CN116535538A - Development and application of thoracic aortic aneurysm and aortic dissection early diagnosis probe - Google Patents

Development and application of thoracic aortic aneurysm and aortic dissection early diagnosis probe Download PDF

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Publication number
CN116535538A
CN116535538A CN202210095431.5A CN202210095431A CN116535538A CN 116535538 A CN116535538 A CN 116535538A CN 202210095431 A CN202210095431 A CN 202210095431A CN 116535538 A CN116535538 A CN 116535538A
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compound
salt
taad
contrast agent
formula
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孔炜
丛馨
徐福建
杨雪媛
许晨
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Peking University
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Peking University
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
    • A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA

Abstract

The invention relates to development and application of a thoracic aortic aneurysm and aortic dissection early diagnosis probe, and particularly provides a compound shown in a formula I or salt thereof, a preparation method of the compound shown in the formula I and application of the compound as the thoracic aortic aneurysm and aortic dissection early diagnosis probe.

Description

Development and application of thoracic aortic aneurysm and aortic dissection early diagnosis probe
Technical Field
The invention relates to the field of medicines, in particular to development and application of a thoracic aortic aneurysm and aortic dissection (thoracic aortic aneurysm and dissection, TAAD) early diagnosis probe.
Background
Thoracic aortic aneurysms and aortic dissection (thoracic aortic aneurysm and dissection, TAAD) are a group of cardiovascular diseases with urgent onset, strong prognosis and high mortality. Wherein, the thoracic aortic aneurysm refers to a vascular disease in which the thoracic aortic aneurysm expands in an irreversible tumor-like manner, resulting in a lesion with a vessel diameter of more than 50% of normal; aortic dissection refers to acute injury of the intima of the aorta, blood flow enters the wall of the aorta from the rupture of the intima, and blood vessels form true and false cavities. With the continuous inflow of blood, the prosthetic cavity extends rapidly along the longitudinal axis of the aorta, severely reaching the abdominal aorta and the iliac arteries, and eventually the pressure in the prosthetic cavity increases dramatically, which can lead to rupture of the aortic wall. TAAD has multiple and complex etiology, unknown pathogenesis, rapid onset, atypical clinical symptoms and extremely easy misdiagnosis and mistreatment, thereby leading to higher fatality rate.
According to studies, the mortality rate of patients after aortic angiogenic tears is about 40% -50% within 48 hours. In recent years, with the rapid development of medical technology, the survival rate of a sandwich patient can be significantly improved by timely performing an operation treatment of an endoluminal prosthesis or an aortic replacement for a TAAD patient. However, as TAAD is hidden from the onset, the patient has no obvious symptoms before tearing occurs. Therefore, it is important to find a method that can diagnose TAAD early before symptoms appear.
The existing TAAD clinical diagnosis means are mainly used for diagnosing the occurrence of TAAD based on the pipe diameter expansion degree or tearing degree of the aorta. However, due to the rapid onset of most TAAD patients, there is no early diagnosis of TAAD currently available due to the lack of significant clinical symptoms before angiogenic tears.
Disclosure of Invention
TAAD is a critical disease of the blood vessel due to intimal tear, and vascular endothelial cells act as the first barrier of the blood vessel, with tight junctions of endothelial cells playing an important role in maintaining vascular function and homeostasis. In our previous studies, it was found that early in TAAD, vascular endothelial cell barrier function was disrupted, tight junction molecular membrane distribution was reduced, and permeability was increased. Based on the phenomenon that TAAD suffers from early barrier destruction, the inventors synthesized a magnetic resonance contrast agent that could make early diagnosis of TAAD.
For this purpose, in a first aspect of the present invention, there is provided a compound represented by formula I or a salt thereof,
in a second aspect of the present invention, there is provided a process for preparing a compound of formula I or a salt thereof, comprising:
1) Allowing FITC-labeled Dextran (FITC-Dextran) to undergo condensation reaction with 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) to obtain intermediate FITC-Dextran-DOTA;
2) Bringing said intermediate into contact with GdCl 3 6H 2 O is subjected to complexation reaction to obtain the compound shown in the formula I.
