved in water; (2) Then 3-maleimide propionic acid hydroxysuccinimide ester is suspended in 1,4-dioxane, and the suspension of 3-maleimide propionic acid hydroxysuccinimide ester is slowly added dropwise to alendronate sodium aqueous solution. During the dropwise addition, the pH of the mixed solution is adjusted to between 9 and 10 using 1 mM NaOH solution. After the dropwise addition is completed, the solution is placed on a shaker and shaken for 15 minutes. (3) After shaking, adjust the pH to 7 using 1 mM hydrochloric acid solution; (4) Extract the pH-adjusted reaction solution with dichloromethane to remove the remaining 3-maleimide propionic acid hydroxysuccinimide ester in the reaction, and collect the aqueous phase after extraction, which contains Alen-Male.

7. The method for preparing an alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 6, characterized in that: The specific steps for synthesizing Alen-FF-SSZ in S5 are as follows: (1) Dissolve SH-FF-SSZ solid in pyridine solution and slowly add Alen-Male aqueous solution to it in multiple batches; (2) After the addition is complete, place the mixture on a shaker and react for 1 h, and use high performance liquid chromatography to detect the formation of the product; (3) After the amount of the final product stops increasing, the final product Alen-FF-SSZ is separated by high performance liquid chromatography.

8. The application of the alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 1 in the preparation of drugs to inhibit osteosarcoma growth.

9. The application of the alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 1 in the preparation of drugs for treating osteosarcoma.

10. The application of the alendronate-based chemical exchange saturation transfer magnetic resonance imaging probe according to claim 1 in the preparation of a reagent for CEST MRI imaging of osteosarcoma tissue.

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