Fluorescence-magnetic resonance bimodal imaging agents and methods for preparing and using same

Abstract

A fluorescence-magnetic resonance bimodal imaging agent having the structure XLY and its preparation and use, comprising in formula (I) R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 are each independently selected from H, halogen, OH, NH2, COOH, CONH2, NO2, CN, and lower alkyl, which may be substituted with halogen, OH, NH2, COOH, CONH2, SO3H, NO2, or CN; R3 and R4, R7 and R8 may each independently be cyclized with the carbon atom to which they are attached to a phenyl group or a heterocycle; L is a linking group; and Y is a metal chelate, as well as methods for preparing and using the same. [Case 1] JPEG2024518592000051.jpg59133

Description

[Technical Field]

[0001] This application claims priority to a Chinese patent application filed with the Intellectual Property Office of the People's Republic of China on May 17, 2021, bearing application number 20211053217.9 and entitled "Fluorescence-Magnetic Resonance Bimodal Imaging Agent and Its Preparation Method and Use," the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of medical diagnostic imaging, more particularly to fluorescence-magnetic resonance bimodal imaging agents and methods for their preparation and use. [Background technology]

[0003] In recent years, significant progress has been made in the early diagnosis of diseases, especially cancer, making it increasingly difficult for traditional clinical imaging technologies to meet the new demands of personalized cancer treatment. Traditional clinical diagnostic techniques, such as positron emission tomography (PET), computed tomography (CT), X-ray imaging, ultrasound imaging (US), and magnetic resonance imaging (MRI), are limited by their inherent shortcomings, such as poor specificity and limited lesion location information. Among these, MRI is the most widely used imaging method in clinical practice. MRI generally utilizes the differences in the "spin-lattice relaxation time" and "spin-spin relaxation time" of protons in different tissues or organs for imaging. MRI is a non-invasive, non-ionizing radiation imaging method that can provide anatomical, physiological, and even molecular information on living animals. MRI's penetration depth is sufficient to image the entire human body, and depending on the magnetic field strength, spatial resolution can reach 10 μm or less, providing image information that is difficult to obtain with other imaging modalities. Although MRI imaging of anatomical structures can generally be performed without the use of contrast agents, when molecular-level information is required, the low sensitivity of MRI makes it difficult to obtain clear images of minute tumor lesions, hindering early detection and treatment. Therefore, the use of contrast agents is necessary to improve image quality. The low sensitivity of commonly used MRI is related to the signal detection mechanism and is difficult to overcome through self-improvement. The currently commonly used MRI contrast agent, gadopentetate meglumine (Gd-DTPA), has a low relaxation rate, and small molecule contrast agents are rapidly eliminated in the body. Therefore, improving the relaxation efficiency of MRI contrast agents is a key step toward enhancing MRI contrast.

[0004] Optical imaging techniques rely on the interaction of different physical parameters of light with tissue, and many different optical imaging methods have been reported. These techniques rely on fluorescence, absorbed light, reflected light, or bioluminescence as a source of contrast. Optical imaging techniques primarily include near-infrared fluorescence imaging (NIRF), reflectance imaging, and bioluminescence imaging. Despite its relatively late emergence, various clinical and basic research studies on optical imaging are progressing rapidly. Optical imaging has the advantages of being simple to use, providing intuitive images, allowing for simultaneous multi-labeling, and being applicable to a wide range of spatial scales from the subcellular to the tissue level. It can also be used in biological experiments, fluorescence-guided surgery, and endoscopic imaging. At the same time, most optical contrast agents are nontoxic, relatively inexpensive, versatile, and highly sensitive. Optical imaging can utilize organic or inorganic fluorescent contrast agents that fluoresce at a variety of different excitation wavelengths. Optical imaging, initially used in cancer diagnosis, was based on changes in endogenous fluorescence in tumor tissue. However, due to the difficulty in distinguishing diagnostic signal components from background fluorescence, exogenous contrast agents have been developed to enhance the contrast between tumor and normal tissues for fluorescence imaging. A major problem facing optical imaging is the difficulty in reliably distinguishing the signal from background noise in normal tissue, which can severely impact image quality. At the same time, optical imaging technology must also address the low tissue penetration depth difference and spatial resolution. Indocyanine green (ICG) is currently at the forefront of clinical clinical use. It was initially used as a dye to assess liver function and effective hepatic blood flow, but is now widely used in intraoperative navigation during liver surgery and lymph node scanning for breast cancer. After intravenous injection, ICG immediately binds to plasma proteins and rapidly distributes throughout the body via the bloodstream. It is efficiently and selectively taken up by hepatocytes, then excreted in free form in the bile, enters the intestine via the biliary tract, and is excreted from the body with feces.Because of its rapid excretion, in normal individuals, approximately 97% is eliminated from the blood 20 minutes after intravenous injection, without being involved in chemical reactions in the body, without enterohepatic circulation, without lymphatic reflux, and without being excreted from other extrahepatic organs such as the kidneys. Due to the structure of ICG, sterilized water for injection is its most preferred solvent, but the stability of this aqueous solution is not very good. Furthermore, in surgical guidance, in cases such as liver cirrhosis, indocyanine green can give false positives in the liver, reducing the accuracy of liver resection surgery.

