CN114632079B - Preparation and application of iron pool targeting molecule image probe based on artemisinin - Google Patents
Preparation and application of iron pool targeting molecule image probe based on artemisinin Download PDFInfo
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- CN114632079B CN114632079B CN202011484700.4A CN202011484700A CN114632079B CN 114632079 B CN114632079 B CN 114632079B CN 202011484700 A CN202011484700 A CN 202011484700A CN 114632079 B CN114632079 B CN 114632079B
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 130
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 59
- 239000000523 sample Substances 0.000 title claims abstract description 42
- 229960004191 artemisinin Drugs 0.000 title claims abstract description 29
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 title claims abstract description 29
- 229930101531 artemisinin Natural products 0.000 title claims abstract description 29
- 230000008685 targeting Effects 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 10
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims abstract description 8
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- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 3
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
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- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
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- 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
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
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- 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
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
- A61K49/105—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA the metal complex being Gd-DTPA
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/0412—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A—HUMAN NECESSITIES
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
Abstract
An artemisinin-based iron pool targeting molecule image probe preparation and application thereof belong to the field of medical image probes. The artemisinin-based iron pool targeting molecule imaging probe is ART-X-CO-Linker-R 1 ART is artemisinin, X is-O-c=o-or S or-O-CO-N-; r is R 1 Is a macrocyclic ligand such as NOTA, DOTA or DTPA. ART is taken as an iron Chi Ba directional group, and a macrocyclic ligand is utilized to chelate metal ions (M is paramagnetic metal ions or radioactive elements), so that a molecular probe MRI (magnetic resonance imaging) contrast or PET (positron emission tomography) imaging function is endowed, and a specific tracing active iron pool Fe in a living body is constructed 2+ Molecular imaging probes of (a). The artemisinin-based iron pool targeting molecule imaging probe has good chemical stability, biological safety and biological distribution property, and the preparation method is simple and easy to implement, and can be applied to PET/MRI living body imaging of iron death related diseases.
Description
Technical Field
The invention belongs to the field of medical image probes, and particularly relates to preparation and application of an artemisinin-based iron pool targeting molecule image probe.
Background
Iron is the most abundant transition metal element in the human body, and can be converted between different oxidation states, which makes it play an important role in functions of oxygen transportation, energy generation, enzyme metabolism and the like. However, this high redox potential also presents potential hazards to the cells, and the abnormally accumulated iron can generate reactive oxygen species ROS such as hydroxyl radicals, which are highly reactive, through the Fenton reaction, resulting inOxidative damage of the osteoblasts, leading to pathological lesions. Thus, there is a sophisticated set of regulation mechanisms in vivo for regulating iron stabilization, i.e. the iron transport system. Fe in peripheral circulation 3+ Binding to transferrin to form complex and then binding to transferrin receptor on cell membrane, and entering endosome in cell, fe 3+ Reduction to Fe by the iron oxygen reductase Steap3 (sixtransmembrane epithelial antigen of the prostate) 2+ Fe subsequently mediated by the divalent metal ion transporter 1 2+ Release from endosomal disintegration into the cytoplasm, and a part of the release is stored in unstable iron pool LIP (Fe 2+ ) Excess iron is stored in the iron-storage protein complex consisting of ferritin light chain and ferritin heavy chain 1, the remainder of Fe 2+ Will be oxidized to Fe 3+ The transfer of iron out of the cells through transferrin is involved in iron recycling in vivo.
Iron death is an iron-dependent oxidative cell death, distinguished from traditional apoptosis, necrosis and autophagy, characterized by the concomitant accumulation of large amounts of iron ions and lipid peroxidation during cell death, while depleting glutathione peroxidase GPX4; intracellular high-enriched LIP is a key factor in lipid peroxidation and induction of iron death. Recent studies have shown that iron death is closely related to pathophysiological processes in many diseases, such as tumors, neurological diseases, ischemia reperfusion injury, kidney injury, etc. Genetic evidence suggests that iron death is associated with brain degeneration, and that induction of GPX4 loss in adult mice results in loss of hippocampal neurons upon astrocyte proliferation, which loss leads to decreased memory function in alzheimer's disease. Fang et al (proc. Natl Acad. Sci. USA 116,2672-2680 (2019) found that after myocardial ischemia reperfusion injury in rats, the iron homeostasis regulation pathway was activated, the iron ion levels were up-regulated, ROS production increased, and iron-dependent cell death, i.e., iron death, was induced, suggesting that iron death was involved in myocardial ischemia reperfusion injury.
