Novel liver and gall specificity contrast agent

Abstract

The invention provides a novel macrocyclic compound, a gadolinium chelate thereof, a method for preparing the compound and application of the compound as a magnetic resonance contrast agent. The compound has pertinence on magnetic resonance detection of liver focal lesions and can be used for liver specific imaging.

Description

Technical Field

[0001] This invention belongs to the field of magnetic resonance imaging diagnostics, and specifically relates to a series of target compounds that can be used for magnetic resonance imaging. Background Technology

[0002] Magnetic resonance imaging (MRI) is a technique that obtains electromagnetic signals through the magnetic resonance phenomenon of atomic nuclei under the influence of a magnetic field, and then uses computer technology and image reconstruction methods to create images. It provides non-invasive detection of lesions in the human body, produces no radiation, and has no other impact on the body. It has a unique advantage, especially in the detection of liver cancer, as it can provide high-contrast imaging patterns. However, MRI has relatively low detection sensitivity, and contrast agents are often used to enhance the detection signal and improve contrast.

[0003] Gadolinium contrast agents can be divided into linear and ring-shaped contrast agents. Years of clinical application and experience have shown that linear contrast agents have relatively low gadolinium complexation stability in vivo, with gadolinium deposition detected in various tissues. Furthermore, long-term use can cause complications such as renal systemic fibrosis. In contrast, ring-shaped contrast agents rarely exhibit these phenomena. Therefore, ring-shaped contrast agents are gradually replacing linear contrast agents, representing a trend in contrast agent development. However, regarding hepatobiliary-specific targeted contrast agents, currently only two are commercially available: gadoxetate disodium and gadobemycin, both of which are linear contrast agents. There are currently no commercially available hepatobiliary-specific ring-shaped contrast agents available clinically. Therefore, developing a stable hepatobiliary-specific MRI contrast agent is an urgent problem to be solved. Summary of the Invention

[0004] This invention provides a compound of formula (I), its stereoisomers, tautomers, pharmaceutically acceptable salts, nitrides, hydrates, solvates, prodrugs, deuterated derivatives, or mixtures thereof.

[0005] ALT

[0006] (I)

[0007] in,

[0008] A is a chelating group, which is a group capable of complexing metal ions. Preferably, the chelating group is a cyclic compound having one or more side chains; such a cyclic compound with one or more side chains may also be called a "macrocyclic ligand" or "macrocyclic chelate". L can be attached to any position of the chelating group; for example, L can be attached to the chelating group by substituting H or other substituents on the chelating group, or by reacting with certain active groups of the chelating group to form a new covalent bond and attaching to the chelating group.

[0009] L is selected from One end marked with * is connected to A;

[0010] T is an optional action by one or more Rs x The substituted benzene ring, said R x Each occurrence is independently selected from H, -C1-C3 alkyl, -OH, -CH2OH, -O-(CH2). n -R 3 n is selected from 0, 1, 2, R 3 Selected from H, -O-C2H5, -O-(CH2)2-O-C2H5, optionally by one or more R y Substituted benzene ring, wherein R y Each time it appears, it is independently selected from one or more of H, C1-C3 alkyl, C1-C4 alkoxy, halogenated C1-C3 alkyl, halogen, -NO2, triethylsilyl, acyl, sulfonyl, amino, alkylamino, ester, carboxyl, sulfonic acid, borate, phosphate, aryl, heteroaryl, for example, R y It can be H, -CH3, or -O(CH2). 0-3 One or more of the following: CH3, -NO2, -F, -CF3, -OCH2CF2CHF2, -CH2CF3, and triethylsilyl.

[0011] Preferably, the chelating group represented by A is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof. The derivative refers to one or more groups on DOTA optionally substituted with different groups, or one or more side chains of DOTA (i.e., acetic acid groups attached to the N atom on the macrocyclic backbone) missing, or both of the above. Specifically, the derivative of the chelating group includes one or more hydrogen atoms on DOTA optionally substituted with R... 1 The substitution occurs at any position in the DOTA macrocycle skeleton or sidechain, and the R 1 Each occurrence is independently selected from H, -C1-C6 alkyl groups, and -(CH2). h OH, -(CH2) i OHCH3, h is selected from 0, 1, 2, 3, 4, 5, i is selected from 1, 2, 3.

[0012] Furthermore, A can be R 1 Each occurrence is independently selected from H, -C1-C3 alkyl groups, and -(CH2). m OH, -CH2OHCH3, m is selected from 1, 2, 3;

[0013] In some embodiments, R 1 Each time it appears, it is independently selected from H and -CH2OH.

[0014] In some embodiments, A is

[0015] In some embodiments, A is

[0016] In some embodiments, A is

[0017] In some embodiments, L is

[0018] In some embodiments, L is

[0019] In some embodiments, R x Selected from -O-(CH2) n -R 3 n is selected from 1 and 2, R 3 Selected from H, -O-C2H5, -O-(CH2)2-O-C2H5, optionally by one or more R y Substituted benzene ring; wherein R y Each time it appears, it is independently selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, CF3, -OCH2CF2CHF2, -CH2CF3, F, Cl, Br, I, -NO2, triethylsilyl;

[0020] In some specific implementation schemes, R x Selected from -O-(CH2) n -R 3 n is selected from 1 or 2, R 3 Selected from the benzene ring, or by one or more R y Substituted benzene ring, wherein R y Each occurrence is independently selected from H, -CH3, and -O(CH2). 0-3 CH3, -NO2, -F, -CF3, -OCH2CF2CHF2, -CH2CF3, triethylsilyl.

[0021] In some specific implementation schemes, R x Selected from

[0022] The present invention also provides a compound of formula (II) or a stereoisomer, tautomer, pharmaceutically acceptable salt, nitride, hydrate, solvate, prodrug, deuterated product, or mixture thereof.

[0023]

[0024] Among them, L, A and R x As defined above.

[0025] In some embodiments, the compound represented by formula (I) may have the following structure:

[0026] Or its stereoisomers, tautomers, pharmaceutically acceptable salts, nitrogen oxides, hydrates, solvates, prodrugs, deuterated derivatives, or mixtures thereof.

[0027] The above-mentioned compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, nitrides, hydrates, solvates, prodrugs, deuterated products, or mixtures thereof provided by this invention are used to prepare metal-containing complexes, wherein the metal may be gadolinium, manganese, or iron.

[0028] The present invention also provides a metal complex, which is formed by chelating the above-mentioned compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, nitrogen oxides, hydrates, solvates, prodrugs, deuterated products, or mixtures thereof with metal ions, wherein the metal may be gadolinium, manganese, or iron.

[0029] The present invention also provides a gadolinium-containing compound, which is any of the aforementioned compounds and Gd 3+ The formed complex form, or its stereoisomers, tautomers, pharmaceutically acceptable salts, nitric oxides, hydrates, solvates, or mixtures thereof, prodrugs, deuterated products.

[0030] Specifically, this gadolinium-containing compound can have the following structure:

[0031]

[0032] Or its stereoisomers, tautomers, pharmaceutically acceptable salts, nitrogen oxides, hydrates, solvates, or mixtures thereof, prodrugs, or deuterated derivatives.

[0033] The compounds provided by this invention can be used for diagnostic imaging.

[0034] The compounds provided by this invention can be used in magnetic resonance imaging (MRI), especially for the hepatobiliary system, such as liver-specific MRI.

[0035] The compounds provided by this invention can be used to manufacture diagnostic reagents.

[0036] The compounds provided by this invention can be used to manufacture magnetic resonance imaging contrast agents.

[0037] The present invention also provides a pharmaceutical composition comprising the compound of the present application or its stereoisomers, tautomers, pharmaceutically acceptable salts, nitrides, hydrates, solvates, or mixtures thereof, prodrugs, and deuterated compounds.

[0038] The compounds of this invention include compounds of general formulas (I) and (II) and their stereoisomers, tautomers, pharmaceutically acceptable salts, nitrides, hydrates, solvates, or mixtures thereof, prodrugs, deuterated derivatives, and compounds of general formulas (I) and (II) with Gd. 3+ The complex forms formed, as well as their stereoisomers, tautomers, pharmaceutically acceptable salts, nitric oxides, hydrates, solvates, or mixtures thereof, prodrugs, and deuterated derivatives.

[0039] The compounds of this invention can be used as liver-specific MRI contrast agents to detect focal liver lesions in patients with known or suspected primary liver cancer (such as hepatocellular carcinoma, HCC) or metastatic disease. They exhibit good stability and high specific uptake in liver cells. Furthermore, the compounds of this invention show more significant and longer-lasting liver signal enhancement in C57BL / 6J mice than praximil, demonstrating superior resolution and sensitivity in the diagnosis of liver cancer or focal lesions, thus contributing to improved diagnostic accuracy. Attached Figure Description

[0040] Figure 1 Curve of liver enhancement rate (%) in C57BL / 6J mice

[0041] Figure 2 MRI imaging results (cross-sectional imaging of mouse liver) in C57BL / 6J mice in Examples 2 and 10.

[0042] Figure 3 Example 4: MRI imaging results in C57BL / 6J mice (cross-sectional imaging of mouse liver).