In some embodiments, the FITC-labeled Dextran (FITC-Dextran) has a molecular weight of 4kDa.
In some embodiments, in step 2), the intermediate is mixed with the GdCl 3 6H 2 The intermediate is protonated prior to the O complexation reaction.
In some embodiments, the protonation is achieved using hydrochloric acid.
In some embodiments, the hydrochloric acid has a concentration of 0.05 to 0.15mM, preferably 0.1mM.
In some embodiments, in step 1), the condensation reaction is performed in the presence of a condensing agent and a base.
In some embodiments, the condensing agent is 1, 1-Carbonyldiimidazole (CDI).
In some embodiments, the base is Triethylamine (TEA).
In some embodiments, in step 1), the solvent of the condensation reaction is an anhydrous solvent, preferably anhydrous dimethylsulfoxide.
In some embodiments, in step 1), the mass ratio of FITC-labeled Dextran (FITC-Dextran) to 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) is 5:2-5:4, preferably 5:3.
In some embodiments, in step 1), the mass ratio of FITC-labeled Dextran (FITC-Dextran) to the condensing agent is 25:8-5:2, preferably 25:9.
In some embodiments, in step 1), the mass ratio of FITC-labeled Dextran (FITC-Dextran) to the base is 10:1 to 10:3, preferably 5:1.
In some embodiments, in step 1), the ratio of the mass of FITC-labeled Dextran (FITC-Dextran) to the volume of the base (e.g., triethylamine) is 10mg: 1. Mu.L to 5mg: 1. Mu.L, preferably 50mg: 7. Mu.L.
In some embodiments, in step 1), the condensation reaction is carried out at room temperature, e.g., at room temperature for 10-15 hours, such as 12 hours.
In some embodiments, after step 1), further comprising: the intermediate FITC-Dextran-DOTA was purified. In some embodiments, the purification is performed using a dialysis membrane (e.g., MWCO 1000).
In some embodiments, in step 2), the intermediate is mixed with the GdCl 3 6H 2 The mass ratio of O is 10:3-2:1, preferably 5:2.
In some embodiments, in step 2), the solvent of the complexation reaction is water, preferably deionized water.
In some embodiments, in step 2), the complexation reaction is performed at room temperature, e.g., at room temperature for 10-15 hours, such as 12 hours.
In some embodiments, after step 2), further comprising: purifying the reaction product of the complexation reaction; optionally, further comprising: the purified product is dried (e.g., freeze-dried). In some embodiments, the purification is performed using a dialysis membrane (e.g., MWCO 1000).
In a third aspect of the present invention there is provided a contrast agent comprising a compound of formula I or a salt thereof as hereinbefore described or a compound prepared by a process as hereinbefore described.
In some embodiments, the contrast agent is a compound of formula I or a salt thereof as described above or a compound prepared by a method as described above or a salt thereof.
In some embodiments, the contrast agent is a magnetic resonance contrast agent.
In some embodiments, the contrast agent is a TAAD targeted magnetic resonance contrast agent.
In a fourth aspect of the invention there is provided the use of a compound of formula I or a salt thereof as hereinbefore described or a compound prepared by a process as hereinbefore described, as or in the preparation of a contrast agent.
In some embodiments, the contrast agent is a magnetic resonance contrast agent.
In some embodiments, the contrast agent is a TAAD targeted magnetic resonance contrast agent.
In a fifth aspect of the present invention there is provided a composition comprising a compound of formula I as hereinbefore described or a salt thereof or a compound prepared by a process as hereinbefore described or a salt thereof or a contrast agent as hereinbefore described.
In a sixth aspect of the present invention, there is provided a kit comprising a compound of formula I as hereinbefore described or a salt thereof or a compound prepared by a process as hereinbefore described or a salt thereof or a contrast agent as hereinbefore described.
