WO2023003411A1 - 가돌리늄계 화합물, 이를 포함하는 mri 조영제 - Google Patents
가돌리늄계 화합물, 이를 포함하는 mri 조영제 Download PDFInfo
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- WO2023003411A1 WO2023003411A1 PCT/KR2022/010743 KR2022010743W WO2023003411A1 WO 2023003411 A1 WO2023003411 A1 WO 2023003411A1 KR 2022010743 W KR2022010743 W KR 2022010743W WO 2023003411 A1 WO2023003411 A1 WO 2023003411A1
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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
-
- 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
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
Definitions
- the present invention relates to a gadolinium-based compound and an MRI contrast agent containing the same.
- Degenerative brain diseases include Parkinson's disease, vascular dementia, Alzheimer's disease, and the like, and neurotoxicity due to excessive accumulation of amyloid beta polymer (oligomeric A ⁇ ) is considered as one of the causes of the disease.
- Amyloid beta is a major component of amyloid plaques found in the brains of Alzheimer's patients, and refers to a 36 to 43 amino acid peptide that is critically involved in Alzheimer's disease.
- the peptide is derived from amyloid precursor protein (APP).
- amyloid beta molecule can aggregate to form a soluble polymer that can exist in various forms.
- the formed amyloid beta polymer (oligomeric A ⁇ ) is toxic to nerve cells and is directly involved in the development of Alzheimer's disease as it accumulates excessively in the brain. It is known to do Therefore, it was expected that detecting changes in the concentration of amyloid beta polymer would enable early diagnosis of degenerative brain diseases.
- Magnetic Resonance Image is a method of obtaining anatomical, physiological, and biochemical information images of the body by using a phenomenon in which the distribution of hydrogen atoms is different between tissues in the body and the hydrogen atoms are relaxed in a magnetic field. .
- MRI does not use radiation that is harmful to the human body and uses radio waves and the gradient of a magnetic field under a strong magnetic field to create images of the inside of the body.
- a contrast agent is injected into an object to obtain an MRI image.
- Contrast between tissues on an MRI image is a phenomenon that occurs because a relaxation action in which a nuclear spin of a water molecule returns to an equilibrium state in a tissue is different for each tissue.
- the contrast agent uses a paramagnetic or superparamagnetic material to affect the relaxation effect, thereby widening the difference in relaxation between tissues and causing a change in the MRI signal, thereby making the contrast between tissues clearer.
- contrast agent based on a gadolinium (Gd) chelate.
- Gd-DTPA Magneticnevist®
- Gd-DOTA Dotaram®
- Gd(DTPA-BMA) Omniscan®
- Gd(DO3A-HP) ProHance®
- Gd(BOPTA) MultiHance®
- most commercially available contrast agents are non-specific contrast agents that are distributed in the extracellular space (ECF). As a specific contrast agent, only a liver-specific contrast agent is used.
- One object of the present invention is to provide a compound that specifically binds to amyloid beta polymer.
- Another object of the present invention is to provide an MRI contrast agent containing the compound.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neuroinflammatory diseases comprising the compound.
- the present invention provides a compound having Formula (1) below.
- L is *-(CH 2 ) x -A 1 -(CH 2 ) y -A 2 -(CH 2 ) z -*;
- x, y and z are each independently selected as any integer from 0 to 5;
- a 1 and A 2 are a single bond, in the group containing *-COO-*, *-CO-*, *-NH-*, *-CH 2 -*, *-CONH-* and *-O-* one or more structures, each independently selected,
- X is a structure having formula (2):
- the A 2 may be *-NH-*.
- the A 1 may be *-CONH-*.
- the x may be 1.
- the y may be 2.
- the z may be 0.
- the compound may have the following formula (3).
- the gadolinium (Gd) may coordinate with one or more water molecules.
- the compound may specifically bind to mammalian amyloid beta polymer (oligomeric A ⁇ ).
- the compound may have a relaxation rate of 3.5 to 4.4 s -1 .
- the compound can cross the blood-brain barrier (BBB) when injected intravenously.
- BBB blood-brain barrier
- the present invention provides an MRI contrast agent containing the compound.
- the MRI contrast agent can be used for diagnosis of degenerative brain disease.
- the MRI contrast agent may be used for diagnosis of Alzheimer's disease.
- the present invention provides a pharmaceutical composition for preventing or treating neuroinflammatory diseases comprising the compound or a pharmaceutically acceptable salt thereof.
- the neuroinflammatory disease may be an inflammatory neurodegenerative brain disease.
- the inflammatory neurodegenerative brain disease may be a disease selected from Alzheimer's disease or Parkinson's disease.