[0043] Figure 4 Example 12: MRI imaging results in C57BL / 6J mice (cross-sectional imaging of mouse liver). Detailed Implementation

[0044] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0045] Definitions and general descriptions:

[0046] "Substitution" refers to the replacement of hydrogen atoms in a molecule with other different atoms or groups.

[0047] Indicates the connection position of this group with other structures, such as The wavy line indicates the connection between the nitrogen atom in the nitrogen-containing butane ring and other groups.

[0048] "Alkyl" refers to a saturated hydrocarbon group consisting only of carbon and hydrogen atoms, with single bonds connecting carbon atoms and hydrogen atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as alkoxy, cyanoalkyl, aminoalkyl, hydroxyalkyl, etc.

[0049] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0050] “C m -C n "" indicates that the part modified by the term has mn carbon atoms (n is greater than m, and both are integers). For example, C1-C6 means that the modified part has 1-6 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. C1-C3 means that the modified part has 1-3 carbon atoms, such as 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0051] (CH2) x-y "This means that CH2 can be repeated x to y times, for example, (CH2) 0-5 It can represent the absence of CH2, or CH2, (CH2)2, (CH2)3, (CH2)4, (CH2)5.

[0052] "Halogenated C1-C3 alkyl" refers to a straight-chain or branched, saturated, monovalent hydrocarbon group in which one or more hydrogen atoms are replaced by halogen atoms in the same or different ways.

[0053] "C1-C3 alkoxy" refers to a straight-chain or branched, saturated, monovalent group of the formula (C1-C3 alkyl)-O-, such as methoxy, ethoxy, n-propoxy, or isopropoxy groups.

[0054] "Optional" or "optional" means that the events or circumstances described below are free to occur or not occur.

[0055] "Solvent compound" refers to a substance formed by combining the compounds of this invention with a pharmaceutically acceptable solvent. Solvent compounds include stoichiometric solvent compounds and non-stoichiometric solvent compounds. Some compounds of this invention may exist in either a non-solventized or solvated form. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0056] "Pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0057] "Pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, etc.

[0058] The compounds of this invention may contain one or more asymmetric centers, depending on the position and nature of the various substituents desired. The asymmetric carbon atom may exist in (R) or (S) configurations, which may produce racemic mixtures, mixtures in which one enantiomer is present in a larger amount than the other, or, in the case of a single asymmetric center, a single enantiomer. In the case of multiple stereocenters, mixtures of diastereomers, single diastereomers, or single enantiomers can be synthesized. In some cases, asymmetry may also exist due to rotational restriction around a given bond, axial chirality, or coordination of the metal center.

[0059] Isolated, pure, or partially purified isomers and stereoisomers, or mixtures of racemic or diastereomers of the compounds of this invention, are also included within the scope of this invention. The purification and isolation of these materials can be accomplished using standard techniques known in the art.

[0060] Optical isomers can be obtained by resolving racemic mixtures according to conventional methods, such as by forming diastereomer salts or covalent diastereomers using optically active acids or bases. Examples of suitable acids are tartaric acid, diacetyltartaric acid, benzoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers based on their physical and / or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomer salts. Different methods for separating optical isomers involve the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, which is optimally chosen to maximize enantiomeric separation. Enzymatic separation with or without derivatization is also useful. The optically active compounds of the present invention can also be obtained by chiral synthesis utilizing optically active starting materials and / or reagents and catalysts.

[0061] This invention includes all possible stereoisomers of the compounds of this invention, which are either single stereoisomers or any mixtures of said stereoisomers, such as R- or S-isomers or diastereomers in any proportion. The separation of single stereoisomers (e.g., single enantiomers or single diastereomers) of the compounds of this invention can be achieved by any suitable prior art method described herein, such as chromatography, particularly chiral chromatography.

[0062] abbreviation:

[0063] TLC stands for Thin-Layer Chromatography;

[0064] LCMS stands for Liquid Chromatography-Mass Spectrometry.

[0065] HPLC stands for High Performance Liquid Chromatography.

[0066] M refers to the molar concentration unit mol / L, for example, 2M means 2mol / L;

[0067] Boc represents tert-butyloxycarbonyl;

[0068] °C refers to degrees Celsius. Specific Implementation

[0070] Example 1: Synthesis of Gadolinium(III) 2,2',2'-(10-(carboxymethyl)-3-(4-ethoxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL1)

[0071]

[0072] Step 1: Synthesis of GdL1-2

[0073]

[0074] Weigh 20.0 g (57.5 mmol, 1.0 eq) of GdL1-1 and place it in a 1 L three-necked flask equipped with a stir bar. Add 400 mL of dichloromethane and stir to mix. Separately weigh 58.1 g (575 mmol, 10.0 eq) of triethylamine and add it to the system. Lower the system temperature to approximately 0 °C. Weigh 36.2 g (189.9 mmol, 3.3 eq) of p-toluenesulfonyl chloride, dissolve it in 200 mL of dichloromethane, and add it to the above system using a constant pressure dropping funnel. Control the temperature between 0 and 5 °C. After the addition is complete, slowly raise the system to room temperature and continue stirring overnight. Detect the reaction as complete by TLC / LCMS. Filter to remove the solids from the system. Wash the filtrate twice with 100 mL of 0.5 M dilute hydrochloric acid, wash the organic phase with sodium chloride (150 mL × 3), dry with anhydrous sodium sulfate, concentrate to obtain the crude product, and then perform column chromatography to obtain 38 g of the target product, with a yield of 94.5%.

[0075] MS(ESI)m / z(M+H) + =700.2.

[0076] Step 2: Synthesis of GdL1-4

[0077]

[0078] Weigh 17.85 g (100 mmol, 1.0 eq) of GdL1-3 and place it in a 500 mL round-bottom flask equipped with a stir bar. Add 300 mL of dichloromethane and mix. Add 32.25 g (250 mmol, 2.5 eq) of N-diisopropylethylamine to the system and stir at room temperature for 10 minutes. After complete dissolution, cool the system to 0–5 °C. Separately weigh 20 g (105 mmol, 1.05 eq) of p-toluenesulfonyl chloride and dissolve it in 100 mL of dichloromethane. Slowly add it to the above system using a constant pressure dropping funnel, controlling the system temperature at 0–5 °C. After the addition is complete, raise the system to room temperature and continue the reaction until GdL1-3 is completely converted. The reaction was confirmed to be complete by TLC. The system was washed twice with 100 mL of 0.5 M dilute hydrochloric acid, separated, and the organic phase was washed with saturated sodium chloride (150 mL × 3). The mixture was dried over anhydrous sodium sulfate, concentrated to remove the solvent, and then purified by column chromatography to obtain 30 g of the target product, with a yield of 98%.

[0079] MS(ESI)m / z(M+H) + =296.0

[0080] Step 3: Synthesis of GdL1-5

[0081]

[0082] Weigh 36 g (51.5 mmol, 1.0 eq) of GdL1-2 and 50.4 g of cesium carbonate into a 500 mL round-bottom flask equipped with a stir bar. Add 300 mL of N,N-dimethylacetamide and stir. Separately weigh 16.7 g (56.6 mmol, 1.1 eq) of GdL1-4 and 12.8 g (77.25 mmol, 1.5 eq) of potassium iodide and add them to the system. Heat the system to 100 °C and react overnight. The reaction was confirmed to be complete by TLC / LCMS. Add 300 mL of ethyl acetate and 1000 mL of water to the system, stir and separate the layers. Extract the aqueous phase with ethyl acetate (150 mL × 3). Combine the organic phases, wash with saturated sodium chloride (150 mL × 3), dry with anhydrous sodium sulfate, concentrate to remove the solvent, and give the crude product. Column chromatography yielded 15 g of the target product, with a yield of 31.5%.

[0083] MS(ESI)m / z(M+H) + =923.4.

[0084] 1 H NMR (400MHz, CDCl3) δ7.73–7.56(m,8H),7.32(t,J=7.1Hz,6H),7.10(d,J=7.4Hz,2H),6.91–6.79(m, 3H),6.65(d,J=8.5Hz,2H),5.00(d,J=5.5Hz,1H),4.51(dd,J=15.8,1.5Hz,1H),4.39(dd,J=9.3,1.5 Hz,1H),3.96(q,J=7.0Hz,2H),3.52(dt,J=15.6,7.1Hz,3H),3.29–3.05(m,8H),2.86(dd,J=14.4,6. 2Hz, 1H), 2.68 (dd, J=14.3, 7.2Hz, 1H), 2.42 (t, J=14.2, 8.2Hz, 9H), 2.32 (s, 3H), 1.43–1.39 (m, 3H).

[0085] Step 4: Synthesis of GdL1-6

[0086]

[0087] Weigh 1.87 g (2.03 mmol, 1.0 eq) of GdL1-5 and dissolve it in 50 mL of ultra-dry ethylene glycol dimethyl ether. Cool the system to 0–5 °C in an ice bath. Under nitrogen protection, slowly add 3.1 g (81.69 mmol, 40.33 eq) of lithium aluminum hydride to the system. Then raise the temperature to 90 °C and react for 5 hours. After cooling, pour the system into 50 mL of ice water. The system changes from gray to white. Centrifuge, collect the solid, dissolve it in 4 M hydrochloric acid, and wash with dichloromethane (20). 0 mL × 4), the aqueous phase was concentrated to obtain a solid, which was detected by LCMS as the target analyte. The obtained solid was dispersed in 10% sodium hydroxide solution, and 200 mL of dioxane was added and stirred. At the same time, 9.2 g of di-tert-butyl dicarbonate was added and stirred at room temperature. The main MS value of LCMS was 607, which is the MS value of the three "Boc" analytes. The system was diluted with ethyl acetate, separated, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 710 mg of "Boc" protected product.