[0005] Therefore, more comprehensive diagnostic information is beneficial for improving diagnostic accuracy, but simple morphological images are unable to provide sufficient information. Meanwhile, imaging techniques with high sensitivity and the ability to provide more information beyond images, such as optical imaging, PET, and single-photon emission computed tomography (SPECT), are limited by their low spatial resolution. While the simultaneous use of multiple contrast agents can achieve better contrast effects across various imaging modalities, establishing a bimodal contrast agent helps ensure the pharmacokinetics of signals from each modality are consistent, allows colocalization, and avoids placing extra stress on the body's blood clearance mechanisms. When designing a multimodal contrast agent, care must be taken to ensure that the functions and advantages of the selected imaging modalities do not overlap, while also compensating for the weaknesses of each imaging modality to maximize synergy. Summary of the Invention

[0006] In response to the deficiencies present in the prior art, the present invention provides a fluorescence-magnetic resonance bimodal imaging agent, The imaging agent has the structure XLY, X is [ka] having the structure R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12are each independently selected from H, halogen, OH, NH, COOH, CONH, NO, CN, and a lower alkyl group, and the lower alkyl group may be substituted with halogen, OH, NH, COOH, CONH, SO, H, NO, or CN; and R and R, R and R, and R, and R, may each independently be cyclized with the carbon atom to which they are bonded to form a phenyl group or a heterocycle. The halogen is a fluorine, chlorine, bromine, or iodine ion. The lower alkyl group is C 1-6 It is preferably an alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a t-butyl group, an n-butyl group, a pentyl group, a cyclopropyl group, a cyclopentyl group, or a cyclohexyl group.

[0007] Preferably, the lower alkyl group is C 1-3 It is an alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0008] The bimodal contrast agent has good magnetic resonance T1-weighted imaging and in vivo fluorescence imaging capabilities, and has a high relaxivity.

[0009] Preferably, X is [ka] having the structure R9, R 10 , R 11 , and R 12 The definition of is the same as above.

[0010] More preferably, X is [ka] It has the following structure.

[0011] L is a linking group, [ka] having the structure A is selected from S, N, and O, and preferably A is N or O.

[0012] L1 is composed of a carbon chain having a length of 8 to 20, a carbon atom in the carbon chain may be substituted with an oxygen atom or a nitrogen atom, a double bond may be contained in the carbon chain, and a hydrogen atom in the carbon chain may be substituted with 1 to 5 R 13 may be substituted with, 13 are each independently a benzyl group, a carboxyl group, or C 1-3 is an alkyl group, or adjacent R 13 may form a ring structure with the atom to which they are bonded, for example, [ka] and the carbons in the carbon chain may be further substituted with carbonyl groups, for example, [ka] Contains:

[0013] More preferably, the structure of L is: [ka] and The definition of A is the same as above, The definition of L2 is the same as L1.

[0014] The bimodal contrast agent has advantages such as high relaxivity, excellent thermal stability, low toxicity and side effects, and good compatibility with fluorescence and magnetic resonance signals, and can be effectively applied to magnetic resonance imaging and fluorescence imaging of living cells and living organisms.

[0015] More preferably, L2 is [ka] and n is 8 to 20, and more preferably 10 to 15.

[0016] The fluorescence-magnetic resonance bimodal contrast agent provided by the present invention utilizes magnetic resonance signals to monitor the distribution and metabolic status of fluorescent dyes in human tissues in real time. Extensive experimental verification has shown that some linking groups are easily decomposed, causing the two components to rapidly separate in the body, which will affect the final monitoring effect. In the present invention, L2 [ka] Therefore, it is predicted that the obtained fluorescence-magnetic resonance bimodal contrast agent is stable, can achieve excellent detection effect, and can meet clinical needs.