Based on the key role that LIP plays in the iron death mechanism, the development of fluorescent probes for LIP detection has received great attention in recent years. A series of iron pool-targeted fluorescent probes have been reported, such as Ac-MtFluNox, lyso-RhoNox and FIPC-1, which are capable of imaging LIP at the cellular level. However, fluorescent probes for such iron ions are limited by the low penetration depth of the fluorescence, and thus are not capable of imaging non-superficial tissues on living subjects. Therefore, there is an urgent need to develop a probe with more clinical potential, such as a positron emission tomography probe/magnetic resonance imaging probe (PET/MRI), for tracing the concentration change of the iron pool on a living body level, and exploring the internal connection between the concentration change of the iron pool and the progress of diseases related to iron death, so as to realize accurate early diagnosis and prognosis evaluation of the diseases.
Artemisinin is a compound isolated and identified in 1972 by the doctor Tu Youyou from the herb Artemisia Annua (Artemisia Annua) and contains an internal peroxy bridge in its structure that is closely related to the antimalarial mechanism. Research shows that plasmodium can produce heme after absorbing and digesting hemoglobin when developing and breeding in erythrocyte inner period, and artemisinin and its derivative specifically target Fe in heme 2+ In Fe 2+ The internal peroxy bridge is opened under catalysis to generate high-activity carbon free radicals or oxygen free radicals, and the high-activity substances are covalently bonded with various proteins of the plasmodium and alkylated to destroy the normal physiological functions of the plasmodium, so that the plasmodium is killed.
Disclosure of Invention
The invention aims to provide an artemisinin-based iron pond targeting molecule imaging probe with high specific selectivity.
The second aim of the invention is to provide a preparation method of the artemisinin-based iron pond targeting molecule image probe molecule.
The third object of the invention is to provide the application of the artemisinin-based iron pond targeting molecule imaging probe in-vivo imaging of iron death related diseases.
The artemisinin-based iron pool targeting molecule imaging probe is ART-X-CO-Linker-R 1 The molecular formula (1) is:
or formula (2) is:
wherein, ART is artemisinin; x is-O-c=o-or S; r is R 1 A macrocyclic ligand such as NOTA, DOTA, DTPA; the labelling paramagnetic metal ion is Gd 3+ ，Mn 2+ ，Eu 2+ The labelling nuclides are 99m Tc、 111 In、 18 F、 177 Lu、 64 Cu or 68 Ga, etc.; n and m represent different algebraic backbone molecules.
The structural formulas of NOTA, DOTA and DTPA are as follows:
the Linker has the structure that:
the probe is selected from, but not limited to, any one of the following structural compounds:
the preparation method of the artemisinin-based iron pool targeting molecule image probe can be as follows: using artemisinin as Fe 2+ A targeting part, leading out a linking group at the 12-position hydroxyl site of the structure, connecting a macrocyclic ligand through an amide reaction, and finally chelating a paramagnetic metal ion Gd with magnetic resonance imaging contrast capability 3+ 、Mn 2+ Or Eu 2+ Or radionuclides with positron emission tomography imaging capability 99m Tc、 111 In、 18 F、 177 Lu、 64 Cu or 68 Ga, constructing an artemisinin-based iron pool targeting molecule image probe.
The artemisinin-based iron pool targeting molecule imaging probe can be applied to in-vivo imaging of iron death related diseases.
The iron death-related diseases include, but are not limited to, alzheimer's disease, parkinson's syndrome, huntington's disease, acute/chronic kidney injury, myocardial injury, rheumatoid arthritis, and the like.
The imaging is Magnetic Resonance Imaging (MRI) or Positron Emission Tomography (PET), and the application is to perform visual analysis on a focus part, and provide accurate tissue structure information.
The beneficial effects of the invention are as follows:
(1) The iron pool targeting molecule image probe based on artemisinin reported by the invention has good chemical stability, biological safety and biological distribution property, and the preparation method is simple and easy to implement, and can be used for PET/MRI living body imaging of iron death related diseases.
(2) The iron pool targeting molecule image probe based on artemisinin reported by the invention has better effect on the imaging of focus. In a mouse model of myocardial injury, the probe is preferably capable of selectively enriching in the myocardial injury region, performing visual analysis on the focal site, and providing accurate tissue structure information.
Drawings
FIG. 1 is a mass spectrum of ART-S-DOTA of preparation example 1 of the present invention.