[0088] The obtained product was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 hours. The reaction was confirmed to be complete by LCMS. The concentrated product was then used directly in the next reaction. The product was dissolved in 10 mL of DMF, and excess potassium carbonate (1.62 g, 11.7 mmol, 10 eq) and tert-butyl bromoacetate (1.14 g, 5.85 mmol, 5 eq) were added. The mixture was reacted at 50 °C for 3 hours. The reaction was confirmed to be complete by LCMS. The system was diluted with ethyl acetate and water, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Column chromatography yielded 480 mg of a pale yellow oil.

[0089] The oily substance was dissolved in 10 mL of 50% ethanol, and 528 mg (12.58 mmol, 20 eq) of lithium hydroxide monohydrate was added. The system was heated to 80 °C and reacted for 5 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by concentration, and the solution was dissolved in 5 mL of water. The pH was adjusted to about 7, and the solution was filtered through an ultrafiltration membrane. The filtrate was purified by HPLC to obtain 61 mg of GdL1-6.

[0090] MS(ESI)m / z(M+H) + =539.3.

[0091] Step 5: Synthesis of GdL1

[0092]

[0093] GdL1-6 was dissolved in 3 mL of water, and 42 mg (0.11 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The reaction was confirmed to be complete by LCMS. The pH of the system was adjusted to 7-8 with 10% sodium hydroxide solution, and then stirred at 100 °C for 30 minutes. After cooling, the mixture was filtered through an ultrafiltration membrane. The filtrate was purified by HPLC and lyophilized to obtain 13.7 mg of GdL1.

[0094] MS(ESI)m / z(M+H) + =694.2.

[0095] Example 2: Synthesis of Gadolinium(III) 2,2',2'-(10-(carboxymethyl)-3-(((4-ethoxybenzyl)oxy)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL2)

[0096]

[0097] Step 1: Synthesis of GdL2-3

[0098]

[0099] Weigh 25 g (171 mmol, 1.0 eq) of GdL2-1 into a 2 L round-bottom flask equipped with a stirrer, add 800 mL of anhydrous acetonitrile, and cool the system to 0–5 °C in an ice bath. Separately, weigh 15 g (171 mmol, 1.0 eq) of 2,3-butanedione and dissolve it in 80 mL of acetonitrile, then slowly add it dropwise to the system using a constant-pressure dropping funnel, controlling the temperature at 0–5 °C. After the addition is complete, continue stirring at 0–5 °C for 3 hours, and the reaction is confirmed to be complete by LCMS. Heat the system to 60 °C, add 47.2 g (342 mmol, 2.0 eq) of potassium carbonate and 52 g (238.7 mmol, 1.4 eq) of 2,3-dibromopropanol, and react overnight. The reaction is confirmed to be complete by LCMS. Concentrate the solution, remove the solvent, and obtain 20 g of GdL2-3 by column chromatography.

[0100] MS(ESI)m / z(M+H) + =253.2

[0101] Step 2: Synthesis of GdL2-4

[0102]

[0103] 20 g (79.2 mmol, 1.0 eq) of GdL2-3 was dissolved in 300 mL of concentrated hydrochloric acid. The system was heated to 100 °C and reacted for 4 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by concentration to obtain a black viscous substance, which was dissolved in 300 mL of ethanol and stirred at 60 °C for 1 hour. A large amount of solid was produced. The system was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (200 mL × 3). After drying, 13 g of GdL2-4 was obtained. The yield was 37%.

[0104] MS(ESI)m / z(M+H) + =203.3.

[0105] Step 3: Synthesis of GdL2-5

[0106]

[0107] 400 mg (1.15 mmol, 1.0 eq) of GdL2-4 was dissolved in 10 mL of N,N-dimethylformamide. 1.58 g (11.43 mmol, 10 eq) of potassium carbonate and 940 mg (4.82 mmol, 4.2 eq) of tert-butyl bromoacetate were added at room temperature. The system was heated to 50 °C and reacted for 3 hours. The reaction was confirmed to be complete by TLC / LCMS (a small amount of the reaction solution was quenched with hydrochloric acid before being sent as a sample). The mixture was diluted with 50 mL of ethyl acetate and 50 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to remove the solvent, yielding a crude product. This crude product was purified by column chromatography to obtain 742 mg of GdL2-5. The yield was 98%.

[0108] MS(ESI)m / z(M+H) + =659.5

[0109] Step 4: Synthesis of GdL2-6

[0110]

[0111] 700 mg (1.06 mmol, 1.0 eq) of GdL2-5 and 362 mg (2.12 mmol, 2.0 eq) of p-ethoxybenzyl chloride were dissolved in 10 mL of dichloromethane. Under ice bath conditions, 700 mg (2.3 mmol, 2.2 eq) of a 50% aqueous solution of cesium hydroxide and a catalytic amount of tetrabutylammonium iodide were added to the system, and the mixture was stirred overnight at room temperature. The system was diluted with 50 mL of ethyl acetate and 50 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, and concentrated to remove the solvent, yielding a crude product. This crude product was purified by column chromatography to give 550 mg of GdL2-6. The yield was 65%.

[0112] MS(ESI)m / z(M+H) + =793.5

[0113] Step 5: Synthesis of GdL2-7

[0114]

[0115] 550 mg (0.97 mmol, 1.0 eq) of GdL2-6 was dissolved in 20 mL of 50% ethanol aqueous solution. Then, 550 mg (13.1 mmol, 13.5 eq) of lithium hydroxide monohydrate was added. The mixture was reacted at 80 °C for 3 hours. LC-MS analysis confirmed the reaction was complete. The solvent was removed by concentration, and the solution was dissolved in 5 mL of water. The pH was adjusted to approximately 7, and the solution was purified by HPLC and lyophilized to obtain 105 mg of GdL2-7. The yield was 19%.

[0116] MS(ESI)m / z(M+H) + =569.3.

[0117] 1 H NMR (400MHz, D2O) δ7.38(d,J=7.6Hz,2H),7.03(d,J=8.0Hz,2H),4.60–4.48(m,2H),4.23–3.64(m,12H),3.61–2.78(m,15H),1.38(t,J=7.0Hz,3H).

[0118] Step 6: Synthesis of GdL2

[0119]

[0120] 105 mg (0.18 mmol, 1.0 eq) of GdL2-7 was dissolved in 5 mL of water. 69 mg (0.18 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using a 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 77 mg of GdL2. The yield was 59%.

[0121] MS(ESI)m / z(M+H) + =724.2.

[0122] Example 3: Synthesis of Gadolinium(III) 2,2',2'-(3-(benzyloxy)methyl)-10-(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL3)

[0123]

[0124] Step 1: Synthesis of GdL3-2

[0125]

[0126] 400 mg (0.61 mmol, 1.0 eq) of GdL2-5 and 210 mg (1.22 mmol, 2.0 eq) of benzyl bromide were dissolved in 10 mL of dichloromethane. Under ice bath conditions, 700 mg (2.3 mmol, 2.2 eq) of a 50% aqueous solution of cesium hydroxide and a catalytic amount of tetrabutylammonium iodide were added to the system, and the mixture was stirred overnight at room temperature. The system was diluted with 50 mL of ethyl acetate and 50 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, and concentrated to remove the solvent, yielding a crude product. This crude product was purified by column chromatography to give 344 mg of GdL3-2. Yield: 75%.

[0127] MS(ESI)m / z(M+H) + =749.5

[0128] Step 2: Synthesis of GdL3-3

[0129]

[0130] 344 mg (0.46 mmol, 1.0 eq) of GdL3-2 was dissolved in 20 mL of 50% ethanol aqueous solution. 207 mg (4.93 mmol, 10.5 eq) of lithium hydroxide monohydrate was added. The mixture was reacted at 90 °C for 3 hours. LC-MS analysis confirmed the reaction was complete. The solvent was removed by concentration, and the solution was dissolved in 5 mL of water. The pH was adjusted to approximately 7, and the solution was purified by HPLC and lyophilized to obtain 145 mg of GdL3-3. The yield was 60%.

[0131] MS(ESI)m / z(M+H) + =525.3.

[0132] 1 H NMR (400MHz, D2O) δ7.42–7.24(m,5H),4.57–4.38(m,2H),3.65(d,J=10.4Hz,1H),3.39(d,J=26.2Hz,1H),3.29–2.36(m,22H),2.30–2.13(m,1H).

[0133] Step 3: Synthesis of GdL3

[0134]

[0135] 140 mg (0.27 mmol, 1.0 eq) of GdL3-3 was dissolved in 5 mL of water. 101 mg (0.27 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using a 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 88 mg of GdL3. The yield was 48%.

[0136] MS(ESI)m / z(M+H) + =680.2.