In a seventh aspect of the invention, there is provided a method of targeted imaging of a leaky vessel or a vessel in which TAAD occurs, comprising:
1) Injecting into a mammal an effective amount of a compound of formula I or a salt thereof, or a compound prepared by a method as described above, or a salt thereof, or a contrast agent as described above;
2) Performing a magnetic resonance test on the mammal.
In some embodiments, the methods are used for non-diagnostic or therapeutic purposes (e.g., for scientific research).
In some embodiments, the mammal is a mouse or a human.
In an eighth aspect of the invention there is provided the use of a compound of formula I as hereinbefore described or a salt thereof or a compound prepared by a process as hereinbefore described or a salt thereof or a contrast agent as hereinbefore described in the manufacture of a reagent for use in diagnosis (preferably early diagnosis) or in the prediction of TAAD.
In a ninth aspect of the invention, there is provided a method of diagnosing (preferably early diagnosing) or predicting TAAD comprising:
1) Providing (e.g., injecting) to a subject an effective amount of a compound of formula I or a salt thereof as described above or a compound prepared by a method as described above or a salt thereof as described above or a contrast agent as described above.
In some embodiments, the method further comprises:
2) Magnetic resonance detection is performed on the subject.
In some embodiments, the subject is a mammal, such as a human or mouse, preferably a human.
In a tenth aspect of the invention there is provided the use of a compound of formula I as hereinbefore described or a salt thereof or a compound prepared by a process as hereinbefore described or a salt thereof or a contrast agent as hereinbefore described for diagnosis (preferably early diagnosis) or prediction of TAAD.
In an eleventh aspect of the invention there is provided a compound of formula I as hereinbefore defined or a salt thereof or a compound prepared by a process as hereinbefore defined or a salt thereof or a contrast agent as hereinbefore defined for use in diagnosis (preferably early diagnosis) or prediction of TAAD.
The contrast agent refers to a compound shown in formula I or a salt thereof or a compound prepared by the method, optionally, one or more pharmaceutically acceptable excipients, for example, a solvent, so that the compound shown in formula I or a salt thereof or the compound prepared by the method or the salt thereof is prepared into a solution for injection.
The beneficial effects are that:
1. the invention can carry out angiography on blood vessels of mammal (such as mice) which leak through magnetic resonance detection in a noninvasive mode;
2. the invention can predict whether the mammal (such as a mouse) generates TAAD by magnetic resonance detection, for example, the invention can predict whether the mouse generates TAAD in a mouse TAAD model induced by the humic acid-3-aminopropionitrile (3-aminopropionitrile fumarate salt, BAPN);
3. the magnetic resonance contrast agent provided by the invention has no obvious organ toxicity to mammals (such as mice), and is high in safety, simple and quick to synthesize, low in cost and easy to obtain.
4. The invention is useful for potential TAAD diagnostic (preferably early diagnostic) probes for mammals (preferably humans or mice).
Drawings
In fig. 1, a is the aorta after 5 days and 10 days of injection of evans blue via the inner canthus vein in control mice and BAPN-fed mice; b is the aortic section results after 5 and 10 days post-intracanthal dextran injection in control mice and BAPN fed mice.
FIG. 2A shows a synthetic route of contrast agent; b is the hydrogen spectrum of FITC-dextran which is a nuclear magnetic resonance detection synthetic raw material; c is hydrogen spectrum of reaction products of FITC-dextran and DOTA detected by nuclear magnetic resonance; d is a chromatographic peak of a synthetic raw material FITC-Dextran in high performance liquid chromatography; e is a chromatographic peak of a reaction product of FITC-Dextran and DOTA in high performance liquid chromatography; f is gadolinium content in the material after thermogravimetric analysis; g is a linear regression fit curve to detect synthesized contrast agent in PBS buffer.
In fig. 3, a is the HE staining of tissue sections of organs of the mice and the control mice after injection of the contrast agent; b is the blood vessel magnetic resonance imaging and blood vessel section staining of the control mice and the BAPN feeding mice before and after contrast agent injection.