- the compound according to the embodiment of the present invention can specifically bind to the amyloid beta polymer, and therefore, an MRI contrast agent containing the compound can be used for diagnosis of degenerative brain diseases including Alzheimer's disease.
- the compound according to the embodiment of the present invention reduces oxidative stress that induces neuroinflammation and reduces inflammatory factors such as NLRP3 and ASC expressed in pathways that induce neuroinflammation due to antioxidant and anti-inflammatory functions, It can be used as an active ingredient of a pharmaceutical composition for preventing or treating neuroinflammatory diseases.
- 1 to 9 are views showing experimental results according to experimental examples of the present invention.
- a compound according to an embodiment of the present invention may have the following formula (1).
- the gadolinium ion (Gd 3+ ) may coordinate with the carboxylate (COO ⁇ ) group of the above formula (1) to form a complex compound.
- L may be *-(CH 2 ) x -A 1 -(CH 2 ) y -A 2 -(CH 2 ) z -*, and x, y and z are any of 0 to 5
- Each can be independently selected as an integer of, A 1 and A 2 are single bonds, *-COO-*, *-CO-*, *-NH-*, *-CH 2 -*, *-CONH-* And *-O-* may be one or more structures each independently selected from the group containing. * is a bonding site.
- the L may be a linker connecting nitrogen and the X in the cyclic structure of the compound.
- the A 1 and A 2 may determine a method in which the linker connects nitrogen and the X in the cyclic structure of the compound or a functional group determined by the method.
- the x, y and z may determine the length of the chain linking the A 1 and A 2 in the linker.
- the A 2 may be *-NH-*.
- the A 1 may be *-CONH-*.
- the x may be 1.
- the y may be 2.
- the z may be 0.
- the gadolinium (Gd) in the compound may coordinate with one or more water molecules.
- X may have a structure having the following Formula (2).
- the compound may have the following formula (3).
- the compound may specifically bind to mammalian amyloid beta polymer (oligomeric A ⁇ ). In one embodiment, the compound may have a relaxation rate of 3.5 to 4.4 s -1 . In one embodiment, the compound can cross the blood-brain barrier (BBB) when injected intravenously.
- BBB blood-brain barrier
- the compound according to the embodiment of the present invention can specifically bind to the amyloid beta polymer.
- An MRI contrast agent according to an embodiment of the present invention may include the compound.
- the MRI contrast agent can be used for diagnosis of degenerative brain disease.
- the MRI contrast agent may be used for diagnosis of Alzheimer's disease.
- the MRI contrast agent according to the embodiment of the present invention can be used for diagnosis of degenerative brain diseases including Alzheimer's disease.
- a pharmaceutical composition for preventing or treating neuroinflammatory diseases may include the compound or a pharmaceutically acceptable salt thereof.
- the neuroinflammatory disease may be an inflammatory neurodegenerative brain disease.
- the inflammatory neurodegenerative brain disease may be a disease selected from Alzheimer's disease or Parkinson's disease.
- the "pharmaceutically acceptable salt” is not limited as long as it forms an addition salt with the compound, and includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
- the compound according to the present invention can be converted into a salt thereof by a conventional method, and the preparation of the salt can be easily performed by a person skilled in the art based on the structure of the compound without a separate explanation.
- the pharmaceutical composition of the present invention may include the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof alone, but may further include a pharmaceutically acceptable carrier in addition thereto.
- the pharmaceutically acceptable carrier may be one commonly used in the pharmaceutical field, and may include an excipient (eg, starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (eg, physiological saline, purified water, etc.).
- prevention means suppressing the development of a disease or disease in a subject who has never been diagnosed with a neuroinflammatory disease or disease, but is prone to such a disease or disease.
- treatment means inhibition of development of a neuroinflammatory disease or disease, alleviation of a disease or disease, and elimination of a disease or disease.
- composition of the present invention can be prepared in various forms for parenteral or oral administration according to known methods.
- a Gd-DO3A-Pca compound was prepared by stepwise synthesis of material 1 to final material 5 .
- Protocatechuic acid (6.97 mmol) was dissolved in dimethylformamide and stirred at 0 °C. Then, EDC ⁇ HCl (7.67 mmol) and HOBt hydrate (7.67 mmol) dissolved in dimethylformamide were added to the gallic acid solution and stirred for 30 minutes. Next, 2 (4.88 mmol) dissolved in dimethylformamide was added to the reaction mixture, and DIPEA (13.94 mmol) was added thereto, followed by stirring at room temperature for 24 hours. Thereafter, dimethylformamide was concentrated as much as possible by filtration under reduced pressure, extracted using dichloromethane and brine, dehydrated with sodium sulfate, and filtered under reduced pressure. Thereafter, the solid was separated by performing open column chromatography in a mixed solvent condition of dichloromethane/methanol. The next reaction proceeded without further separation and purification.