[0137] Example 4: Synthesis of Gadolinium(III) 2,2',2'-(3-(((4-(benzyloxy)benzyl)oxy)methyl)-10-(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL4)

[0138]

[0139] Step 1: Synthesis of GdL4-2

[0140]

[0141] 340 mg (0.52 mmol, 1.0 eq) of GdL2-5 and 240 mg (1.04 mmol, 2.0 eq) of 4-benzyloxybenzyl chloride were dissolved in 10 mL of dichloromethane. 776 mg (2.59 mmol, 5.0 eq) of a 50% aqueous solution of cesium hydroxide and a catalytic amount of tetrabutylammonium iodide were added to the system under ice bath conditions, and the mixture was stirred overnight at room temperature. The system was diluted with 50 mL of ethyl acetate and 50 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, and concentrated to remove the solvent, yielding crude GdL4-2.

[0142] MS(ESI)m / z(M+H) + =855.5

[0143] Step 2: Synthesis of GdL4-3

[0144]

[0145] Crude GdL4-2 was dissolved in 20 mL of 50% ethanol aqueous solution. 218 mg (5.2 mmol, 10.0 eq) of lithium hydroxide monohydrate was added, and the mixture was reacted at 90 °C for 3 hours. The reaction was confirmed to be complete by LC-MS. The solvent was removed by concentration, and the solution was dissolved in 5 mL of water. The pH was adjusted to approximately 7, and the solution was purified by HPLC and lyophilized to obtain 237 mg of GdL4-3. The yield was 72%.

[0146] MS(ESI)m / z(M+H) + =631.3.

[0147] 1 H NMR (400MHz, D2O) δ7.54–7.36(m,7H),7.10(d,J=8.4Hz,2H),5.20(s,2H),4.57–4.49(m,2H),3.83–3.01(m,25H).

[0148] Step 3: Synthesis of GdL4

[0149]

[0150] 237 mg (0.37 mmol, 1.0 eq) of GdL4-3 was dissolved in 5 mL of water. 152 mg (0.37 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using a 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 76 mg of GdL4. The yield was 26%.

[0151] MS(ESI)m / z(M+H) + =786.2.

[0152] Example 5: Synthesis of Gadolinium(III) 2,2',2'-(10-(carboxymethyl)-3-(((4-(2-ethoxyethoxy)benzyl)oxy)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL5)

[0153] Step 1: Synthesis of GdL5-2

[0154]

[0155] 310 mg (0.47 mmol, 1.0 eq) of GdL2-5 and 202 mg (0.94 mmol, 2.0 eq) of 1-(chloromethyl)-4-(2-ethoxyethoxy)benzene were dissolved in 10 mL of dichloromethane. Under ice bath conditions, 1.1 g (3.67 mmol, 7.8 eq) of a 50% aqueous solution of cesium hydroxide and a catalytic amount of tetrabutylammonium iodide were added to the system, and the mixture was stirred overnight at room temperature. The system was diluted with 50 mL of ethyl acetate and 50 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, and concentrated to remove the solvent, yielding a crude product. This crude product was purified by column chromatography to give 300 mg of GdL5-2. Yield: 77%.

[0156] MS(ESI)m / z(M+H) + =837.6

[0157] Step 2: Synthesis of GdL5-3

[0158]

[0159] 300 mg (0.36 mmol, 1.0 eq) of GdL5-2 was dissolved in 20 mL of 50% ethanol aqueous solution. 151 mg (3.6 mmol, 10.0 eq) of lithium hydroxide monohydrate was added. The mixture was reacted at 90 °C for 3 hours. LC-MS analysis confirmed the reaction was complete. The solvent was removed by concentration, and the solution was dissolved in 5 mL of water. The pH was adjusted to approximately 7, and the solution was purified by HPLC and lyophilized to obtain 150 mg of GdL5-3. The yield was 68%.

[0160] MS(ESI)m / z(M+H) + =613.3.

[0161] 1 H NMR(400MHz,D2O)δ7.38(d,J=6.1Hz,2H),7.04(d,J=8.1Hz,2H),4.61–4.45(m,2H),4.22–4.07(m, 3H),4.02–3.70(m,10H),3.65(dd,J=14.1,7.0Hz,3H),3.59–2.81(m,15H),1.20(t,J=7.0Hz,3H).

[0162] Step 3: Synthesis of GdL5

[0163]

[0164] 150 mg (0.24 mmol, 1.0 eq) of GdL5-3 was dissolved in 5 mL of water. 88 mg (0.24 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using a 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 81 mg of GdL5. The yield was 44%.

[0165] MS(ESI)m / z(M+H) + =768.2.

[0166] Example 6: Synthesis of Gadolinium(III) 2,2',2'-(10-(carboxymethyl)-3-(((4-(2-(2-ethoxyethoxy)ethoxybenzyl)oxy)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL6)

[0167] Step 1: Synthesis of GdL6-2

[0168]

[0169] 340 mg (0.52 mmol, 1.0 eq) of GdL2-5 and 268 mg (1.04 mmol, 2.0 eq) of 1-(chloromethyl)-4-(2-(2-ethoxyethoxy)ethoxybenzene) were dissolved in 10 mL of dichloromethane. Under ice bath conditions, 840 mg (2.80 mmol, 5.4 eq) of 50% cesium hydroxide aqueous solution and a catalytic amount of tetrabutylammonium iodide were added to the system, and the mixture was stirred overnight at room temperature. The system was diluted with 50 mL of ethyl acetate and 50 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, and concentrated to remove the solvent, yielding a crude product. This crude product was purified by column chromatography to obtain 260 mg of GdL6-2. The yield was 57%.

[0170] MS(ESI)m / z(M+H) + =881.6

[0171] Step 2: Synthesis of GdL6-3

[0172]

[0173] 260 mg (0.30 mmol, 1.0 eq) was dissolved in 20 mL of 50% ethanol aqueous solution. 126 mg (3.0 mmol, 10.0 eq) of lithium hydroxide monohydrate was added to the solution. The mixture was reacted at 90 °C for 3 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by concentration, and the product was dissolved in 5 mL of water. The pH was adjusted to approximately 7. The solvent was removed by concentration to obtain crude GdL6-3, which was directly used in the next step of the reaction.

[0174] MS(ESI)m / z(M+H) + =657.3

[0175] 1 H NMR (400MHz, D2O) δ7.40(d,J=8.1Hz,2H),7.06(d,J=8.2Hz,2H),4.61–4.45(m,2H),4.30–4.19(m,2H),4.13–2.83(m,33H),1.18(t,J=7.1Hz,3H).

[0176] Step 3: Synthesis of GdL6

[0177]

[0178] Crude GdL6-3 was dissolved in 5 mL of water, and 147 mg (0.39 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 with 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 56 mg of GdL6. The two-step yield was 18%.

[0179] MS(ESI)m / z(M+H) + =812.3.

[0180] Example 7: Synthesis of Gadolinium(III) 2,2',2'-(10-(2-(4-hydroxy-3-methylphenyl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL7)

[0181]

[0182] Step 1: Synthesis of GdL7-1

[0183]

[0184] 17.2 g (100 mmol, 1.0 eq) of cyclohexane was dissolved in 300 mL of N,N-dimethylacetamide, and 27 g (330 mmol, 3.3 eq) of sodium acetate was added. The system was cooled to 0–5 °C and stirred for 10 minutes. Separately, 64.4 g (330 mmol, 3.3 eq) of tert-butyl bromoacetate was dissolved in 150 mL of N,N-dimethylacetamide and slowly added dropwise to the system using a constant pressure dropping funnel, controlling the temperature not to exceed 5 °C. After the addition was complete, the reaction was continued at 0–5 °C for 4 hours. A large amount of white solid was present in the system. 1000 mL of purified water was added to the system, controlling the temperature not to exceed 20 °C. The mixture was then filtered using a Buchner funnel. The filter cake was washed with purified water (200 mL × 3), and then dissolved in ethyl acetate by heating. After cooling and separation, hexane was added to the organic phase, and a large amount of solid precipitated. The solid was filtered, washed with hexane, and dried to obtain 47.6 g of GdL7-1, with a yield of 80%.

[0185] MS(ESI)m / z(M+H) + =515.5.

[0186] Step 2: Synthesis of GdL7-3

[0187]

[0188] Weigh 1.0 g (1.68 mmol, 1.0 eq) of GdL7-1 and dissolve it in 10 mL of N,N-dimethylacetamide. Add 0.69 g (5.04 mmol, 3.0 eq) of potassium carbonate and stir at room temperature for 10 minutes. Separately weigh 0.45 g (1.85 mmol, 1.1 eq) of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl-1-one (GdL7-2) and add it to the above system. React at room temperature for 3 hours. After the reaction is complete as detected by TLC, add 50 mL of ethyl acetate and 50 mL of water to dilute the system. Separately extract the aqueous phase with ethyl acetate (50 mL × 3). Combine the organic phases, wash with 100 mL of saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain crude GdL7-3, which can be used directly in the next reaction.