Fig. 4a is a blood vessel magnetic resonance image of control mice and BAPN fed mice after 5 days and 10 days of contrast agent injection; b is the enhancement factor (improvement) of brightness at the vessel wall of the mice after BAPN feeding for 5 days relative to the control mice after injection of magnetic resonance contrast agent relative to the non-injected contrast agent; c is the enhancement factor (improvement) of brightness at the vessel wall of the mice injected with magnetic resonance contrast agent relative to the control mice after BAPN feeding for 10 days relative to the non-injected contrast agent; d is a line graph of enhancement coefficients (improvement) of brightness at the vessel wall of control mice, mice with TAAD after BAPN feeding and mice without TAAD after BAPN feeding for 5 days and 10 days; e is an aortic general picture corresponding to the line diagram of the D picture; f is the ascending aorta diameter measurement after 5 days and 10 days in control mice and BAPN fed mice; g is the ascending aortic diameter of the mice relative to control mice after 5 days BAPN feeding; h is the ascending aortic diameter of mice relative to control mice after 10 days BAPN feeding.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The invention discloses development and application of a TAAD early diagnosis probe. The invention discloses a synthesis method and safety of a magnetic resonance contrast agent and usability evaluation. The invention further discloses that the magnetic resonance contrast agent can predict the occurrence of TAAD and can be applied to early diagnosis of TAAD.
The invention uses tightly-connected tracer molecules as probes of the contrast agent, and connects complexing molecules DOTA, and the molecules are gadolinium-modified to synthesize the contrast agent FMRI-1. To investigate the early diagnostic effect of this contrast agent on TAAD, a BAPN-induced TAAD model was used, and magnetic resonance detection was performed after injection of the contrast agent at an early stage in which the mice had not yet developed TAAD, to investigate whether or not the mice having a contrast effect developed TAAD later.
The invention is further illustrated below in conjunction with specific examples.
Example 1: determination of early endothelial barrier damage in TAAD
The barrier function of the aorta was examined at the early BAPN-induced TAAD, i.e. 5 and 10 days in mice, by injecting tracer molecules, which diffuse only via the paracellular route, into the inner canthus vein. It can be seen from fig. 1A that in early TAAD, the mouse evans blue dye exudes, and that early TAAD endothelial barrier function is impaired. In addition to this. The integrity of vascular barrier function can be assessed by injecting rhodamine B-labeled dextran into the inner canthus vein, and observing rhodamine B fluorescence after vascular sectioning. As can be seen from fig. 1B, the vascular barrier is damaged and dextran leaks.
Example 2: synthesis and identification of magnetic resonance contrast agents
1. Synthesis
FMRI-1 was synthesized according to the manner shown in FIG. 2A. The method comprises the following steps: 100mg of FITC-labeled Dextran (FITC-Dextran) with a molecular weight of 4kDa was dissolved in 3mL of anhydrous dimethyl sulfoxide (DMSO), the reaction mixture was stirred at room temperature for 10min, 60mg of DOTA,36mg of 1, 1-Carbonyldiimidazole (CDI) and 14. Mu.L of Triethylamine (TEA) were added, respectively, and the mixture was complexed for 12h at room temperature. The crude product was purified using a dialysis membrane (MWCO 1000) in which case the product was FITC-Dextran-DOTA. To prepare the final product FMRI-1, 20mg of this step was dissolved in 3mL of deionized water, protonated with 0.1mM hydrochloric acid and added with GdCl 3 6H 2 O (8 mg), the reaction mixture was stirred at room temperature for 12h, and the crude product was purified using a dialysis membrane (MWCO 1000), and the final product was freeze-dried to give the title compound, finally designated FMRI-1.