[0017] Y is a metal chelate.

[0018] Preferably, the metal chelate is complexed with Gd to form a Gd complex (Z).

[0019] More preferably, the Gd complex is [ka] It has the following structure.

[0020] More preferably, the fluorescence-magnetic resonance bimodal contrast agent of the present invention comprises [ka] It has the structure JPEG0007814422000012.jpg177170JPEG0007814422000013.jpg9462.

[0021] In another aspect, the present invention provides a method for preparing the fluorescence-magnetic resonance bimodal imaging agent, wherein the reaction scheme is as follows: [ka]

[0022] The method involves the condensation of a compound of formula I with a compound of formula II to give the desired compound III.

[0023] The compound of formula II is [ka] and gadolinium chloride hydrate form a complex. R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 , Y, A, L, and Z are defined as above.

[0024] Alternatively, the fluorescence-magnetic resonance bimodal imaging agent provided by the present invention may be obtained by complexing the compound of formula III-1 with gadolinium chloride hydrate, and the reaction scheme is as follows: [ka]

[0025] Furthermore, the compound of formula III-1 can be obtained by condensing the compound of formula I-2 with the compound of formula II-2, and the reaction formula is as follows: [ka] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , and R 12 , A, L2, and Y are defined as above.

[0026] At the same time, the present invention provides uses of the fluorescence-magnetic resonance bimodal contrast agent, which are mainly used in medical diagnosis, specifically in medical magnetic resonance enhanced imaging, liver function measurement, preoperative planning assistance, intraoperative fluorescence navigation, prediction of fluorescence distribution in internal organs by magnetic resonance imaging, liver function measurement, kidney function measurement, monitoring of internal circulation status and labeled cells, and as an analytical label for ex vivo cells.

[0027] The beneficial effects of the present invention are as follows: The bimodal contrast agent provided by the present invention has good magnetic resonance T1-weighted imaging contrast ability and in vivo fluorescence imaging ability, and has advantages such as high relaxivity, excellent thermal stability, low toxicity and side effects, and good correspondence between fluorescence and magnetic resonance signals, which can be effectively used in magnetic resonance imaging and fluorescence imaging of living cells and living organisms, and can significantly enhance the magnetic resonance signals of the liver and kidney even 6 hours after administration, significantly improve the resolution of organ boundaries, and have a relatively high correspondence between the magnetic resonance signal intensity and the fluorescence intensity, providing the clinically required effect of a magnetic resonance-fluorescence bimodal contrast agent for tumor diagnosis and surgical navigation, and has great potential for clinical application. [Brief explanation of the drawings]

[0028] [Figure 1] In Figure 1, A is magnetic resonance T1-enhanced imaging of compound PL-001 in mice, B is a bar graph of the average T1-enhanced magnetic resonance imaging signal of the liver and kidney, C is a fluorescent imaging image of the liver and kidney 6 hours after administration of PL-001, and D is a bar graph of the fluorescent efficiency values ​​of the liver and kidney. [Figure 2] FIG. 2 shows the results of the migration rate of the contrast agent into H22 cells measured by a flow cytometer. [Figure 3] FIG. 3 shows cross-sectional images of magnetic resonance T1-enhanced imaging of a mouse liver intraepithelial tumor before and after injection of a contrast agent, with the tumor tissue indicated within the dotted line. [Figure 4]Figure 4 shows the results of fluorescent imaging of the main tissues of mice with liver intraepithelial tumors. [Figure 5] FIG. 5 is the HPLC purity spectrum of PL-003. DETAILED DESCRIPTION OF THE INVENTION

[0029] In order to better understand the embodiments of the present invention, the following will further describe the embodiments of the present invention with reference to specific examples. However, the following examples are merely for the purpose of understanding the present invention and should not be considered as specific limitations of the present invention.

[0030] Example 1: Preparation of compound PL-001 [ka] The reaction pathway is as follows: [ka]

[0031] Reaction steps: 1. IR-820 (New Indocyanine Green) and 1,11-diamino-3,6,9-trioxaundecane were added to a DMSO solution in a ratio of 1:1 to 1:5, and triethylamine was used as an acid scavenger. The mixture was heated at 20 to 80°C for 2 hours to react, and after precipitation, the target product B01 was obtained.

[0032] 2. B01 and DOTA-NHS (NBS is N-hydroxysuccinimide) were dissolved in a DMSO solution in a ratio of 1:1 to 1:3, and 1 to 20 equivalents of triethylamine were added. The mixture was reacted at 10 to 40°C for 24 hours, and after precipitation, the target product B02 was obtained.

