Preparation method and application of folic acid-based magnetic resonance imaging contrast agent

Abstract

The present invention discloses a preparation method and application of a nuclear magnetic resonance imaging contrast agent based on folic acid. Specifically, the present invention discloses a preparation method of a nuclear magnetic resonance imaging contrast agent based on folic acid, which comprises the following steps: step I: reacting folic acid with glucosamine in water under the action of alkali to obtain a reaction solution 1; step II: reacting the reaction solution 1 with NaBH4 to obtain a reaction solution 2; step III: dialyzing the reaction solution 2 to obtain a dialysate 1 after dialyzation; step IV: mixing the dialysate 1 with acetonitrile, trifluoroacetic acid, trimethylsilyl chloride and glucose, and reacting to obtain a reaction solution 3; step V: reacting the reaction solution 3 with anhydrous sodium sulfate to obtain a reaction solution 4; step VI: dialyzing the reaction solution 4 to obtain a liquid containing the nuclear magnetic resonance imaging contrast agent based on folic acid. The nuclear magnetic resonance imaging contrast agent prepared by the present invention has a good targeted imaging effect on prostate cancer.

Description

Technical Field

[0001] The present invention relates to the field of medical imaging technology, and specifically to a preparation method and application of a folic acid-based nuclear magnetic resonance imaging contrast agent. Background Art

[0002] In the imaging diagnosis of prostate cancer, gd-DTPA (gadolinium-diethylenetriaminepentaacetic acid)-enhanced magnetic resonance imaging (MRI) is often used to evaluate tumor hemodynamic characteristics and locate cancerous areas by comparing the perfusion differences between tumor areas and normal tissues. As a nonspecific contrast agent, gd-DTPA mainly enters tumor blood vessels through passive diffusion and enhances high blood supply areas. However, due to the lack of affinity for specific molecules of cancer cells, its ability to distinguish between benign lesions and malignant tumors is limited, especially in the case of prostate hyperplasia or inflammation, which may lead to misdiagnosis. DTPA contains metallic gadolinium. Although it can be excreted through the kidneys under normal circumstances, the retention of gadolinium may lead to tissue accumulation in patients with renal insufficiency, and in rare cases, it may induce gadolinium deposition disease (such as gadolinium deposition disease or systemic sclerosis).

[0003] Nuclear medicine tracers (such as fluorine-18 fluorodeoxyglucose (F-18 FDG), sodium-18 fluoride, or carbon-11 labeled acetic acid) achieve more specific imaging through the metabolic activity of cancer cells or the bone resorption characteristics, but often lack accuracy in prostate cancer. PSMA-PET is currently a more accurate nuclear medicine tracer, but radioactive tracers require the use of radioactive isotopes and have a certain risk of radiation exposure.

[0004] In summary, the probes reported in the prior art have problems such as poor specificity, tissue metal accumulation or radioactivity, which limits their clinical application. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent and its application in view of the lack of specificity of existing MRI probes in clinical practice and the potential tissue accumulation problem caused by the components of the probes. The folic acid-based nuclear magnetic resonance imaging contrast agent prepared by the present invention avoids the need for radioactive or metal labeling, reduces the risk of immune response, is biodegradable, has high safety, has a good targeted imaging effect on prostate cancer, and is easy to clinically transform.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] The present invention provides a method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent, which comprises the following steps:

[0008] Step I: reacting folic acid with glucosamine in water under the action of a base to obtain a reaction solution 1;

[0009] Step II: Reaction solution 1 and NaBH 4 Carry out reaction to obtain reaction solution 2;

[0010] Step III: dialyzing the reaction solution 2 to obtain a dialyzate 1;

[0011] Step IV: mixing the dialysate 1 with acetonitrile, trifluoroacetic acid, trimethylsilyl chloride and glucose, and reacting to obtain a reaction solution 3;

[0012] Step V: reacting the reaction solution 3 with anhydrous sodium sulfate to obtain a reaction solution 4;

[0013] Step VI: dialyze the reaction solution 4 to obtain a liquid containing the folic acid-based nuclear magnetic resonance imaging contrast agent.