[0189] MS(ESI)m / z(M+H) + =679.4

[0190] Step 3: Synthesis of GdL7-4

[0191]

[0192] Crude GdL7-3 was dissolved in 20 mL of 50% ethanol aqueous solution, and 0.71 g (16.8 mmol, 10 eq) of lithium hydroxide monohydrate was added. The mixture was reacted at 90 °C for 5 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by concentration, and the product was dissolved in 10 mL of water. The pH was adjusted to approximately 7, and the solvent was removed by concentration to obtain the crude product. The crude product was purified by HPLC to obtain 530 mg of GdL7-4. The two-step yield was 61%.

[0193] MS(ESI)m / z(M+H) + =511.2.

[0194] 1 H NMR(400MHz,D2O)δ7.80(d,J=1.9Hz,1H),7.74(dd,J=8.5,2.1Hz,1H),6.86(d,J=8.5Hz,1H) ,4.56(s,2H),4.35(s,2H),3.73(s,4H),3.63(s,2H),3.50–3.27(m,8H),3.19–2.93(m,8H).

[0195] Step 4: Synthesis of GdL7

[0196]

[0197] 530 mg (1.04 mmol, 1.0 eq) of GdL7-4 was dissolved in 20 mL of water. 386 mg (1.04 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using a 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 418 mg of GdL7. The yield was 60%.

[0198] MS(ESI)m / z(M+H) + =666.2.

[0199] Example 8: Synthesis of Gadolinium(III) 2,2',2'-(10-(2-(4-hydroxy-3-(hydroxymethyl)phenyl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL8)

[0200]

[0201] Step 1: Synthesis of GdL8-2

[0202]

[0203] Weigh 5.0 g (33.3 mmol, 1.0 eq) of 4-hydroxy-3-methylacetophenone (GdL8-1) and dissolve it in 100 mL of chloroform. Then, use a constant pressure dropping funnel to add it to boiling ethyl acetate and 14.9 g of copper bromide.

[0204] The mixture of (66.6 mmol, 2.0 eq) was refluxed overnight. The reaction was confirmed to be complete by TLC / LCMS. After cooling, the mixture was filtered through diatomaceous earth, decolorized by activated carbon, concentrated to remove solvent, and then purified by column chromatography to obtain 4.3 g of the target product, with a yield of 58%.

[0205] MS(ESI)m / z(M+H) + =229.0, 231.0.

[0206] Step 2: Synthesis of GdL8-3

[0207]

[0208] Weigh 1.0 g (1.68 mmol, 1.0 eq) of GdL7-1 and dissolve it in 10 mL of N,N-dimethylacetamide. Add 0.69 g (5.04 mmol, 3.0 eq) of potassium carbonate and stir at room temperature for 10 minutes. Separately weigh 0.42 g (1.85 mmol, 1.1 eq) of GdL8-2 and add it to the above system. React at room temperature for 4 hours. After the reaction is complete as detected by TLC, dilute the system with 50 mL of ethyl acetate and 50 mL of water. Separately extract the aqueous phase with ethyl acetate (50 mL × 3). Combine the organic phases, wash with 100 mL of saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain crude GdL8-3, which can be used directly in the next reaction.

[0209] MS(ESI)m / z(M+H) + =663.4

[0210] Step 3: Synthesis of GdL8-4

[0211]

[0212] Crude GdL7-3 was dissolved in 20 mL of 50% ethanol aqueous solution, and 0.71 g (16.8 mmol, 10 eq) of lithium hydroxide monohydrate was added. The mixture was reacted at 90 °C for 5 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by concentration, and the product was dissolved in 10 mL of water. The pH was adjusted to approximately 7, and the solvent was removed by concentration to obtain the crude product. The crude product was purified by HPLC to obtain 650 mg of GdL8-4. The two-step yield was 78%.

[0213] MS(ESI)m / z(M+H) + =495.2.

[0214] 1 H NMR(400MHz,D2O)δ7.67(s,1H),7.62(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),4.3 6(s,2H),3.77(s,4H),3.67(s,2H),3.38(s,8H),3.25–2.97(m,8H),2.13(s,3H).

[0215] Step 4: Synthesis of GdL8

[0216]

[0217] 650 mg (1.32 mmol, 1.0 eq) of GdL8-4 was dissolved in 20 mL of water. 489 mg (1.32 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using a 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 536 mg of GdL8. The yield was 62%.

[0218] MS(ESI)m / z(M+H) + =650.2.

[0219] Example 9: Synthesis of Gadolinium(III) 2,2',2'-(10-(3-(4-ethoxyphenyl)-2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL9)

[0220]

[0221] Step 1: Synthesis of GdL9-2

[0222]

[0223] 7.4 g (50 mmol, 1.0 eq) of 4-allyl anisole (GdL9-1) was weighed and dissolved in 50 mL of dichloromethane. The system was cooled to 0–5 °C, and 55 mL of boron tribromide (1 M / DCM, 55 mmol, 1.1 eq) was slowly added dropwise, controlling the temperature not to exceed 5 °C. After the addition was complete, the system was allowed to continue reacting at 0 °C for 4 hours. The reaction was confirmed to be complete by TLC. The system was quenched with ice water, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 6.6 g of GdL9-2. The yield was 98%.

[0224] MS(ESI)m / z(M+H) + =133.0.

[0225] Step 2: Synthesis of GdL9-3

[0226]

[0227] 3.3 g (24.6 mmol, 1.0 eq) of GdL9-2 was weighed and dissolved in 50 mL of N,N-dimethylacetamide. 6.79 g (49.2 mmol, 2.0 eq) of potassium carbonate and 4.22 g (27.1 mmol, 1.1 eq) of iodoethane were added sequentially at room temperature. The mixture was then reacted overnight at room temperature. The reaction was monitored by TLC until complete. The system was diluted with 100 mL of ethyl acetate and 200 mL of water. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 3.0 g of GdL9-3. The yield was 75%.

[0228] 1 H NMR(400MHz, CDCl3)δ7.12–7.03(m,2H),6.86–6.78(m,2H),6.03–5.86(m,1H), 5.11–4.98(m,2H),4.07–3.95(m,2H),3.32(d,J=6.7Hz,2H),1.46–1.34(m,3H).

[0229] Step 3: Synthesis of GdL9-4

[0230]

[0231] 3.0 g (18.49 mmol, 1.0 eq) of GdL9-3 was dissolved in 50 mL of dichloromethane. 5.0 g (24.63 mmol, 1.33 eq) of m-chloroperoxybenzoic acid was added under ice bath conditions. The reaction was carried out at room temperature for 2 hours, and LC-MS analysis confirmed complete reaction. 50 mL of saturated sodium thiosulfate solution and 50 mL of saturated sodium bicarbonate solution were added to the system, and the mixture was stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give 1.6 g of GdL9-4. Yield: 48%.

[0232] MS(ESI)m / z(M+H) + =179.1.

[0233] Step 4: Synthesis of GdL9-5

[0234]

[0235] 20 g (33.6 mmol, 1.0 eq) of GdL7-1 was weighed and dissolved in a 50% aqueous ethanol solution. 6.35 g (151.3 mmol, 4.5 eq) of lithium hydroxide monohydrate was added to the solution. The system was heated to 90 °C and reacted for 5 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by concentration, and the product was crystallized from water and isopropanol to obtain 8.4 g of GdL9-5, with a yield of 68%.

[0236] MS(ESI)m / z(M+H) + =347.2.

[0237] Step 5: Synthesis of GdL9-6

[0238]

[0239] 650 mg (1.78 mmol, 1.0 eq) of GdL9-5 was weighed and dissolved in 10 mL of 50% ethanol aqueous solution. 410 mg (2.3 mmol, 1.3 eq) of GdL9-4 was added to the solution. The system was heated to 50 °C and reacted overnight. The reaction was confirmed to be complete by LCMS. The pH of the system was adjusted to about 7 with dilute hydrochloric acid, and the solution was concentrated to a volume of about 5 mL. After purification by HPLC, 505 mg of GdL9-6 was obtained, with a yield of 54%.

[0240] MS(ESI)m / z(M+H) + =525.3.

[0241] 1 H NMR(400MHz,D2O)δ7.18(d,J=8.5Hz,2H),6.91(d,J=8.5Hz,2H),4.15–3.99(m,3H),3.51(d,J=9.3Hz,2 H),3.47–3.35(m,4H),3.23–2.91(m,17H),2.72(ddd,J=32.2,13.7,6.8Hz,3H),1.31(t,J=7.0Hz,3H).

[0242] Step 6: Synthesis of GdL9

[0243]

[0244] 505 mg (0.96 mmol, 1.0 eq) of GdL9-6 was dissolved in 20 mL of water. 357 mg (0.96 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using a 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, and filtered through an ultrafiltration membrane. The filtrate was purified by HPLC to obtain 365 mg of GdL9. The yield was 56%.

[0245] MS(ESI)m / z(M+H) + =680.2.

[0246] Example 10: Synthesis of Gadolinium(III) 2,2',2'-(10-(3-(4-(benzyloxy)phenyl)-2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL10)

[0247]

[0248] Step 1: Synthesis of GdL10-1

[0249]

[0250] 3.0 g (22.36 mmol, 1.0 eq) of GdL9-2 was weighed and dissolved in 50 mL of N,N-dimethylacetamide. 6.1 g (44.7 mmol, 2.0 eq) of potassium carbonate and 4.0 g (23.48 mmol, 1.05 eq) of benzyl bromide were added sequentially at room temperature. The mixture was then reacted overnight at room temperature. The reaction was monitored by TLC until complete. The system was diluted with 100 mL of ethyl acetate and 200 mL of water. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 3.4 g of GdL10-1. The yield was 68%.