FIG. 2 is a graph showing the MRI imaging effect of ART-S-DOTA-Gd and the relaxation rate r 1 。
FIG. 3 is an MRI image of a mouse model of ART-S-DOTA-Gd myocardial injury.
FIG. 4 shows ART-S-DOTA- 68 PET imaging of Ga mice model of myocardial injury.
Detailed Description
The invention will be further illustrated by the following examples in conjunction with the accompanying drawings. The following examples illustrate probe molecules encompassed by the present invention and their design, preparation, use, which are not limiting of the invention:
the invention provides a compound of the formula:
or the following formula:
ART is artemisinin; x is-O-c=o-or S; r is R 1 Is NOTA, DOTA, DTPA and other macrocyclic ligand, and the labelling paramagnetic metal ion is Gd 3+ ，Mn 2+ ，Eu 2+ The labelling nuclides are 99m Tc、 111 In、 18 F、 177 Lu、 64 Cu or 68 Ga, etc.; n and m represent different algebraic backbone molecules.
The structural formulas of the coordination groups NOTA, DOTA and DTPA are as follows:
in a preferred embodiment of the present invention, formula (1) is selected, wherein X is S, R 1 Is DOTA, the probe molecule is used for marking Gd 3+ ART-S-DOTA-Gd or a marker for MRI probe 68 Ga PET probe ART-S-DOTA- 68 Ga。
Specific examples of the preparation method are given below.
EXAMPLE 1 preparation of ART-S-DOTA-Gd/ART-S-DOTA- 68 Ga
1) Synthesis of ART-S-COOH
200mg of dihydroartemisinin was dissolved in anhydrous dichloromethane, 67. Mu.l of mercaptopropionic acid was added by syringe, and the reaction was carried out at 50℃for 10min. The flask was then transferred to ice bath conditions and 88. Mu.l of boron trifluoride etherate were gradually added dropwise, the solution changing from colorless to pale pink, and the process continued for 30min. After the reaction, adding a proper amount of water to quench excess boron trifluoride diethyl etherate, adding enough methylene dichloride to separate liquid, collecting and combining organic phases, drying the organic phases with anhydrous magnesium sulfate, concentrating the organic phases under reduced pressure, and separating the organic phases by column chromatography (PE: EA=10-5:1) to obtain white solid with the yield of 60%.
2) Synthesis of ART-S-NHS
120mg of ART-S-COOH was dissolved in anhydrous methylene chloride solution, followed by sequentially adding 44.4mg of N-hydroxysuccinimide, 71mg of 4-dimethylaminopyridine and 73.7mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, stirring at room temperature for 2 hours, then adding an appropriate amount of water, collecting the organic phase by liquid separation, drying over anhydrous magnesium sulfate, concentrating under reduced pressure to give an orange-yellow oil in a yield of 70%.
3)DOTA-NH 2 Is synthesized by (a)
50mg of 2-aminoethyl monoamide-DOTA-tris was dissolved in 1mL of 35% HCl and reacted at room temperature for 30 minutes, after which the solvent was removed by rotary evaporation, acetone was added, stirring was continued for 1 hour, a white solid was precipitated, and after suction filtration, the cake layer was washed with acetone and diethyl ether. Drying to obtain DOTA-NH 2 The yield was 72%.
4) Synthesis of ART-S-DOTA
50mg DOTA-NH 2 After dissolving in water, DIPEA or TFA was added to adjust the pH to 12, followed by dissolving 57mg of ART-S-NHS in 2mL of DMF, and after completion of the dissolution, the solution was added to water and stirred at 35℃for 12 to 24 hours. Preparative high performance liquid chromatography, white solid 20mg, yield 20.9%.
5) Synthesis of ART-S-DOTA-Gd
In a 10mL single-necked flask, 20mg of ART-S-DOTA was dissolved in 1.5mL of water to completely dissolve it. GdCl 3 ·6H 2 O was dissolved in 1mL of water and added to the reaction system. The pH of the system is maintained in the range of 6 to 7 by 0.1M NaOH, and the room temperature is maintained for 48 hours. After the reaction was completed, insoluble matter was filtered off with a 0.22 μm microporous membrane, and the filtrate was collected and lyophilized to give 15mg of solid in a yield of 68%.