[0014] In a certain embodiment of the present invention, in the step I, when the folic acid reacts with the glucosamine, the pH of the reaction solution is 7 to 7.5, for example, 7; preferably, the pH of the reaction solution is adjusted by a phosphate buffer, and the phosphate buffer is a conventional phosphate buffer in the art, for example, a phosphate buffer with a pH of 7.4, further for example, a 50 mM phosphate buffer with a pH of 7.4. Preferably, in the phosphate buffer, the components and their concentrations are: NaCl: 137 mM, KCl: 2.7 mM, Na 2 HPO 4 : 10 mM, KH 2 PO 4 : 1.8 mM.

[0015] In a certain embodiment of the present invention, in the step I, the CAS number of the glucosamine is 3416-24-8.

[0016] In one embodiment of the present invention, in step I, the water is deionized water.

[0017] In one embodiment of the present invention, in step I, the base is an alkali metal hydroxide, such as sodium hydroxide.

[0018] In a certain embodiment of the present invention, in the step I, the molar ratio of the base to the folic acid is (1.5-2.5):1, for example 1.8:1.

[0019] In a certain embodiment of the present invention, in the step I, the molar ratio of the folic acid to the glucosamine is 1: (2-8), for example 1:5.

[0020] In one embodiment of the present invention, in step I, the molar volume ratio of folic acid to water is 0.01-0.05 mmol / ml, for example 0.03 mmol / ml.

[0021] In a certain embodiment of the present invention, the step I is to react the mixture of folic acid and the base with the glucosamine, the solvent in the mixture is water, and the glucosamine is a glucosamine aqueous solution; the pH of the mixture may be 7~7.5, for example 7; the pH of the glucosamine aqueous solution may be 7~7.5, for example 7; preferably, the volume ratio of water in the mixture to water in the glucosamine aqueous solution is 1:1.

[0022] In a certain embodiment of the present invention, in the step I, the reaction time of the reaction is 2 to 4 hours.

[0023] In one embodiment of the present invention, in step I, the reaction temperature of the reaction is 25-27°C, for example, 30-37°C.

[0024] In a certain embodiment of the present invention, in step II, the NaBH 4 The molar ratio of the folic acid in step I is (10-15):1, for example 12:1.

[0025] In one embodiment of the present invention, in step II, the reaction temperature of the reaction is 0-4°C.

[0026] In a certain embodiment of the present invention, in the step II, the reaction time of the reaction is 30 to 60 minutes, for example 45 minutes.

[0027] In a certain embodiment of the present invention, in the step III, the dialysis is performed using a dialysis material with a molecular weight cutoff of 900-1100 Da (eg, 1000 Da).

[0028] In one embodiment of the present invention, in step III, the dialysis is performed using a dialysis material composed of regenerated cellulose or cellulose ester.

[0029] In a certain embodiment of the present invention, in the step III, the dialysis is performed using a dialysis bag, and the specification of the dialysis bag is: Spectrum Labs Spectra / Por® 1 Dialysis Membrane, MWCO: 1000Da.

[0030] In a certain embodiment of the present invention, in the step III, the dialysis time is 10 to 15 hours, for example, 12 hours.

[0031] In a certain embodiment of the present invention, in step III, during the dialysis process, the dialysate is replaced every 2 to 6 hours, for example, every 4 hours.

[0032] In a certain embodiment of the present invention, in the step III, the dialysis is dialysis in deionized water.

[0033] In a certain embodiment of the present invention, in step IV, the molar ratio of the glucose to the folic acid in step I is (2-8):1, for example, 5:1.

[0034] In a certain embodiment of the present invention, in step IV, the molar ratio of trimethylsilyl chloride to glucose is (0.6-1):1, for example, 0.8:1.

[0035] In a certain embodiment of the present invention, in step IV, the molar ratio of the trifluoroacetic acid to the glucose is (8-15):1, for example, 12:1.

[0036] In a certain embodiment of the present invention, in step IV, the volume molar ratio of the acetonitrile to the trimethylsilyl chloride is (1.5-2.5):1, for example, 2.2:1.

[0037] In one embodiment of the present invention, in step IV, the reaction temperature of the reaction is 25-35°C, for example, 30°C.

[0038] In a certain embodiment of the present invention, in step IV, the reaction time of the reaction is 1 to 5 minutes, for example, 3 minutes.

[0039] In a certain embodiment of the present invention, in step IV, the CAS number of the glucose is 50-99-7.