[0033] 3. B02 was reacted with 0.5 to 2 equivalents of gadolinium chloride hydrate in DMSO at 10 to 50°C for 10 to 50 hours, and after precipitation, the target product PL-001 was obtained with a yield of 83% and a purity of 91%.

[0034] 4. The resulting product was dissolved in purified water to prepare a solution. It was administered to ICR mice via tail vein injection at doses of 5 mg / kg and 30 mg / kg, respectively. Magnetic resonance T1-enhanced imaging (SE sequence) was performed on major slices of the mouse liver and kidney before and after administration. After magnetic resonance imaging was completed, the liver and kidney were removed and subjected to fluorescence imaging. The obtained images were analyzed using ImageJ software. The results are shown in Table 1. Figure A shows the magnetic resonance T1-enhanced imaging of the mouse treated with compound PL-001. The liver and kidney were significantly enhanced. Figure B shows a histogram of the mean T1-enhanced magnetic resonance imaging signal of the liver and kidney. Figure C shows a fluorescent imaging image of the liver and kidney 6 h after PL-001 administration. The liver and kidney showed obvious fluorescence. Figure D shows a histogram of the fluorescent efficiency values ​​of the liver and kidney. The figures reveal that the results of magnetic resonance T1-enhanced imaging and fluorescent imaging of the liver and kidney were nearly consistent.

[0035] Example 2: Preparation of Compound PL-002 [ka] Reaction Pathway: [ka] [ka]

[0036] Reaction steps: 1. IR-820 and sodium p-(sodium oxy)phenylpropionate were dissolved in DMSO in an equivalent ratio of 1:1 to 1:5, reacted at 20 to 80°C for 1 to 8 hours, and then precipitated to obtain the target intermediate C01.

[0037] 2. C01 and dipyrrolidinyl(N-succinimidyloxy)carbonium hexafluorophosphate were dissolved in DMSO in an equivalent ratio of 1:05 to 1:3, and 1 equivalent of N,N-diisopropylethylamine was added. The mixture was reacted at 10 to 50°C for 10 to 30 hours, and after precipitation, the target intermediate C02 was obtained.

[0038] 3. N-Boc-1,11-diamino-3,6,9-trioxaundecane and DOTA-NHS were dissolved in DMSO in a ratio of 1:1 to 1:3, and 1 to 3 equivalents of triethylamine were added. The mixture was allowed to react at room temperature for 24 hours, and after precipitation, the target intermediate D01 was obtained.

[0039] 4. D01 was added to a mixed solution of trifluoroacetic acid and dichloromethane, and the mixture was reacted at 0 to 40°C for 24 hours. After precipitation with ethyl ether, the target intermediate D02 was obtained.

[0040] 5. D02 and gadolinium chloride hydrate were dissolved in water in an equivalent ratio of 1:0.5 to 1:3, and the mixture was reacted at room temperature for 1 to 5 days. After purification by column chromatography, intermediate D03 was obtained.

[0041] 6. D03 and C02 were dissolved in DMSO in an equivalent ratio of 1:0.5 to 1:3, and 1 to 5 equivalents of N,N-diisopropylethylamine were added. The mixture was reacted at 0 to 50°C for 8 hours. After purification by column chromatography, the target product PL-002 was obtained with a purity of 91.2% and a yield of 55%.

[0042] Example 3: Preparation of compound PL-003 [ka] Reaction Pathway: [ka]

[0043] Reaction steps: N-Boc-1,10-diaminodecane and DOTA-NHS were dissolved in DMSO in a ratio of 1:1 to 1:3, and 1 to 3 equivalents of triethylamine were added. The mixture was allowed to react at room temperature for 24 hours, and after precipitation, the target intermediate E01 was obtained.

[0044] D01 was added to a mixed solution of trifluoroacetic acid and dichloromethane, and the mixture was reacted at 0 to 40°C for 24 hours. After precipitation with ethyl ether, the target intermediate E02 was obtained.

[0045] D02 and gadolinium chloride hydrate were dissolved in water in an equivalent ratio of 1:0.5 to 1:3, and reacted at room temperature for 1 to 5 days. After purification by column chromatography, intermediate E03 was obtained.

[0046] D03 and C02 were dissolved in DMSO in an equivalent ratio of 1:0.5 to 1:3, and 1 to 5 equivalents of N,N-diisopropylethylamine were added. The mixture was reacted at 0 to 50°C for 8 hours. After purification by column chromatography, the target product PL-003 was obtained with a purity of 96.3% and a yield of 51%. The HPLC spectrum is shown in Figure 5, and the data are shown in Table 1.