- Gd-DO3A-Pca was analyzed through HR-MS.
- 1 is a diagram showing the result. Referring to FIG. 1, it can be confirmed that a peak (738.1731 m/z) corresponding to the predicted peak (738.1734 m/z) for Gd-DO3A-Pca appears.
- FIG. 2 results of analyzing the purity of Gd-DO3A-Pca using HPLC are shown in FIG. 2 .
- FIG. 2 it can be confirmed that Gd-DO3A-Pca has a purity of about 98%.
- a phantom was prepared by diluting the gadolinium complex in tertiary distilled water at 5 concentrations (0.0625, 0.125, 0.25, 0.5, 1 mM), and then the T 1 and T 2 relaxation times were measured in 3T MRI. .
- r 1 of Gd-DO3A-Pca has a value of 3.6 ⁇ 0.1 and r 2 has a value of 4.3 ⁇ 0.1, which is a self-relaxation value sufficient for clinical use, so Gd-DO3A- It was confirmed that Pca can be used as a contrast medium.
- the Gd-DO3A-Pca of the present invention has sufficient stability to be used as an MRI contrast medium because the R 2 change rate maintains a large value of 0.9 or more.
- R 2 values are measured by taking T 2 -weighted images in 3T MRI for 3 weeks. By measuring the R 2 value over time, it is possible to confirm the change in the value immediately after dilution, and when the value is kept constant, the pH stability can be evaluated as high.
- Gd-DO3A-Pca of the present invention showed no change in R 2 value for 3 weeks in the pH range of 3-9, and even under strong acidic conditions of pH 1 and pH 11, the value The change was not great. Through the results, it was confirmed that Gd-DO3A-Pca was stable under pH conditions in the body and stable even under strong acidic conditions.
- the free radical scavenging ability of Gd-DO3A-Pca was evaluated by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay.
- DPPH 2,2-Diphenyl-1-picrylhydrazyl
- protocatechuic acid and vitamin C ascorbic acid
- vitamin C ascorbic acid
- DPPH radical has a deep purple color and turns yellow when reduced by reacting with antioxidants.
- the antioxidant effect of Gd-DO3A-Pca can be verified by measuring the absorbance change at 517 nm wavelength due to the redox reaction.
- Gd-DO3A-Pca showed a higher radical scavenging activity than that of protocatechuic acid, a comparative group, and vitamin C (ascorbic acid), a representative antioxidant. These results show that Gd-DO3A-Pca has an excellent effect of inhibiting oxidative stress.
- amyloid beta polymer targeting properties of Gd-DO3A-Pca and a commercial contrast agent (Gadovist ® ) according to an embodiment of the present invention were evaluated in a 9.4T MR instrument.
- Fibrils amyloid beta polymers formed by aggregation of overexpressed amyloid beta, accumulate in the brain, cause toxicity, destroy nerve cells, and cause Alzheimer's disease, a degenerative brain disease.
- Gd-DO3A-Pca according to an embodiment of the present invention has a function of targeting amyloid beta polymer, a toxic protein, and thus may have a function of diagnosing Alzheimer's disease.
- BV-2 cells are activated by LPS (Lipopolysaccharides), they are commonly used in neuroinflammatory cell experiments. 5x10 4 BV-2 cells were seeded in 6 wells and treated with 200 ng LPS derived from Escherichia coli O127:B8 under serum free media. After 4 hours, LPS was removed, and Gd-DO3A-Pca was treated at different concentrations (0, 100, 200, 400 uM), and after 20 hours, Griess assay was performed using the cell supernatant. In the recovered cells, the expression level of inflammatory factors was confirmed by western blotting. In this experiment, the cells not treated with LPS and the group treated with Gd-DO3A-Pca in the corresponding normal BV-2 cells were tested together to confirm the single effect of Gd-DO3A-Pca on BV-2 cells.
- LPS Lipopolysaccharides
- Gd-DO3A-Pca inhibited free radicals NO (nitric oxide) and iNOS (inducible nitric oxide synthase) induced by LPS, thereby reducing oxidative stress.