[0251] MS(ESI)m / z(M+H) + =225.1

[0252] Step 2: Synthesis of GdL10-2

[0253]

[0254] 1.8 g (8.02 mmol, 1.0 eq) of GdL10⁻¹ was dissolved in 50 mL of dichloromethane. 2.0 g (9.85 mmol, 1.23 eq) of m-chloroperoxybenzoic acid was added under ice bath conditions. The reaction was allowed to proceed overnight at room temperature. TLC analysis confirmed the reaction was complete. 50 mL of saturated sodium thiosulfate solution and 50 mL of saturated sodium bicarbonate solution were added to the system, and the mixture was stirred for 30 minutes. The mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give 1.2 g of GdL10⁻². Yield: 63%.

[0255] MS(ESI)m / z(M+H) + =241.1

[0256] Step 3: Synthesis of GdL10-3

[0257]

[0258] 650 mg (1.78 mmol, 1.0 eq) of GdL9-5 was weighed and dissolved in 10 mL of 50% ethanol aqueous solution. 428 mg (1.78 mmol, 1.0 eq) of GdL10-2 was added to the solution. The system was heated to 50 °C and reacted overnight. The reaction was confirmed to be complete by LCMS. The pH of the system was adjusted to about 7 with dilute hydrochloric acid, and the solution was concentrated to a volume of about 5 mL. After purification by HPLC, lyophilized the solution to obtain 590 mg of GdL10-3, with a yield of 57%.

[0259] MS(ESI)m / z(M+H) + =587.3.

[0260] 1 H NMR(400MHz,D2O)δ7.32–7.17(m,5H),7.02(d,J=8.5Hz,2H),6.82(d,J=8.6Hz,2H),4.9 3(s,2H),3.84–3.71(m,1H),3.07–2.90(m,4H),2.89–2.76(m,2H),2.68–1.90(m,20H).

[0261] Step 4: Synthesis of GdL10

[0262]

[0263] 316 mg (0.54 mmol, 1.0 eq) of GdL10⁻³ was weighed and dissolved in 10 mL of water. 220 mg (0.59 mmol, 1.1 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to 7–8 with 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 41.7 mg of GdL10. The yield was 10%.

[0264] MS(ESI)m / z(M+H) + =742.2.

[0265] Example 11: Synthesis of Gadolinium(III) 2,2',2'-(10-(3-(4-(benzyloxy)phenyl)-2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tris(3-hydroxypropionate) (GdL11)

[0266]

[0267] Step 1: Synthesis of GdL11-1

[0268]

[0269] 3 mL (23.7 mmol, 1.0 eq) of methyl 2,3-epoxypropionate was dissolved in 3 mL (52.65 mmol, 2.2 eq) of tert-butanol. Under nitrogen protection, 2.0 g (8.97 mmol, 0.38 eq) of magnesium perchlorate was added, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solution was diluted with 50 mL of dichloromethane and 50 mL of water, and the mixture was separated. The aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated ammonium chloride and 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 3.6 g of GdL11-1. Yield: 86%.

[0270] MS(ESI)m / z(M+H) + =177.1

[0271] Step 2: Synthesis of GdL11-2

[0272]

[0273] Weigh 6.0 g (34.1 mmol, 1.0 eq) of GdL11-1 and 5.5 g (51.1 mmol, 1.5 eq) of 2,6-dimethylpyridine and dissolve them in 60 mL of dichloromethane. Cool the system to -78 °C. Separately weigh 11.5 g (40.8 mmol, 1.2 eq) of trifluoromethanesulfonic anhydride and dissolve it in 20 mL of dichloromethane. Slowly add the solution dropwise to the system using a constant pressure dropping funnel. Continue the reaction at -78 °C for 3 hours. Wash the system with 30 mL of 1 M hydrochloric acid and 30 mL of saturated brine. Dry the system with anhydrous sodium sulfate and concentrate to remove the solvent to obtain GdL11-2 for later use.

[0274] Step 3: Synthesis of GdL11-3

[0275]

[0276] Weigh 50 mg (0.29 mmol, 1.0 eq) of cyclohexane and 42 mg (0.17 mmol, 0.6 eq) of GdL10-2 and dissolve them in 50% aqueous ethanol solution. React overnight at room temperature. LCMS was used to determine if the reaction of GdL10-2 was complete. The solvent was removed by concentration to obtain crude GdL11-3, which was directly used in the next step of the reaction.

[0277] MS(ESI)m / z(M+H) + =413.3

[0278] Step 4: Synthesis of GdL11-4

[0279]

[0280] Crude GdL11-3 was dissolved in 5 mL of acetonitrile. 536 mg (1.74 mmol, 6.0 eq) of GdL11-2 and 480 mg (3.48 mmol, 12.0 eq) of potassium carbonate were added sequentially at room temperature. The system was then reacted at 50 °C for 5 hours. The reaction was confirmed to be complete by LC-MS. The system was diluted with 20 mL of ethyl acetate and 20 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude GdL11-4, which was directly used in the next reaction.

[0281] MS(ESI)m / z(M+H) + =887.6

[0282] Step 5: Synthesis of GdL11-5

[0283]

[0284] The crude GdL11-4 was dissolved in 10 mL of dichloromethane. 5 mL of trifluoroacetic acid was added to the system, and the mixture was stirred at room temperature until GdL11-4 was completely converted. The solvent was removed by concentration, and the mixture was dissolved again in 50% aqueous ethanol solution. The pH of the system was adjusted to about 12 with lithium hydroxide monohydrate, and then stirred at room temperature until the intermediate was completely converted. The solvent was removed by concentration, and the mixture was purified by HPLC to obtain 10 mg of GdL11-5. The overall yield of the 5 steps was 5%.

[0285] MS(ESI)m / z(M+H) + =677.3.

[0286] 1 H NMR(400MHz,D2O)δ7.56–7.39(m,5H),7.30–7.22(m,2H),7.10–7.03(m,2H ),5.18(s,2H),4.44–4.28(m,1H),4.25–2.93(m,27H),2.89–2.76(m,2H).

[0287] Step 6: Synthesis of GdL11

[0288]

[0289] 10 mg (0.015 mmol, 1.0 eq) of GdL11-5 was dissolved in 3 mL of water. 5.5 mg (0.015 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added. The pH of the system was adjusted to approximately 7–8 using 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, and filtered through an ultrafiltration membrane. The filtrate was purified by HPLC to obtain 4.7 mg of GdL11. The yield was 37%.

[0290] MS(ESI)m / z(M+H) + =832.2.

[0291] Example 12: Synthesis of Gadolinium(III) 2,2',2”-(10-(2-(4-(benzyloxy)phenyl)-1-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (GdL12)

[0292]

[0293] Step 1: Synthesis of GdL12-1

[0294]

[0295] Weigh 27.1 g (100 mmol, 1.0 eq) of O-benzyl-L-tyrosine and dissolve it in 200 mL of purified water. Add 100 g (48% aqueous solution, 600 mmol, 6 eq) of hydrobromic acid to the solution. Cool the system to 0–5 °C. Separately, dissolve 6.9 g (100 mmol, 1.0 eq) of sodium nitrite in 50 mL of purified water and slowly add it dropwise to the above system using a constant pressure dropping funnel, keeping the system temperature below 5 °C. After the addition is complete, continue the reaction at 0–5 °C. After 2 hours, 20.6 g (200 mmol, 2.0 eq) of sodium bromide was added to the system, and then the system was moved to room temperature and reacted for 5 hours. The reaction was confirmed to be complete by TLC / LCMS. 200 mL of ethyl acetate was added to the system, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with 200 mL of saturated sodium bicarbonate and 200 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude GdL12-1, which was used directly in the next reaction.

[0296] MS(ESI)m / z(M+H) + =335.0.

[0297] Step 2: Synthesis of GdL12-2

[0298]

[0299] Crude GdL12-1 was dissolved in 300 mL of anhydrous ethanol, and a few drops of concentrated sulfuric acid were added. The system was then heated to reflux until GdL12-1 was completely converted. The solvent was removed by concentration, and 200 mL of purified water and 200 mL of ethyl acetate were added. The mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and washed with 200 mL of saturated sodium bicarbonate solution and 200 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by concentration to obtain the crude product. The crude product was purified by column chromatography to obtain 15 g of GdL12-2, with a yield of 41%.

[0300] MS(ESI)m / z(M+H) + =363.1

[0301] Step 3: Synthesis of GdL12-3

[0302]

[0303] Weigh 500 mg (2.9 mmol, 1.0 eq) of cyclohexane and dissolve it in 10 mL of acetonitrile. Add 488 mg (5.8 mmol, 2.0 eq) of sodium bicarbonate to the solution and cool the system to 0–5 °C. Separately, dissolve 1.95 g (5.8 mmol, 2.0 eq) of GdL12-2 in 10 mL of acetonitrile and add it to the system. Then react at room temperature overnight. Dilute the system with 50 mL of purified water and wash with petroleum ether / ethyl acetate (1:1) (50 mL × 3). Concentrate the aqueous phase under reduced pressure to obtain 710 mg of crude GdL12-3, which can be used directly in the next step of the reaction.