[0047] [Table 1]

[0048] The HPLC method was as follows: flow rate 0.8 mL / min, injection volume 10 μL, detection wavelength 254 nm, column Xtimate C 18 Welch 250 × 4.6 mm × 3 μm, eluent A 120 mM ammonium acetate + 5 mM citric acid solution (pH 6.0), eluent B acetonitrile, diluent methanol, and mobile phase gradient as follows:

[0049] [Table A]

[0050] Example 4: Preparation of compound PL-004 [ka] Reaction equation [ka]

[0051] Reaction Step N-Boc-2,2′-(ethylenedioxy)bis(ethylamine) and DOTA-NHS were dissolved in DMSO in a ratio of 1:1 to 1:3, and 1 to 3 equivalents of triethylamine were added. The mixture was allowed to react at room temperature for 24 hours, and after precipitation, the target intermediate F01 was obtained.

[0052] F01 was added to a mixed solution of trifluoroacetic acid and dichloromethane, and the mixture was reacted at 0 to 40°C for 24 hours. After precipitation with ethyl ether, the target intermediate F02 was obtained.

[0053] F02 and gadolinium chloride hydrate were dissolved in water in an equivalent ratio of 1:0.5 to 1:3, and reacted at room temperature for 1 to 5 days. After purification by column chromatography, intermediate F03 was obtained.

[0054] F03 and C02 were dissolved in DMSO in an equivalent ratio of 1:0.5 to 1:3, and 1 to 5 equivalents of N,N-diisopropylethylamine were added. The mixture was reacted at 0 to 50°C for 8 hours. After purification by column chromatography, the target product PL-003 was obtained with a purity of 93.3% and a yield of 43%.

[0055] Example 5: [ka] Reaction equation [ka]

[0056] Reaction Step N1-Boc-N4-N9-dimethylspermine and DOTA-NHS were dissolved in DMSO in a ratio of 1:1 to 1:3, and 1 to 3 equivalents of triethylamine were added. The mixture was allowed to react at room temperature for 24 hours, and after precipitation, the target intermediate J01 was obtained.

[0057] J01 was added to a mixed solution of trifluoroacetic acid and dichloromethane, and the mixture was reacted at 0 to 40°C for 24 hours. After precipitation with ethyl ether, the target intermediate J02 was obtained.

[0058] J02 and gadolinium chloride hydrate were dissolved in water in an equivalent ratio of 1:0.5 to 1:3, and reacted at room temperature for 1 to 5 days. After purification by column chromatography, intermediate J03 was obtained.

[0059] J03 and C02 were dissolved in DMSO in an equivalent ratio of 1:0.5 to 1:3, and 1 to 5 equivalents of N,N-diisopropylethylamine were added. The mixture was reacted at 0 to 50°C for 8 hours. After purification by column chromatography, the target product PL-005 was obtained.

[0060] In the following Table 2, the compounds obtained in Examples 6 to 13 were obtained by preparing them according to the method of Example 2 after changing the reaction intermediates.

[0061] [Table 2] JPEG0007814422000032.jpg235165JPEG0007814422000033.jpg171165

[0062] After obtaining PL-005, PL-008, and PL-013 through preparation, it was found that these compounds were easily soluble in highly polar organic solvents (e.g., methanol, N,N-dimethylformamide, dimethyl sulfoxide) and poorly soluble in water (<0.1 mg / mL).

[0063] Example 13 The longitudinal relaxation rates (r1) of the contrast agents were measured using an IR response sequence on a 0.35 T miniature nuclear magnetic resonance imaging system. The relaxation rates of the contrast agents in different solvents, pure water and bovine serum protein solution (1%, w / w), are shown in Table 3 below.

[0064] [Table 3]

[0065] Example 14 The contrast agent aqueous solution (0.1 mg / mL) was left at room temperature, and its relative content was calibrated by HPLC at different time points to measure its stability. The stability of the contrast agent is shown in Table 4.

[0066] [Table 4]

[0067] Example 15 The maximum tolerated dose (MTD) of the contrast agent was initially determined by tail vein administration in mice. Four ICR female mice (8 weeks old) were selected per group and administered 25, 50, 75, 100, 125, or 150 mg / kg of the contrast agent via the tail vein. Clinical observations were conducted continuously for one week. The results are shown in Table 5.