[0040] In a certain embodiment of the present invention, in the step V, the molar ratio of the anhydrous sodium sulfate to the glucose in the step IV is (1-2):1, for example, 1.25:1.

[0041] In a certain embodiment of the present invention, in the step V, the reaction time of the reaction is 20 to 40 minutes, for example, 30 minutes.

[0042] In one embodiment of the invention, in step VI, the dialysis is the same as the dialysis in step III described in any of the above embodiments.

[0043] The present invention also provides a liquid containing the folic acid-based nuclear magnetic resonance imaging contrast agent prepared by the method for preparing the folic acid-based nuclear magnetic resonance imaging contrast agent described in any of the above schemes, that is, the liquid containing the folic acid-based nuclear magnetic resonance imaging contrast agent in the above step VI.

[0044] The present invention also provides a folic acid-based nuclear magnetic resonance imaging contrast agent prepared by the method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent described in any of the above schemes.

[0045] The present invention also provides a use of the folic acid-based nuclear magnetic resonance imaging contrast agent or the liquid containing the folic acid-based nuclear magnetic resonance imaging contrast agent in the preparation of a prostate cancer contrast agent.

[0046] In one embodiment of the present invention, the prostate cancer contrast agent is a chemical exchange saturation transfer magnetic resonance imaging contrast agent.

[0047] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0048] The reagents and raw materials used in the present invention are commercially available.

[0049] The positive and progressive effects of the present invention are:

[0050] (1) The present invention uses highly biocompatible materials to synthesize contrast agents, which are highly safe and easy to transform;

[0051] (2) The contrast agent of the present invention avoids metal and radioactive labels, reducing the risk of toxicity and immune response;

[0052] (3) The intracellular metabolism of the contrast agent of the present invention provides the possibility for designing CEST MRI probes for specific applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 3 is a CEST signal comparison diagram before and after incubation of the contrast agent with DU145 cells obtained in Example 1, wherein the left side is the CEST signal diagram measured before incubation of the contrast agent with DU145 cells and the corresponding test curve, and the right side is the CEST signal diagram measured after incubation of the contrast agent with DU145 cells and the corresponding test curve.

[0054] Figure 2 This is a diagram showing the imaging effect of the contrast agent obtained in Example 2 in mice. DETAILED DESCRIPTION

[0055] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0056] Example 1: Synthesis of folic acid-based MRI contrast agents.

[0057] 1. Dissolve 0.05 g (0.11 mmol) folic acid in 2 mL 0.1 M NaOH (0.2 mmol) aqueous solution, and then use 50 mM phosphate buffer with a pH of 7.4 (the phosphate buffer contains 137 mM NaCl, 2.7 mM KCl, and 2 HPO 4 : 10 mM, KH 2 PO 4 : 1.8 mM) to adjust pH to 7.

[0058] 2. Dissolve 0.1 g (0.56 mmol) of glucosamine (CAS: 3416-24-8) in 2 mL of deionized water and adjust the pH to 7 with buffer (50 mM phosphate buffer as described above).

[0059] 3. Mix the above folic acid and glucosamine solutions in a flask to ensure a homogeneous solution. Slightly heat (30-37°C) to allow the condensation reaction between the two to proceed smoothly for 4 hours.

[0060] 4. Adjust the reaction solution to 0-4°C and add 0.05 g (1.32 mmol) NaBH 4 , and the reaction continued for 45 minutes.

[0061] 5. The reaction solution obtained in step 4 was dialyzed against deionized water using a dialysis bag (Spectrum Labs Spectra / Por® 1 Dialysis Membrane, MWCO: 1000 Da) for 12 hours, with the dialysate replaced every 4 hours to remove unreacted substances and by-products.

[0062] 6. Add 0.1 g (0.56 mmol) of glucose (CAS: 50-99-7) to the dialyzed liquid, and add 0.5 mL of trifluoroacetic acid (6.6 mmol), 1 mL of CH 3 CN, 0.05 g (0.46 mmol) trimethylsilyl chloride. The temperature was adjusted to 30°C, and after reacting for 3 min, 0.1 g (0.7 mmol) anhydrous sodium sulfate was added and the reaction was maintained for 30 min.

[0063] 7. The reaction solution obtained in step 6 was dialyzed again in deionized water using a dialysis bag (Spectrum Labs Spectra / Por® 1 Dialysis Membrane, MWCO: 1000 Da) for 12 hours, with the dialysate replaced every 4 hours to remove unreacted substances and by-products.