[0304] MS(ESI)m / z(M+H) + =455.3.

[0305] Step 4: Synthesis of GdL12-4

[0306]

[0307] 710 mg (1.56 mmol, 1.0 eq) of crude GdL12-3 was dissolved in 10 mL of acetonitrile. 1.2 g (11.3 mmol, 7.3 eq) of sodium carbonate was added to the system, followed by 1.5 g (7.81 mmol, 5.0 eq) of tert-butyl bromoacetate at room temperature. The mixture was reacted overnight at room temperature, and TLC was used to determine the completeness of the reaction. The system was diluted with 50 mL of ethyl acetate and 50 mL of water, separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, and concentrated to remove the solvent, yielding 1.1 g of crude GdL12-4, which was used directly in the next reaction.

[0308] MS(ESI)m / z(M+H) + =797.5

[0309] Step 5: Synthesis of GdL12-5

[0310]

[0311] Weigh 500 mg (0.63 mmol, 1.0 eq) of crude GdL12-4 and dissolve it in a 50% aqueous ethanol solution. Add 500 mg (12.5 mmol, 20 eq) of sodium hydroxide to the solution and heat the system to 50 °C for 3 hours. LCMS analysis showed that the reaction was complete. Concentrate the solution to remove the solvent and obtain crude GdL12-5, which can be used directly in the next step of the reaction.

[0312] MS(ESI)m / z(M+H) + =639.2.

[0313] 1 H NMR (400MHz, D2O) δ7.38–7.16(m,7H),6.92(d,J=7.2Hz,2H),4.97(s,2H),4.07(s,1H),3.90–3.55(m,5H),3.46–2.67(m,19H).

[0314] Step 6: Synthesis of GdL12

[0315]

[0316] Crude GdL12-5 was dissolved in 10 mL of water, and the pH was adjusted to about 5 with 1 M hydrochloric acid. 297 mg (0.63 mmol, 1.0 eq) of gadolinium chloride hexahydrate was added, and the pH of the system was adjusted to about 7-8 with 10% sodium hydroxide solution. The mixture was then stirred at 100 °C for 30 minutes, cooled, filtered through an ultrafiltration membrane, and the filtrate was purified by HPLC and lyophilized to obtain 65 mg of GdL12. The three-step yield was 14%.

[0317] MS(ESI)m / z(M+H) + =756.2.

[0318] Test Example 1: Compound Uptake by Primary Mouse Hepatocytes

[0319] Part 1: Extraction of primary hepatocytes from C57BL / 6J mice

[0320] method

[0321] Mouse cannulation and perfusion

[0322] Prepare perfusion buffer 1 and digestion buffer 2 as follows:

[0323] Perfusion buffer 1: Hank's balanced salt solution: free of phenol red and Ca2+ 2+ Mg 2+ It contains 0.5 mM ethylenediaminetetraacetic acid and 25 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid;

[0324] Digestion Buffer 2: Hank's Balanced Salt Solution: Contains phenol red and Ca2+ 2+ Mg 2+ It contains 25 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, and 10 mL contains 250 μl of digestive enzyme when digesting cells.

[0325] Preheat the above-mentioned buffer solution. Fix the anesthetized mouse on the dissection table, disinfect the abdomen by wiping it with alcohol, open the abdomen through the groin, and move the intestine to the right to fully expose the portal vein and inferior vena cava. Insert the needle into the inferior vena cava of the mouse and begin perfusion with perfusion buffer 1. White spots should be seen forming on the liver or the portal vein should be filled. After white spots appear on the liver and / or the inferior vena cava is filled, immediately cut open the portal vein, and immediately remove the blood from the liver. The liver will quickly turn yellowish-white. This perfusion process should fill the entire liver with perfusion buffer 1.

[0326] Hepatocyte digestion

[0327] After perfusion with buffer 1, digestion buffer 2 was perfused into the mouse liver. After perfusion with digestion buffer 2, the liver was separated from other organs and removed, placed in digestion buffer 2 without digestive enzymes, and placed on ice for the next step.

[0328] Hepatocyte purification

[0329] Transfer the liver cells to a cell culture dish, add an appropriate amount of untreated digestion buffer 2, tear open the liver capsule, and repeatedly crush the liver tissue with a cell scraper to fully release the hepatocytes; filtration is performed using a 50 mL sterile BD tube and a 70 μm cell sieve; add an appropriate amount of untreated digestion buffer 2 to the cell culture dish again, wash away the remaining hepatocytes, filter, and centrifuge at 4°C for 3 minutes; discard the supernatant, add 10 mL of DuPont modified Eagle medium (1% penicillin and streptomycin, 5% fetal bovine serum), and thoroughly invert the BD tube to resuspend the cells; add 10 mL of Percoll separation buffer (90% Percoll, 1× phosphate buffer), and gently invert the BD tube 15 times to mix completely. Centrifuge at 4°C for 10 minutes; discard the supernatant, add 20 mL of DuPont modified Eagle medium, invert and resuspend thoroughly, centrifuge at 4°C for 2 minutes, resuspend the cells again, take 20 μL of the cell suspension, add 20 μL of 0.2% trypan blue staining solution, count the cells, seed in 6-well plates, 5 × 10⁵ cells per well.

[0330] Part 2: Compound uptake by mouse primary hepatocytes

[0331] method

[0332] Preparation of test solution

[0333] The test solution was prepared at a concentration of 0.25 mM. Prucalopyr and gadobenzamide were used as positive controls, and gadoterol was used as a negative control. Gibco was used as the solvent for dissolving the compounds. TM William's E medium (containing 1% glutamine, 1% penicillin and streptomycin, and 5% fetal bovine serum).

[0334] Uptake of compounds by mouse primary hepatocytes

[0335] Primary mouse hepatocytes (first part extraction) were extracted from a CO2 incubator. Cell count (cell viability > 70%) and morphology (adherent and uniform growth) were observed. Cells were labeled according to their sample numbers on 6-well plates. The culture medium was discarded, and 2 mL of the corresponding sample solution was added. The cells were then incubated in a CO2 incubator for 6 hours. After incubation, the 6-well plates were removed, the added sample solution was discarded, and the cells were gently washed three times with an appropriate amount of phosphate-buffered saline (PFS) buffer. 300 μL of 0.01% Triton X-100 was added. X-100 lysis buffer was placed on ice and shaken for 1 hour. Cells were then scraped off and the lysed mixture was collected. The collected solution was centrifuged at 4°C for 15 minutes, and 1 μL of the supernatant was used for protein concentration quantification using the dioctanine method (denoted as A). Protein absorbance was detected at 562 nm using a full-wavelength microplate reader. 250 μL of the supernatant sample (denoted as V) was transferred to a 15 mL centrifuge tube, 550 μL of nitric acid was added, and the mixture was thoroughly mixed. The mixture was briefly centrifuged at room temperature and then shaken at room temperature for 24 hours. 4.2 mL of ultrapure water was added to each sample, and the mixture was centrifuged at room temperature for 30 minutes. 4 mL of the supernatant sample was then used for Gd elemental content detection by inductively coupled plasma mass spectrometry (ICP-MS) (denoted as H). The gadolinium content per milligram of protein in each sample was first calculated.

[0336] Right now The final volume is 5 mL.

[0337] The final result is expressed as the percentage of hepatocyte uptake of the tested compound relative to primax.

[0338] Right now As shown in the table below.

[0339] Table 1. Results of compound uptake by primary mouse hepatocytes in vitro.

[0340] Example % of Pomegranate Example % of Pomegranate 1 18.81 2 49.89 3 7.41 4 73.99 5 17.89 6 23.46 7 0.80 8 0.60 9 16.48 10 62.35 11 54.45 12 87.98

[0341] The compound in this application showed excellent uptake of the compound in in vitro mouse primary hepatocytes.

[0342] Test Example 2: MRI Imaging of C57BL / 6J Mice

[0343] method

[0344] Compound weighing and preparation

[0345] Calculate the mass of the test compound to be weighed at a concentration of 5 mM, using pymetrozine as a positive control. After instantaneous centrifugation, add the corresponding 0.9% sodium chloride injection solution to each compound according to the calculation and dissolve it completely.