2. Authentication
First, nuclear magnetic resonance hydrogen spectrum analysis was performed on FITC-dextran, which is a synthetic raw material, and reaction products of FITC-dextran and DOTA, respectively, to find peak broadening between 5-6ppm of chemical shift in hydrogen spectrum (FIGS. 2B, 2C). Meanwhile, the synthesis starting material FITC-dextran and the reaction products of FITC-dextran and DOTA were examined by high performance liquid chromatography, and it was found that the residence time in the chromatographic peak was reduced (1.98 min) due to the increased polarity of the reaction products compared to FITC-dextran (FIGS. 2D, 2E). Both methods prove that the target compound is successfully synthesized. In addition, the thermogravimetric analysis method, i.e. the temperature rise in a nitrogen atmosphere is used to decompose the organic substances and finally leave gadolinium as an inorganic substance, so that it is determined that 21% gadolinium is contained in each 1mg of magnetic resonance contrast material (fig. 2F). In addition, the sample is placed in a nuclear magnetic resonance imaging instrument for scanning by preparing contrast agents containing gadolinium ion concentrations with different concentrations in 200 mu L of phosphate buffer solution, and the 1/T1 of the sample is quantified after imaging. As can be seen from fig. 2G, 1/T1 is in a linear relationship with gadolinium ion concentration, and the linear regression coefficient of the synthetic material is obtained through calculation, that is, R is 0.9953, which indicates that the higher the concentration of the compound, the stronger the contrast capability.
Example 3: application of magnetic resonance contrast agent
1. Mouse TAAD model modeling and magnetic resonance detection
C57BL/6J male mice at 3 weeks of age were fed normal diet or BAPN feed containing 0.4% for 14 days. Mice were anesthetized with isoflurane at 5 and 10 days of molding, and injected with 8mg/mL FMRI-1 (physiological saline solvent) at inner canthus intravenously at 100 μl for 5min, followed by vessel T1 weighted imaging using a mouse magnetic resonance scanner. At day 14, the mouse aorta was isolated and the mortality and TAAD incidence of the mice were counted.
2. Safety and usability of magnetic resonance contrast agents
The mice were injected with FMRI-1 probe 18 days later, dissected after sacrifice, and HE stained after removal of heart, liver, spleen, lung and kidney tissue sections, respectively (fig. 3A). As a result, after the injection of the magnetic resonance probe (namely, the prepared FMRI-1), the organs of each tissue of the mice are not significantly different from those of the control mice (namely, the mice fed with normal diet), which indicates that the FMRI-1 has high safety. In addition, since the probe has not only gadolinium (Gd) which is a metal atom that can be visualized by nuclear magnetic resonance, it also contains FITC groups that can be imaged under a confocal microscope. To investigate the usability of this magnetic resonance probe, mice fed control mice and BAPN for 14 days were subjected to magnetic resonance detection before and after injection of the magnetic resonance probe, respectively (fig. 3B). As a result, the increase of the vessel wall of the control mice was found to be weak, and the sections were free of obvious FITC fluorescence. Whereas BAPN-fed mice had increased contrast signal at the vessel wall in the T1 image after FMRI-1 injection, the sections also showed enhanced FITC fluorescence compared to control mice. The FMRI-1 is shown to have a targeted contrast effect on TAAD.
