Small-molecule contrast agent as well as preparation method and application thereof

Abstract

The invention relates to the technical field of small-molecule contrast agents, in particular to a small-molecule contrast agent and a preparation method thereof. According to the micromolecule contrast agent provided by the invention, a divalent glycosyl group is introduced into a binary triiodo-benzene ring structure, so that each molecule contains six iodine atoms (the theoretical iodine content reaches 48.7 wt%), the molecular weight is controlled to be 2000Da or below, the water solubility is remarkably improved, the viscosity is reduced, and the performance is superior to that of a traditional contrast agent. Preliminary CT imaging experiments show that under the same molar concentration, the average CT value generated by the contrast agent YJY-86-2 is obviously higher than that generated by iohexol, and the contrast agent shows stronger imaging contrast ability. The characteristic is expected to realize better image quality while reducing the dosage of administration and reducing the risk of iodine exposure, and provides a powerful candidate material for realizing high-sensitivity detection of early tumors.

Description

Technical Field

[0001] This invention relates to the field of small molecule contrast agent technology, and in particular to a small molecule contrast agent, its preparation method, and its application. Background Technology

[0002] X-ray computed tomography (CT) is an indispensable core technology in clinical imaging diagnosis. With its high spatial resolution (down to sub-millimeter level), rapid imaging capabilities, and wide organ coverage, it plays a crucial role in tumor screening, cardiovascular disease assessment, and emergency medicine. However, CT imaging inherently relies on differences in X-ray attenuation coefficients between tissues, and the natural contrast between most soft tissues (such as muscle, fat, and early-stage tumors) is low, severely limiting its sensitivity in detecting small lesions or functional abnormalities. Furthermore, CT examinations involve exposure to ionizing radiation, especially in patients undergoing multiple contrast-enhanced scans or in pediatric patients, where the cumulative radiation dose may pose a potential carcinogenic risk. Therefore, optimizing imaging efficiency and safety has become a pressing clinical challenge.

[0003] To enhance image contrast, intravenous injection of iodine-based contrast agents has become standard procedure in contrast-enhanced CT (CE-CT). Currently, widely used non-ionic small-molecule iodine contrast agents include iohexol, iopromide, and iopamidol, all with a core structure based on a triiodophenyl ring skeleton. These compounds have low solution viscosity, moderate osmotic pressure (close to physiological levels), good water solubility, and rapid renal clearance, thus exhibiting high short-term safety. However, their pharmacokinetic characteristics also have significant limitations: an extremely short blood circulation half-life (usually less than 30 minutes), with rapid excretion primarily through glomerular filtration, resulting in a narrow vascular phase contrast window. Therefore, high-pressure injection with a large dose is often required clinically to ensure sufficient contrast enhancement, but this inevitably increases the patient's total iodine load, thereby increasing the risk of contrast-induced nephropathy (CIN), especially in patients with renal insufficiency or diabetes. Meanwhile, some patients may experience allergic-like reactions or even severe hypersensitivity reactions, which further restricts its long-term or repeated use.

[0004] In recent years, researchers have attempted to couple the triiodobenzene backbone with polysaccharides, polymers, or peptides to prolong blood pool retention time and endow them with active targeting capabilities. However, most systems suffer from excessively high viscosity due to their large molecular weight, or have lengthy synthetic routes and significant batch-to-batch variations, hindering clinical translation.

[0005] Therefore, the existing technology still needs further improvement and enhancement. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the present invention aims to provide a small molecule contrast agent, which aims to embed a divalent sugar group into a binary triiodobenzene ring skeleton so that each molecule contains six iodine atoms, maintains a molecular weight of <2000 Da, and the contrast agent has better water solubility and viscosity than traditional formulations.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] Firstly, a small molecule contrast agent has the following structure:

[0009]

[0010] Secondly, a method for preparing the small molecule contrast agent described in the first aspect, comprising:

[0011] Will and The reaction yields a compound

[0012] The YJY-82-1 and The reaction yields a compound

[0013] YJY-83-1 was dissolved in dichloromethane, and a mixed solvent was added under ice-water bath conditions to obtain the compound.