[0346] Mouse MRI imaging preparation

[0347] Assemble an indwelling needle using PE tubing (PE8: outer diameter 0.5 mm, inner diameter 0.25 mm) and a sterile injection needle (long needle: 30G / 0.3*25). Use a 1 mL sterile syringe to draw 200 μl of heparin sodium injection solution to moisten the entire indwelling needle and remove air bubbles. The drug concentration for mice is 0.025 mmol / kg (body weight), and the administration volume is calculated at 5 mL / kg. Weigh the mice, number and record their weight, and anesthetize them for 1-2 minutes in a respiratory anesthesia machine (1-2% isoflurane) to induce anesthesia. Place the mice in a fixation tube and insert the indwelling needle. The mice were secured with needles and tape, then placed back into the respiratory anesthesia machine to maintain anesthesia. They were then placed on a 1.5T MRI imaging stage, positioned appropriately, and scanned at the 0-minute time point. Throughout the imaging process, the mice remained under respiratory anesthesia. Using a new 1mL sterile syringe, a volume of the compound solution was drawn at a rate of 5mL / kg (body weight) and injected through an indwelling needle. Finally, twice the volume of the compound solution was drawn and injected into the mouse with 0.9% sodium chloride injection. Imaging was performed at the set detection time points (0, 5, 10, 15, 20, 30, and 40 minutes). After imaging, the mice were removed, allowed to recover naturally, and then euthanized. Data were processed using RadiAnt DICOM Viewer software to calculate the relative liver enhancement rate (RER%) after erector spinae muscle correction following drug administration, using the following formula:

[0348]

[0349] SL: Signal intensity in the liver parenchyma

[0350] SM: Signal intensity in the erector spinae region

[0351] result

[0352] T1-weighted images of the liver cross-section were recorded in mice within 0-40 minutes after intravenous injection, and the relative enhancement rate of the liver was calculated. The results are shown in Table 2 and... Figure 1As shown, compared to PIMI, Example 4 produced a significantly stronger liver signal enhancement at 5-15 minutes; while Example 10 produced a significantly stronger and more persistent liver signal enhancement at 5-40 minutes. Therefore, Examples 4 and 10 may have better resolution and sensitivity than PIMI in the diagnosis of liver cancer.

[0353] Table 2. Relative liver enhancement rate (%) in C57BL / 6J mice

[0354]

[0355]

[0356] Test Example 3: Stability Experiment

[0357] Thermodynamic stability:

[0358] The analyte compounds were dissolved in 10 mM Tris-HCl buffer at pH 7.4 to a final concentration of 1 mmol Gd / L. The solutions were autoclaved three times at 121°C for 20 minutes each. Before and after each autoclaving step, the analyte samples were removed and frozen at -20°C for subsequent HPLC-ICP-MS (Gd157) analysis to determine compound integrity. Before ICP measurement, the samples were mixed with 50% MeCN (+0.1% HNO3 + 0.5 mM DTPA + 25 nM Lu as an internal standard). Chromatograms showing the intensity of detected Gd were visually compared. If the change in the chromatogram before and after autoclaving was <1%, the stability of the compound was assessed. Our compounds are thermodynamically stable.

[0359] Dynamic stability:

[0360] The method used was a known method (Laurent S et al., Stability of MRI paramagnetic contrast media: a proton relaxometric protocol for transmetallation assessment. Invest Radiol. 2001 Feb; 36(2):115-22). In short: Incubate 26 mM phosphate buffer containing 2.5 mmol / L of the test compound and 2.5 mmol / L of ZnCl2 at 37°C for at least 3 days. If the test compound is unstable under these conditions, Zn... 2+ Then Gd 3+ New Zn is formed by displacement from the chelating agent. 2+ The complex, and the Gd that was displaced 3+It will then form a highly insoluble GdPO4 precipitate with phosphate buffer. Because Zn 2+ It does not affect the T1 relaxation time, and Gd 3+ The ion exchange reaction causes the solution to be removed by precipitation, thus increasing the T1 relaxation time (measured at 0.5T).

[0361] The T1 relaxation time was observed after 3 days of incubation. Compared with plemethoxazole and gadobenzamide, all the compounds studied showed lower Gd under these conditions. 3+ It dissociates and exhibits kinetic stability.

[0362] Test Example 4: Relaxation Rate Experiment

[0363] Five solutions of the test compound at different concentrations (1.6 mg / mL, 0.8 mg / mL, 0.4 mg / mL, 0.2 mg / mL, 0.1 mg / mL) were prepared and measured on a Suzhou Niumai PQ001 (0.5T) relaxation meter. The main parameters detected were the transverse relaxation time (T1) and longitudinal relaxation time (T2) of different concentrations of the compound. Then, the transverse relaxation time and longitudinal relaxation time of different concentrations were plotted against the concentration, and the slopes obtained were the relaxation rates r1 and r2 of the compound.

[0364] The results show that our compound has excellent relaxation properties.

Claims

1. A compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, nitride, hydrate, solvate, or mixture thereof, a prodrug, or a deuterated derivative thereof. ALT (I) in, A is a chelating group, which is a group capable of complexing metal ions; L can be attached to any position of the chelating group. L is selected from One end marked with * is connected to A; T is an optional action by one or more Rs x The substituted benzene ring, said R x Each occurrence is independently selected from H, -C1-C3 alkyl, -OH, -CH2OH, -O-(CH2). n -R 3 n is selected from 0, 1, 2, R 3 Selected from H, -O-C2H5, -O-(CH2)2-O-C2H5, optionally by one or more R y Substituted benzene ring, wherein R y Each time it appears, it is independently selected from one or more of H, C1-C3 alkyl, C1-C4 alkoxy, halogenated C1-C3 alkyl, halogen, -NO2, triethylsilyl, acyl, sulfonyl, amino, alkylamino, ester, carboxyl, sulfonic acid, boric acid, phosphate, aryl, and heteroaryl.

2. The compound according to claim 1, wherein A represents a chelating group of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or a derivative thereof, wherein the derivative refers to one or more groups of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid optionally substituted by different groups, or one or more side chains of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid are missing, or both of the above occur simultaneously.

3. The compound according to claim 2, wherein the derivative refers to one or more hydrogen atoms on 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, optionally with R 1 Substitution, wherein the substitution occurs at any position in the macrocyclic skeleton or side chain of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, and wherein R 1 Each occurrence is independently selected from H, -C1-C6 alkyl groups, and -(CH2). h OH, -(CH2) i OHCH3, h is selected from 0, 1, 2, 3, 4, 5, i is selected from 1, 2, 3.

4. The compound according to claim 3, wherein, A is selected independently each time it appears. R 1 Each occurrence is independently selected from H, -C1-C3 alkyl groups, and -(CH2). m OH, -CH2OHCH3, m is selected from 1, 2, 3.

5. The compound according to claim 4, wherein, R 1 Selected from H, -CH2OH.

6. The compound according to claim 1, wherein, A is 7. The compound according to claim 1, wherein, A is 8. The compound according to claim 1, wherein, A is 9. The compound according to claim 1, having the structure shown in formula (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt, nitride, hydrate, solvate, or mixture thereof, a prodrug, a deuterated derivative, in, A is selected from L is selected from One end marked with * is connected to A; R x Selected from H, -C1-C3 alkyl, -OH, -CH2OH, -O-(CH2) n -R 3 n is selected from 0, 1, 2, R 3 Selected from H, -O-C2H5, -O-(CH2)2-O-C2H5, optionally by one or more R y Substituted benzene ring, wherein R y Each time it appears, it is independently selected from one or more of H, C1-C3 alkyl, C1-C4 alkoxy, halogenated C1-C3 alkyl, halogen, -NO2, and triethylsilyl.

10. The compound according to any one of the preceding claims, wherein, R x Selected from -O-(CH2) n -R 3 n is selected from 1 and 2, R 3 Selected from H, -O-C2H5, -O-(CH2)2-O-C2H5, optionally by one or more R y Substituted benzene ring; wherein R y Each time it appears, it is independently selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, CF3, -OCH2CF2CHF2, -CH2CF3, F, Cl, Br, I, -NO2, triethylsilyl.

11. The compound according to claim 10, wherein, R x Selected from -O-(CH2) n -R 3 n is selected from 1 or 2, R 3 Selected from the benzene ring, or by one or more R y Substituted benzene ring, wherein R y Each occurrence is independently selected from H, -CH3, and -O(CH2). 0-3 CH3, -NO2, -F, -CF3, -OCH2CF2CHF2, -CH2CF3, triethylsilyl.

12. The compound according to claim 10, wherein, R x Selected from 13. Compounds with the following structures: Or its stereoisomers, tautomers, pharmaceutically acceptable salts, nitrogen oxides, hydrates, solvates, or Its mixtures, prodrugs, and deuterated products.

14. A metal complex comprising a compound, stereoisomer, tautomer, pharmaceutically acceptable salt, nitride, hydrate, solvate, or mixture thereof, a prodrug, a deuterated compound, or a metal ion complex as described in any one of claims 1-13.

15. The metal complex of claim 14, wherein the metal is selected from gadolinium, manganese, and iron.

16. The compound according to claim 15, having the following structure: Or its stereoisomers, tautomers, pharmaceutically acceptable salts, nitrogen oxides, hydrates, solvates, or mixtures thereof, prodrugs, or deuterated derivatives.

17. Use of the compound according to any one of the preceding claims for diagnostic imaging.

18. Use of the compound according to any one of claims 1-16 for magnetic resonance imaging, preferably for magnetic resonance imaging of the hepatobiliary system, more preferably for magnetic resonance imaging of the liver.

19. Use of the compound according to any one of claims 1-16 in the manufacture of a diagnostic agent.

20. Use of the compound according to any one of claims 1-16 in the manufacture of a magnetic resonance imaging contrast agent.

21. The use of any compound or stereoisomer, tautomer, pharmaceutically acceptable salt, nitride, hydrate, solvate, or mixture thereof, prodrug, or deuterated derivative according to any one of claims 1-16 for the preparation of metal-containing complexes.

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