- NLRP3 inflammasome pathway that induces neuroinflammation is well known, and Gd-DO3A-Pca reduces inflammatory factors such as NLRP3 and ASC expressed in the corresponding pathway (western blot) Figure 9 can be checked through
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- Radiology & Medical Imaging (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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Abstract
Description
r1 | r2 | |
Gd-DO3A-Pca | 3.6±0.1 | 4.3±0.1 |
Gadovist® | 3.9±0.1 | 4.8±0.1 |
Dotarem® | 3.4±0.1 | 3.9±0.2 |
Claims (15)
- 제1항에 있어서,상기 A2는 *-NH-*인,화합물.
- 제2항에 있어서,상기 A1은 *-CONH-* 인,화합물.
- 제3항에 있어서,상기 x는 1이고,상기 y는 2이고,상기 z는 0인,화합물.
- 제1항에 있어서,상기 가돌리늄(Gd)이 하나 이상의 물 분자와 배위하는,화합물.
- 제1항에 있어서,상기 화합물은, 포유동물의 아밀로이드 베타 중합체 (oligomeric Aβ)에 특이적으로 결합하는,화합물.
- 제1항에 있어서,상기 화합물은, 3.5 내지 4.4 s-1의 자기이완율(relaxivity)을 가지는,화합물.
- 제1항에 있어서,상기 화합물은, 정맥 주사를 통해 주입되는 경우 뇌-혈관 장벽(Blood-Brain-Barrier; BBB)을 통과하는,화합물.
- 제1항 내지 제9항 중 어느 한 항에 따른 화합물을 포함하는,MRI 조영제.
- 제10항에 있어서,상기 MRI 조영제는 퇴행성 뇌질환의 진단에 사용되는,MRI 조영제.
- 제11항에 있어서,상기 MRI 조영제는 알츠하이머(Alzheimer) 병의 진단에 사용되는,MRI 조영제.
- 제1항 내지 제9항 중 어느 한 항에 따른 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는,신경염증성 질환의 예방 또는 치료용 약학적 조성물.
- 제13항에 있어서,상기 신경염증성 질환은 염증성 신경 퇴행성 뇌질환인 것인,약학적 조성물.
- 제14항에 있어서,상기 염증성 신경 퇴행성 뇌질환은 알츠하이머(Alzheimer) 병 또는 파킨슨 병으로부터 선택된 질환인 것인,약학적 조성물.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040241096A1 (en) * | 2000-10-19 | 2004-12-02 | The General Hospital Corporation, A Massachusetts Corporation | Imaging of enzymatic activity |
KR20210068973A (ko) * | 2019-12-02 | 2021-06-10 | 경북대학교 산학협력단 | 신규한 가돌리늄계 화합물, 이를 함유하는 염증성 질환의 치료 또는 예방용 약제학적 조성물, 및 mri 조영 조성물 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040241096A1 (en) * | 2000-10-19 | 2004-12-02 | The General Hospital Corporation, A Massachusetts Corporation | Imaging of enzymatic activity |
KR20210068973A (ko) * | 2019-12-02 | 2021-06-10 | 경북대학교 산학협력단 | 신규한 가돌리늄계 화합물, 이를 함유하는 염증성 질환의 치료 또는 예방용 약제학적 조성물, 및 mri 조영 조성물 |
Non-Patent Citations (3)
Title |
---|
CHEN JOHN W., PHAM WELLINGTON, WEISSLEDER RALPH, BOGDANOV ALEXEI: "Human myeloperoxidase: A potential target for molecular MR imaging in atherosclerosis", MAGNETIC RESONANCE IN MEDICINE, WILEY-LISS, US, vol. 52, no. 5, 1 November 2004 (2004-11-01), US , pages 1021 - 1028, XP093027171, ISSN: 0740-3194, DOI: 10.1002/mrm.20270 * |
ENDRES PAUL J., PAUNESKU TATJANA, VOGT STEFAN, MEADE THOMAS J., WOLOSCHAK GAYLE E.: "DNA-TiO 2 Nanoconjugates Labeled with Magnetic Resonance Contrast Agents", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 129, no. 51, 1 December 2007 (2007-12-01), pages 15760 - 15761, XP055830967, ISSN: 0002-7863, DOI: 10.1021/ja0772389 * |
KIM HEE-KYUNG, LEE JUNG-JIN, CHOI GARAM, SUNG BOKYUNG, KIM YEOUN-HEE, BAEK AH RUM, KIM SOYEON, SONG HUIJIN, KIM MINSUP, CHO ART E.: "Gadolinium-Based Neuroprognostic Magnetic Resonance Imaging Agents Suppress COX-2 for Prevention of Reperfusion Injury after Stroke", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 63, no. 13, 9 July 2020 (2020-07-09), US , pages 6909 - 6923, XP055863120, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c00285 * |
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