[0014] The compound YJY-84-1 was combined with The reaction yields the small molecule contrast agent.

[0015] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. The purpose and beneficial effects of the present invention can be better achieved and realized through the following preferred technical solutions.

[0016] As a preferred technical solution, in the method for preparing the small molecule contrast agent, the reagents used in the reaction of compound 1 and compound 3 are HATU and N,N-diisopropylethylamine; the equivalent ratio of HATU to N,N-diisopropylethylamine is 1:2-3.

[0017] As a preferred technical solution, the method for preparing the small molecule contrast agent, wherein the compound YJY-82-1 reacts with the compound 2 to obtain the compound YJY-83-1, includes:

[0018] The compound YJY-82-1 was dissolved, and compound 2, HATU, and N,N-diisopropylethylamine were added to it to obtain a first reaction mixture;

[0019] The first reaction mixture was heated, and compound 2, HATU, and N,N-diisopropylethylamine were added to give compound YJY-83-1.

[0020] As a preferred technical solution, in the method for preparing the small molecule contrast agent, the first reaction mixture is heated to a temperature of 60-80°C.

[0021] As a preferred technical solution, in the method for preparing the small molecule contrast agent, the mixed solvent is a mixture of trifluoroacetic acid and dichloromethane, with a volume ratio of 1:1-2.

[0022] As a preferred technical solution, in the preparation method of the small molecule contrast agent, the equivalent ratio of the compound YJY-84-1 to the RSM3-disaccharide is 1:1-1.5.

[0023] Thirdly, a small molecule targeted contrast agent containing the small molecule contrast agent as described in the first aspect.

[0024] Beneficial Effects: Compared with existing technologies, the small molecule contrast agent provided by this invention, by embedding divalent glycosyl groups into a binary triiodobenzene ring backbone, ensures that each molecule contains six iodine atoms (theoretical iodine content 48.7 wt%) while maintaining a molecular weight <2000 Da. Its water solubility and viscosity are superior to traditional formulations. Preliminary CT experiments show that the average CT value of YJY-86-2 at equimolar concentrations is significantly higher than that of iohexol, indicating that better imaging contrast can still be obtained while reducing the dosage and iodine exposure, laying a material basis for subsequent early tumor detection. Attached Figure Description

[0025] Figure 1 The CT test results provided in this embodiment of the invention are for a small molecule contrast agent concentration of 27.5878 mmol / mL.

[0026] Figure 2 The results are CT test results provided in this embodiment of the invention, where the concentration of the small molecule contrast agent is 13.7939 mmol / mL. Detailed Implementation

[0027] It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other. The invention will now be described in detail with reference to the embodiments. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0028] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0029] Unless otherwise specifically stated, the relative arrangement, numerical expressions, and values ​​of the components and steps set forth in these embodiments do not limit the scope of the invention. Techniques, methods, and apparatus known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques, methods, and apparatus should be considered part of the specification. In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0030] The HPLC testing process involved in this invention includes:

[0031] The chromatographic conditions involved in HPLC are shown below:

[0032] Liquid chromatography system: Agilent LC system; Column: ZORBAX RR Eclipse Plus C18, 95A, 4.6 x 150 mm, 3.5 μm; Column temperature: 25 °C; Autosampler temperature: 25 °C; Injection volume: 5 μL; Mobile phase: (Aqueous phase: 0.1% formic acid aqueous solution, Organic phase: 0.1% formic acid in acetonitrile); Flow rate: 0.5 mL / min; Run time: 15 min; Gradients are shown in the table below:

[0033] Time (min) 0 2 13 15 % organic phase 5 50 95 95

[0034] Automatic syringe needle washing solution (F11): methanol.