6)ART-S-DOTA- 68 Synthesis of Ga
Rinsing with 5ml of 0.1mmol/L hydrochloric acid 68 Ge/ 68 Ga generator is obtained 68 Adding 1.25mol/L sodium acetate into Ga stock solution to adjust the pH to 3.5-4.0, adding 20 mug ART-S-DOTA, uniformly mixing, adding at 100 ℃ for 10min, and cooling at room temperature. Filtering with sterile filter membrane to obtain ART-S-DOTA- 68 Ga。
EXAMPLE 2 preparation of ART-O-DOTA-Gd/ART-O-DOTA- 68 Ga
1) Synthesis of ART-O-COOH
200mg of dihydroartemisinin, 400mg of succinic anhydride and 19.6mg of DMAP were dissolved in anhydrous DCM and stirred overnight at room temperature. Water, 50mM HCl and saturated brine were added thereto to wash them with water, and the organic phase was collected and concentrated to dryness. Column chromatography (PE: ea=5-3:1) to obtain white solid with a yield of 80%.
2) Synthesis of ART-O-NHS
100mg of ART-O-COOH was dissolved in an anhydrous methylene chloride solution, followed by 40mg of N-hydroxysuccinimide, 65mg of 4-dimethylaminopyridine and 70mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in this order, followed by stirring at room temperature for 2 hours, then adding an appropriate amount of water, collecting the organic phase by separation, drying over anhydrous magnesium sulfate, and concentrating under reduced pressure to give a white solid in a yield of 68%.
3)DOTA-NH 2 Is synthesized by (a)
50mg of 2-aminoethyl monoamide-DOTA-tris was dissolved in 1ml of 35% HCl and reacted at room temperature for 30 minutes, after which the solvent was removed by rotary evaporation, acetone was added, stirring was continued for 1 hour, a white solid was precipitated, and after suction filtration, the cake layer was washed with acetone and diethyl ether. Drying to obtain DOTA-NH 2 The yield was 72%.
4) Synthesis of ART-O-DOTA
50mgDOTA-NH 2 After dissolving in water, DIPEA or TFA was added to adjust the pH to 12, followed by dissolving 57mg of ART-O-NHS in 2mL of DMF, and after completion of the dissolution, the solution was added to water and stirred at 35℃for 12 to 24 hours. Preparative high performance liquid chromatography, 23mg of white solid with 32% yield.
5) Synthesis of ART-O-DOTA-Gd
In a 10mL single-necked flask, 20mg of ART-O-DOTA was dissolved in 1.5mL of water to completely dissolve it. GdCl 3 ·6H 2 O was dissolved in 1mL of water and added to the reaction system. The pH of the system is maintained in the range of 6 to 7 by 0.1M NaOH, and the room temperature is maintained for 48 hours. After the reaction was completed, insoluble matter was filtered off with a 0.22 μm microporous membrane, and the filtrate was collected and lyophilized to give 15mg of solid in 79% yield.
6)ART-O-DOTA- 68 Synthesis of Ga
Rinsing with 5ml of 0.1mmol/L hydrochloric acid 68 Ge/ 68 Ga generator is obtained 68 Adding 1.25mol/L sodium acetate into Ga stock solution to adjust the pH to 3.5-4.0, adding 20 mug ART-O-DOTA, uniformly mixing, adding at 100 ℃ for 10min, and cooling at room temperature. Filtering with sterile filter membrane to obtain ART-O-DOTA- 68 Ga。
With the ART-S-DOTA-Gd/ART-S-DOTA- 68 The Ga probe is taken as an example, and the experimental result shows that the Ga probe has the following basic performances:
1. ART-S-DOTA-Gd relaxation rate r 1 Is measured by (a)
The mass spectrum of ART-S-DOTA prepared in example 1 is shown in FIG. 1, in order to evaluate r of ART-S-DOTA-Gd 1 Relaxation rate A series of ART-S-DOTA-Gd solutions (0.125 mM, 0.25mM, 0.5mM and 1 mM) were prepared in buffer. For determination of ART-S-DOTA-Gd by Fe 2+ R after activation 1 Relaxation rate of ART-S-DOTA-Gd and Fe 2+ Co-incubation in BSA buffer at a ratio of 1:1. Then in a 7T magnetic resonance scanner (Bruker ICON TM ) T for each solution was collected using the T1-FLASH sequence 1 Weighted spin echo image (TR/TE, 500/20 ms), relaxation rate (R 1 Defined as 1/T 1 ) The concentrations of the different probes are plotted. The curves were fitted by linear regression and the longitudinal molar relaxation rate (r) was calculated from the slope of each curve 1 Units are mM -1 s -1 ). The result is shown in FIG. 2, which shows the relaxation rate r of ART-S-DOTA-Gd 1 At 5.1mM -1 s -1 The method comprises the steps of carrying out a first treatment on the surface of the With Fe 2+ Relaxation Rate after BSA co-incubation 1 11.4mM -1 s -1 (see Table 1), 2-fold improvement.