[0068] [Table 5]

[0069] Example 16 The cellular translocation rate of contrast agents was measured using a flow cytometer. Mouse-derived hepatoma cells H22 in logarithmic growth phase were uniformly spread onto a 12-well plate at approximately 1.5 x 10 cells per well. After 24 hours of cell adhesion, PBS, PL-002, PL-003, PL-004, and PL-006 were added to each well. After incubation for a set period, the cells were digested with pancreatic enzymes, washed twice with PBS, and finally resuspended in 0.5 mL of PBS. The cellular translocation rate was measured using a flow cytometer. As shown in Figure 2, PL-003 exhibited the fastest cellular translocation rate.

[0070] Example 17 Magnetic resonance imaging of liver intraepithelial neoplasia using contrast agents was completed using a GE 3.0T magnetic resonance imaging system. Balb / c mice were inoculated with H22 cells via local in situ liver injection, and the liver was monitored by magnetic resonance imaging. After tumor formation, 1 mg / mL of contrast agent solution (5 mL / kg) was injected through the tail vein. T1-enhanced magnetic resonance imaging of the liver was performed at different time points after administration. The results are shown in Figure 3. After injection of the contrast agent, the imaging effect at the tumor site was significantly enhanced, with PL-003 showing a relatively good overall enhancement effect.

[0071] Example 18 The liver intraepithelial tumor mouse tissue fluorescence was observed using a small animal bioimaging analyzer (Perkin Elmer). After magnetic resonance imaging, the major organs of the mouse were removed and observed using a bioimaging device. The results are shown in Figure 4. The contrast agent exhibited relatively clear fluorescence in the liver, and the main fluorescence spectrum was consistent with the magnetic resonance imaging results. Among them, PL-003 tumors were somewhat distinguishable from normal tissues, with relatively good fluorescence intensity. This spectrum indicates that the contrast agent of the present invention can effectively enhance the degree of differentiation between normal tissues and tumor tissues in imaging, thereby providing advantages for supporting preoperative planning and intraoperative fluorescence navigation.

Claims

1. A fluorescence-magnetic resonance bimodal imaging agent having the structure XLY, X is 【Chemistry 1】 having the structure L is a linking group; 【Chemistry 2】 having the structure A is O, L2 is composed of a carbon chain having a length of 8 to 20 carbon atoms, and a carbon atom in the carbon chain may be substituted with an oxygen atom, and the carbon chain may contain a double bond; Y is a metal chelate, and the metal chelate is complexed with Gd to form a Gd complex, and the Gd complex is 【Transformation 3】 A fluorescence-magnetic resonance bimodal imaging agent having the structure:

2. The structure of L is 【Chemistry 4】 and Said L ２ teeth, 【Transformation 5】 and n is 8 to 20. 【Request Item 3】 【Chemistry 6】 2. The fluorescence-magnetic resonance bimodal imaging agent of claim 1, wherein the compound is selected from the structure:

4. 1. A method for preparing a fluorescence-magnetic resonance bimodal imaging agent, comprising: The preparation method is a method for preparing a fluorescence-magnetic resonance bimodal contrast agent according to any one of claims 1 to 3, The fluorescence-magnetic resonance bimodal imaging agent III is obtained by condensing a compound of formula I with a compound of formula II, wherein said compound of formula II is 【Transformation 7】 and gadolinium chloride hydrate are complexed together, 【Transformation 8】 Y, A, and L ２ is the same as that of any one of claims 1 to 3, and Z is the Gd complex; Alternatively, the fluorescence-magnetic resonance bimodal imaging agent is obtained by complexing a compound of formula III-1 with gadolinium chloride hydrate, 【Chemistry 9】 The compound of formula III-1 is obtained by condensing a compound of formula I-2 with a compound of formula II-2, 【Chemistry 10】 A method for preparing a fluorescence-magnetic resonance bimodal imaging agent, wherein Y is defined as in any one of claims 1 to 3, and Z is the Gd complex.

5. Use of a fluorescence-magnetic resonance bimodal contrast agent in medical magnetic resonance enhanced imaging, in supporting preoperative planning, in intraoperative fluorescence navigation, in predicting fluorescence distribution in internal organs by magnetic resonance imaging, in measuring liver function, in measuring kidney function, in monitoring the status of internal circulation and labeled cells, and in preparing reagents for analytical labeling of cells in vitro, The use of said fluorescence-magnetic resonance bimodal imaging agent as defined in any one of claims 1 to 3.

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