[0064] Example 2: CEST MRI detection of the CEST signal generated by the folic acid-based nuclear magnetic resonance imaging contrast agent synthesized in Example 1 under tumor cell metabolism.

[0065] 20 mL of the solution prepared in Example 1 above was fixed on a test tube rack, and the test tube rack was then fixed in a plastic box of appropriate size with double-sided tape, and sufficient water was added to the plastic box so that the water completely covered the height of the solution in the sample tube to eliminate the influence of field inhomogeneity caused by the change in magnetic susceptibility of the air cavity.

[0066] After the tube was fixed, a CEST (chemical exchange saturation transfer) sequence was performed to acquire data at B1 = 1.0 µT using a vertical bore Bruker 7T MRI scanner equipped with a 15 mm volume coil. A rapid spin echo (RARE) sequence with fat suppression was used to acquire a continuous wave pre-saturation pulse at B1 = 1.0 µT (repetition time / echo time (TR / TE) = 5000 / 5 ms, RARE factor = 10). To correct for B0 inhomogeneity, a water saturation offset reference (WASSR) was acquired twice before and after the CEST acquisition. All acquisitions were corrected for B0 inhomogeneity using the WASSR method.

[0067] CEST data were collected at the initial time point, and then DU145 was added to collect data again. The average Delta MTR = (S A -S B ) / S A To quantify the CEST signal value, specifically: at the initial time point, that is, before adding DU145 cells, CEST scanning was performed to obtain Figure 1 The graph and curve diagram on the left (where the horizontal and vertical coordinates of the curve diagram represent the chemical shift and signal intensity S respectively) A ); add 100 µL (cell number: 5×10 6 ) DU145 cells, and then CEST scanning was performed to obtain Figure 1 The graph and curve on the right side of the figure (the horizontal and vertical axes represent the chemical shift and signal intensity S B ).

[0068] According to the test results, after adding DU145 cells to the tested liquid, an obvious signal change was observed at the 1 ppm position, indicating that the signal after DU145 interacted with the tested liquid could be specifically characterized by the CEST sequence.

[0069] Example 3: Results of imaging in an animal model using the folic acid-based MRI contrast agent synthesized in Example 1.

[0070] The CEST sequence was performed to acquire data at B1 of 1.0 µT using a Bruker 7T MRI scanner equipped with an abdominal coil. The fat-suppressed rapid spin echo (RARE) sequence was used, which had a continuous wave pre-saturation pulse with B1 = 1.0 µT at 3 seconds (repetition time / echo time (TR / TE) = 5000 / 5 ms, RARE factor = 10). To correct for B0 inhomogeneity, two water saturation offset references (WASSR) were acquired before and after the CEST acquisition. After correcting for B0 inhomogeneity using the WASSR method, the water saturation offset reference (WASSR) was calculated by averaging the Delta MTR = (S 0 -S T ) / S 0 To quantify the CEST signal, specifically:

[0071] DU145 cells were used as the PSMA positive experimental group. MBT2 cells were used as the negative control group. DU145 cells were cultured in RPMI-1640 medium until the logarithmic growth phase, and MBT2 cells were cultured in DMEM medium until the logarithmic growth phase, supplemented with 10% fetal bovine serum. DU145 and MBT2 cells were collected and 50-100 µL (5×10 6 ) cells were injected into the prostate of BALB / c nude mice, with a total of 4 mice in the positive experimental group and 4 mice in the negative control group. When the tumor diameter reached 5-10 mm, the prostate area of ​​the mice was imaged and the signal intensity at 1 ppm at 0 min time point was collected for each group of mice (the signal intensity at 0 min was recorded as S 0 ), and then the liquid in Example 1 was injected into the mice through the tail vein at a dose of 0.2 ml / kg, and the signal intensity at 1 ppm was collected for each group of mice at 5 min, 10 min, 30 min, 60 min, 120 min and 240 min (the signal intensity at each time point was recorded as S T ), the experimental results are shown in Table 1 and Figure 2 .