TABLE 1
2. ART-S-DOTA-Gd in vivo MRI imaging of myocardial mouse model
T performed on mouse model of myocardial injury 1 In the weighted MRI experiment, 200. Mu.L of physiological saline solution containing ART-S-DOTA-Gd was injected through the tail vein. Isoflurane gas anesthesia, mice T1-weighted magnetic resonance imaging were scanned 0min, 30min, 1h and 2h after injection. The acquired nuclear magnetic resonance data were transferred as DICOM images to RadiAnt DICOM Viewer for quantitative image analysis. As shown in FIG. 3, after the injection of ART-S-DOTA-Gd for 60min, the signal enhancement of the myocardial part can be obviously observed, and the myocardial damage is suggested.
3、ART-S-DOTA- 68 Ga in vivo PET imaging in myocardial mouse model
PET imaging experiments were performed on myocardial injury mouse models by tail vein injection of ART-S-DOTA- 68 Ga injection 100 microlitres (200 uCi). Isoflurane gas was anesthetized and microPET imaging was performed 0min, 15min,30min, 1h, 2h and 4h after injection. Observation of the mice with myocardial injury at different time points on ART-S-DOTA- 68 Ga uptake. The results are shown in FIG. 4, which shows the results after injection of ART-S-DOTA- 68 After Ga for 15min, there is a significant accumulation of signals at the myocardial injury site.
The invention is based on the peroxy bridge structure in artemisinin for Fe 2+ Is prepared from artemisinin as Fe 2+ Targeting part, utilizing chelation of macrocyclic ligand (DTPA, DOTA, NOTA) and metal ion (M is paramagnetic metal ion or radioactive element) to endow molecular probe with MRI contrast or PET imaging function, and constructing in-vivo specific tracing active iron pool Fe 2+ Molecular shadow of (C)Like a probe. The invention relates to a probe molecule and Fe 2+ Has high specific selectivity, and can realize dynamic visual evaluation of the high-accumulation iron pool on the focus part on the living body level. The probe can be used for PET/MRI living body imaging of iron death related diseases (such as Alzheimer disease, parkinson syndrome, huntington disease, acute/chronic kidney injury, myocardial injury, rheumarthritis, etc.). In addition, the invention also relates to a structural design and a preparation method of the probe molecule and application of the probe molecule in living body imaging in iron death related diseases.
Claims (5)
1. An artemisinin-based iron pool targeting molecule imaging probe is characterized in that: the structure is a molecular formula (1) or a molecular formula (2), and the molecular formula (1) is as follows:
molecular formula (2):
wherein X is-O-c=o-or S; r is R 1 Is DOTA macrocyclic ligand, which chelates paramagnetic metal ion with magnetic resonance imaging contrast capability or radionuclide with positron emission tomography imaging capability, wherein the paramagnetic metal ion is Gd 3+ 、Mn 2+ 、Eu 2+ The radionuclide is 99m Tc、 111 In、 18 F、 177 Lu、 64 Cu or 68 Ga。
2. An artemisinin-based iron pond targeting molecular imaging probe according to claim 1 wherein the probe is selected from any one of the following structural compounds:
3. the method for preparing the artemisinin-based iron pond targeting molecule image probe according to claim 1 is characterized by comprising the following specific steps: using artemisinin as Fe 2+ A targeting part, leading out a linking chain at the 12-position hydroxyl site of the structure, connecting a macrocyclic ligand through an amide condensation reaction, and finally chelating a paramagnetic metal ion Gd with magnetic resonance imaging contrast capability 3+ 、Mn 2+ Or Eu 2+ Or radionuclides with positron emission tomography imaging capability 99m Tc、 111 In、 18 F、 177 Lu、 64 Cu or 68 Ga, constructing an artemisinin-based iron pool targeting molecule image probe.
4. Use of an artemisinin-based iron pond targeting molecule imaging probe according to claim 1 for the preparation of a live imaging probe for iron death-related diseases.
5. The use according to claim 4, wherein the iron death-related disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, huntington's disease, acute/chronic kidney injury, myocardial injury, rheumatoid arthritis.
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