3. Materials can predict the occurrence of TAAD
Based on the above-described evaluation of the safety and usability of the magnetic resonance contrast agent, the inventors analyzed whether the contrast agent can predict the occurrence of TAAD. 100 mu L of FMRI-1 (physiological saline solvent) was injected at 8mg/mL for 5 days and 10 days of BAPN-induced TAAD, respectively, and the mice were harvested after 14 days, and vascular tissues of the mice were preserved. Fig. 4A illustrates that after early (5 and 10 days) injection of magnetic resonance contrast agent in BAPN-induced mice TAAD, the contrast signal at blood vessels was significantly higher in BAPN group mice than in control mice (fig. 4b,4 c). The mice were further grouped according to whether or not BAPN was fed and whether or not TAAD occurred in mice after BAPN 14 feeding, i.e., three groups of control mice, groups of no TAAD after 14 days of BAPN feeding, and groups of TAAD after 14 days of BAPN feeding. Plotting the 5-day angiographic signal delta coefficient versus the 10-day angiographic signal delta coefficient for each mouse revealed that the increase in angiographic intensity delta coefficient (broken line slope) was significantly increased in mice that developed TAAD after 14 days in BAPN relative to the control mice and in the groups that did not develop TAAD in BAPN. It follows that the magnetic resonance contrast agent of the present invention predicts the occurrence of TAAD. In addition, the inventors performed diameter measurements of the aorta using magnetic resonance imaging, and found that there was no significant difference in ascending aorta diameter in mice compared to control mice at days 5 and 10 of the BAPN-induced TAAD model (fig. 4F-H), which is also consistent with the literature report that most TAAD-developing patients had no significant dilation before vessel tear. This result demonstrates that the magnetic resonance probe of the present invention predicts the occurrence of TAAD without significant aortic expansion.
The above experiments were analyzed using the following statistical methods: (1) The continuous random variable of the normal distribution is represented by Mean ± standard error (Mean ± SEM); (2) Paired data all used paired t-test (double sided test); (3) Unpaired data were tested using the group t-test (two-sided test).
While certain specific embodiments of the invention have been described in detail by way of example, it will be appreciated by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the invention. It will be appreciated by those skilled in the art that modifications may be made to the above embodiments without departing from the scope and spirit of the invention. The scope of the invention is defined by the appended claims.

Claims (8)

1. A compound represented by formula I or a salt thereof,
2. a process for preparing a compound of formula I or a salt thereof, comprising:
1) Allowing FITC-labeled Dextran (i.e., FITC-Dextran) to undergo condensation reaction with 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) to obtain intermediate FITC-Dextran-DOTA;
2) Bringing said intermediate into contact with GdCl 3 6H 2 O is subjected to complexation reaction to obtain the compound shown in the formula I.
3. The method of claim 2, wherein in step 2), the intermediate is combined with the GdCl 3 6H 2 Pre-protonating the intermediate before O is subjected to a complexation reaction;
preferably, the protonation is achieved using hydrochloric acid.
4. A process according to any one of claims 2 to 3, wherein in step 1) the condensation reaction is carried out in the presence of a condensing agent and a base;
preferably, the condensing agent is 1, 1-Carbonyldiimidazole (CDI);
preferably, the base is Triethylamine (TEA).
5. Use of a compound of formula I as defined in claim 1 or a salt thereof or a compound prepared by a process as defined in any one of claims 2 to 4 or a salt thereof as or in the preparation of a contrast agent;
preferably, the contrast agent is a magnetic resonance contrast agent;
more preferably, the contrast agent is a thoracic aortic aneurysm and aortic dissection (TAAD) targeted magnetic resonance contrast agent.
6. A kit comprising a compound of formula I as defined in claim 1 or a salt thereof or a compound prepared by a method as defined in any one of claims 2 to 4 or a salt thereof.
7. A method of targeted imaging of leaky vessels or vessels that develop thoracic aortic aneurysms and aortic dissection (TAAD), comprising:
1) Injecting into a mammal an effective amount of a compound of formula I as described in claim 1 or a salt thereof or a compound prepared by a process as described in any one of claims 2 to 4;
2) Performing a magnetic resonance test on the mammal;
preferably, the method is used for non-diagnostic or therapeutic purposes (e.g. for scientific research);
preferably, the mammal is a mouse or a human.
8. Use of a compound of formula I as defined in claim 1 or a salt thereof or a compound prepared by a method as defined in any one of claims 2 to 4, for the preparation of a reagent for diagnosing (preferably early diagnosing) or predicting thoracic aortic aneurysms and aortic dissection (TAAD).
CN202210095431.5A 2022-01-26 2022-01-26 Development and application of thoracic aortic aneurysm and aortic dissection early diagnosis probe Pending CN116535538A (en)

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