[0072] Table 1 DELTA MTR of positive experimental group and negative control group at different time points

[0073]

[0074] Table 1 and Figure 2 The results showed that in the DU145 group (positive experimental group), DELTA MTR was significantly higher than that in the MBT2 group (negative control group), indicating that the imaging was targeted. At the same time, within the effective imaging time window (60 minutes), the difference in DELTA MTR between the two groups was more significant, indicating the effectiveness of the imaging strategy.

Claims

1. A method for preparing a folic acid-based magnetic resonance imaging contrast agent, comprising the following steps: Step I: reacting folic acid with glucosamine in water under the action of a base to obtain a reaction solution 1; Step II: reacting the reaction solution 1 with NaBH4 to obtain a reaction solution 2; Step III: dialyzing the reaction solution 2 to obtain a dialyzate 1; Step IV: mixing the dialysate 1 with acetonitrile, trifluoroacetic acid, trimethylsilyl chloride and glucose, and reacting to obtain a reaction solution 3; Step V: reacting the reaction solution 3 with anhydrous sodium sulfate to obtain a reaction solution 4; Step VI: dialyze the reaction solution 4 to obtain a liquid containing the folic acid-based nuclear magnetic resonance imaging contrast agent.

2. The method for preparing a folic acid-based magnetic resonance imaging contrast agent according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In the step I, when the folic acid and the glucosamine react, the pH of the reaction solution is 7 to 7.5; (2) In the step I, when the folic acid reacts with the glucosamine, the pH of the reaction solution is adjusted by a phosphate buffer; (3) In the step I, the CAS number of the glucosamine is 3416-24-8; (4) In the step I, the base is an alkali metal hydroxide; (5) In the step I, the molar ratio of the base to the folic acid is (1.5-2.5):1; (6) In the step I, the molar ratio of the folic acid to the glucosamine is 1:(2-8); (7) In the step I, the molar volume ratio of the folic acid to the water is 0.01-0.05 mmol / ml; (8) The step I is to react the mixture of folic acid and base with the glucosamine, the solvent in the mixture is water, and the glucosamine is a glucosamine aqueous solution; (9) In the step I, the reaction time is 2 to 4 hours; (10) In step I, the reaction temperature is 25-27°C; (11) In the step II, the molar ratio of the NaBH4 to the folic acid in the step I is (10-15): 1; (12) In step II, the reaction temperature is 0-4°C; (13) In step II, the reaction time of the reaction is 30 to 60 minutes; (14) In step III, the dialysis is performed using a dialysis material with a molecular weight cutoff of 900 to 1100 Da; (15) In step III, the dialysis is performed using a dialysis material composed of regenerated cellulose or cellulose ester; (16) In step III, the dialysis time is 10 to 15 hours; (17) In step III, during the dialysis process, the dialysate is replaced every 2 to 6 hours; (18) In step III, the dialysis is performed in deionized water; (19) In step IV, the molar ratio of the glucose to the folic acid in step I is (2-8):1; (20) In step IV, the molar ratio of trimethylsilyl chloride to glucose is (0.6-1):1; (21) In step IV, the molar ratio of trifluoroacetic acid to glucose is (8-15):1; (22) In step IV, the volume molar ratio of acetonitrile to trimethylsilyl chloride is (1.5-2.5):1; (23) In step IV, the reaction temperature is 25-35°C; (24) In step IV, the reaction time of the reaction is 1 to 5 min; (25) In step IV, the CAS number of the glucose is 50-99-7; (26) In the step V, the molar ratio of the anhydrous sodium sulfate to the glucose in the step IV is (1-2):1; (27) In step V, the reaction time of the reaction is 20 to 40 min; (28) In step VI, the dialysis is performed using a dialysis material with a molecular weight cutoff of 900 to 1100 Da; (29) In step VI, the dialysis is performed using a dialysis material composed of regenerated cellulose or cellulose ester; (30) In step VI, the dialysis time is 10 to 15 hours; (31) In step VI, during the dialysis process, the dialysate is replaced every 2 to 6 hours; (32) In step VI described above, the dialysis is performed in deionized water.