[0035] The CT parameter conditions involved in this invention are as follows:

[0036] Tube voltage: 80kV; Tube current: 5mA; Beam filter: 1.5mm aluminum + 0.1mm copper; Scan angle: 360 degrees; Number of scan projections: 450; Distance from light source to detector (SDD) = 1320mm; Distance from light source to object (SOD) = 770mm; Detector model: Varex PaxScan 4343CB; X-ray tube model: Varex G-242; Image reconstruction pixel size: 0.2mm; Sample preparation: The target object was dissolved in water and placed in a 1.5mL centrifuge tube for CT scanning.

[0037] The following specific preparation examples will further explain and illustrate the small molecule contrast agent and its preparation method provided by the present invention.

[0038] Example 1

[0039] Step 1: Compound 3 (532 mg, 1.5 eq) was dissolved in DMF (20 mL). HATU (404 mg, 1.5 eq) and DIPEA (371 μL, 3 eq) were added at room temperature. Finally, compound 1 (500 mg, 1.0 eq) was added, and the mixture was heated to 50 °C and stirred for 5 hours. The synthetic route is as follows:

[0040]

[0041] The reaction products were analyzed using LCMS. Post-processing was performed after LCMS showed that the majority of the product was present. Here, "majority" refers to a product content typically exceeding 80%.

[0042] Post-processing included: pouring the reaction solution into 150 mL of water to obtain a white solid suspension, filtering, and drying the solid to obtain 800 mg of a near-white crude solid, YJY-82-1. LCMS (ESI): m / z Calcd for C 21 H 20 I6N3O7,[M+H] + :1187.6,found:1188.0.

[0043] Step 2: Dissolve YJY-82-1 (690 mg) in DMF (10 mL). At room temperature, add compound 2 (200 mg, 1.5 eq), HATU (331 mg, 1.5 eq), and DIPEA (305 μL, 3 eq). Heat to 70 °C and stir for 2 hours. Then add 66 mg of compound 2, 100 mg of HATU, and 100 μL of DIPEA. The synthetic route is as follows:

[0044]

[0045] The reaction products were detected by LCMS, and the LCMS showed the presence of the main product peak.

[0046] Add 200 mL of ice water to the reaction solution, then add 200 mL of ethyl acetate / methanol (10 / 1) for extraction and separation. Repeat this process 5-6 times. After washing the organic phase with saturated sodium chloride solution, dry it with anhydrous sodium sulfate and then evaporate it to dryness to obtain the crude product.

[0047] The crude product was purified by column chromatography (EA:PE = 0:1, 1:1, 3:2, 3:1, 4:1) to separate the product YJY-83-1 (290 mg) as a white solid.

[0048] LCMS(ESI): m / z Calcd for C 29 H 32 I6N3O 10 ,[M + H] + :1343.6,found:1344.0.

[0049] Step 3: Dissolve YJY-83-1 (0.29 g) in DCM (5 mL), and add TFA / DCM (1 / 1, 5 mL) to the stirred reaction mixture under ice bath conditions. Stir at room temperature for 0.5 hours. The synthetic route is as follows:

[0050]

[0051] The reaction products were detected by LCMS, and the LCMS showed that the reaction was complete.

[0052] After adding 50 mL of ethyl acetate and 10 mL of petroleum ether to the reaction solution, a white solid precipitated. After stirring for 30 minutes, the mixture was filtered to obtain product YJY-84-1 (0.24 g, crude), which was a white solid.

[0053] LCMS(ESI): m / z Calcd for C 25 H 24 I6N3O 10 [M+H] + :1287.6,found:1287.9.

[0054] In the fourth step, YJY-84-1 (190 mg, 1.0 eq) was dissolved in DMF (4 mL), and RSM3-disaccharide (96.2 mg, 1.2 eq), HATU (84 mg, 1.5 eq), and DIPEA (84 μL) were added to the reaction mixture. The reaction was stirred at room temperature for 1-2 hours. The synthetic route is as follows:

[0055] The reaction products were detected by LCMS, and the LCMS showed that the reaction was complete.