3. The method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent according to claim 2, characterized in that: It meets one or more of the following conditions: (1) In the step I, when the folic acid reacts with the glucosamine, the pH of the reaction solution is adjusted by using a phosphate buffer with a pH of 7.4; (2) In the step I, the base is sodium hydroxide; (3) In the step I, the molar ratio of the base to the folic acid is 1.8:1; (4) In the step I, the molar ratio of the folic acid to the glucosamine is 1:5; (5) In the step I, the molar volume ratio of the folic acid to the water is 0.03 mmol / ml; (6) The step I is to react the mixture of folic acid and base with the glucosamine, the solvent in the mixture is water, the glucosamine is a glucosamine aqueous solution, and the pH of the mixture is 7-7.5; (7) The step I is to react the mixture of folic acid and base with the glucosamine, the solvent in the mixture is water, the glucosamine is a glucosamine aqueous solution, and the pH of the glucosamine aqueous solution is 7 to 7.5; (8) The step I is to react the mixture of folic acid and the base with the glucosamine, the solvent in the mixture is water, the glucosamine is a glucosamine aqueous solution, and the volume ratio of water in the mixture to water in the glucosamine aqueous solution is 1:1; (9) In the step I, the reaction temperature is 30-37°C; (10) In step II, the molar ratio of the NaBH4 to the folic acid in step I is 12:1; (11) In step II, the reaction time of the reaction is 45 min; (12) In step III, the dialysis is performed using a dialysis material with a molecular weight cutoff of 1000 Da; (13) In step III, the dialysis time is 12 hours; (14) In step III, during the dialysis process, the dialysate is replaced every 4 hours; (15) In step IV, the molar ratio of the glucose to the folic acid in step I is 5:1; (16) In step IV, the molar ratio of trimethylsilyl chloride to glucose is 0.8:1; (17) In step IV, the molar ratio of trifluoroacetic acid to glucose is 12:1; (18) In step IV, the volume molar ratio of acetonitrile to trimethylsilyl chloride is 2.2:1; (19) In step IV, the reaction temperature is 30°C; (20) In step IV, the reaction time of the reaction is 3 min; (21) In step V, the molar ratio of the anhydrous sodium sulfate to the glucose in step IV is 1.25:1; (22) In step V, the reaction time of the reaction is 30 min; (23) In step VI, the dialysis is performed using a dialysis material with a molecular weight cutoff of 1000 Da; (24) In step VI, the dialysis time is 12 hours; (25) In step VI described above, during the dialysis process, the dialysate is replaced every 4 hours.

4. The method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent according to claim 3, characterized in that: It meets one or more of the following conditions: (1) In the step I, when the folic acid reacts with the glucosamine, the pH of the reaction solution is adjusted by using a 50 mM phosphate buffer solution with a pH of 7.4; (2) Step I is to react the mixture of folic acid and base with the glucosamine, the solvent in the mixture is water, and the glucosamine is a glucosamine aqueous solution; the pH of the mixture is 7; (3) The step I is to react the mixture of folic acid and base with the glucosamine, the solvent in the mixture is water, the glucosamine is a glucosamine aqueous solution; the pH of the glucosamine aqueous solution is 7; (4) In step III, the dialysis is performed using a dialysis bag, and the specification of the dialysis bag is: Spectrum Labs Spectra / Por® 1 Dialysis Membrane, MWCO: 1000 Da; (5) In step VI, the dialysis is performed using a dialysis bag, and the specification of the dialysis bag is: Spectrum Labs Spectra / Por® 1 Dialysis Membrane, MWCO: 1000 Da.

5. The method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent according to claim 4, characterized in that: In the step I, when the folic acid reacts with the glucosamine, the pH of the reaction solution is adjusted by a phosphate buffer, and the components and their concentrations in the phosphate buffer are: NaCl: 137 mM, KCl: 2.7 mM, Na2HPO4: 10 mM, KH2PO4: 1.8 mM.

6. A liquid containing a folic acid-based nuclear magnetic resonance imaging contrast agent prepared by the method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent according to any one of claims 1 to 5.

7. A folic acid-based nuclear magnetic resonance imaging contrast agent prepared by the method for preparing a folic acid-based nuclear magnetic resonance imaging contrast agent according to any one of claims 1 to 5.

8. Use of the folic acid-based nuclear magnetic resonance imaging contrast agent according to claim 7 or the liquid containing the folic acid-based nuclear magnetic resonance imaging contrast agent according to claim 6 in the preparation of a prostate cancer contrast agent.

9. The use according to claim 8, characterized in that The prostate cancer contrast agent is a chemical exchange saturation transfer magnetic resonance imaging contrast agent.

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