[0056] Add 40 mL of ethyl acetate to the reaction system. A large amount of white solid precipitates out. After 2 hours of slurrying, centrifuge the solid obtained. After purification by Pre-HPLC, freeze-dry the solid to obtain product YJY-86-2 (70 mg, 26.2% yield) as a white solid.

[0057] 1 H NMR (400MHz, d6-DMSO) δ8.57(d,J=19.2Hz,2H),8.40(d,J=1.7Hz,1H),8.26(d,J=33.2Hz,1H),8.09(d,J=7.6Hz,1H),7.88(s,1H),7. 84(s,1H),7.76(s,1H),5.48(s,2H),5.32(d,J=2.9Hz,1H),5.13(s,1H),5.01(dd,J=7.0,4.3Hz,2H),4.97-4.90(m,4H),4.55(dt,J= 12.9,6.4Hz,3H),4.40(d,J=11.3Hz,1H),4.28-4.22(m,1H),4.14(dd,J=7.7,2.3Hz,3H),4.04(s,2H),3.93(s,1H),3.75-3.65(m,5H ),3.45(dd,J=12.3,5.8Hz,5H),3.24(s,5H),3.17-3.02(m,7H),2.96(d,J=4.4Hz,2H),2.68(s,1H),2.62(s,1H),2.46-2.32(m,3H).

[0058] HRMS(ESI): m / z Calcd for C 45 H 58 I6N6O 23 Na, [M+H] + :1834.7714,found:1834.7681.

[0059] Experimental Example

[0060] In summary, this invention provides a small molecule contrast agent and its preparation method. Its structure is shown below:

[0061] The small-molecule contrast agent provided by this invention introduces a divalent glycosyl group into the binary triiodobenzene ring structure, ensuring that each molecule contains six iodine atoms (theoretically reaching 48.7 wt%) while controlling the molecular weight below 2000 Da. This significantly improves water solubility and reduces viscosity, resulting in superior performance compared to traditional contrast agents. Preliminary CT imaging experiments show that, at the same molar concentration, the contrast agent YJY-86-2 produces a significantly higher average CT value than iohexol, demonstrating stronger imaging contrast capability. This characteristic promises to achieve better image quality while reducing dosage and iodine exposure risk, providing a strong candidate compound basis for highly sensitive early tumor detection.

[0062] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A small molecule contrast agent, the structure of which is shown below:

2. The method for preparing the small molecule contrast agent according to claim 1, characterized in that, include: Will and The reaction yields a compound The YJY-82-1 and The reaction yields a compound YJY-83-1 was dissolved in dichloromethane, and a mixed solvent was added under ice-water bath conditions to obtain the compound. The compound YJY-84-1 was combined with The reaction yields the small molecule contrast agent.

3. The method for preparing the small molecule contrast agent according to claim 2, characterized in that, The reagents used in the reaction of compound 1 and compound 3 are HATU and N,N-diisopropylethylamine; the equivalent ratio of HATU to N,N-diisopropylethylamine is 1:2-3.

4. The method for preparing the small molecule contrast agent according to claim 2, characterized in that, The reaction of compound YJY-82-1 with compound 2 yields compound YJY-83-1, comprising: The compound YJY-82-1 was dissolved, and compound 2, HATU, and N,N-diisopropylethylamine were added to it to obtain a first reaction mixture; The first reaction mixture was heated, and compound 2, HATU, and N,N-diisopropylethylamine were added to give compound YJY-83-1.

5. The method for preparing the small molecule contrast agent according to claim 4, characterized in that, The first reaction mixture is heated to a temperature of 60-80°C.

6. The method for preparing the small molecule contrast agent according to claim 2, characterized in that, The mixed solvent is a mixture of trifluoroacetic acid and dichloromethane, with a volume ratio of 1:1-2.

7. The method for preparing the small molecule contrast agent according to claim 2, characterized in that, The equivalent ratio of compound YJY-84-1 to the RSM3-disaccharide is 1:1-1.

5.

8. A small molecule targeted contrast agent comprising the small molecule contrast agent as described in claim 1.

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