WO2018033132A1 - Composé d'imagerie par résonance magnétique, intermédiaire de celui-ci, agent d'imagerie par résonance magnétique et son application, et procédé d'imagerie par résonance magnétique - Google Patents

Composé d'imagerie par résonance magnétique, intermédiaire de celui-ci, agent d'imagerie par résonance magnétique et son application, et procédé d'imagerie par résonance magnétique Download PDF

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WO2018033132A1
WO2018033132A1 PCT/CN2017/098003 CN2017098003W WO2018033132A1 WO 2018033132 A1 WO2018033132 A1 WO 2018033132A1 CN 2017098003 W CN2017098003 W CN 2017098003W WO 2018033132 A1 WO2018033132 A1 WO 2018033132A1
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compound
formula
acid
magnetic resonance
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刘潜
张亚卓
杨潇骁
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Beijing Neurosurgical Institute
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Beijing Neurosurgical Institute
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K49/10—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • G01N24/088—Assessment or manipulation of a chemical or biochemical reaction, e.g. verification whether a chemical reaction occurred or whether a ligand binds to a receptor in drug screening or assessing reaction kinetics

Definitions

  • the present invention relates to nuclear magnetic resonance imaging compounds, intermediates thereof, nuclear magnetic resonance imaging reagents and applications, and nuclear magnetic resonance imaging methods.
  • Dopamine (English name dopamine, hereinafter also referred to as DA) is the most important catecholamine neurotransmitter in the central nervous system and plays an important role in both the central and peripheral nervous systems.
  • DA dopamine
  • the discovery of DA and its receptors has led to major breakthroughs in neurological and clinical psychiatry.
  • dopamine D 2 receptor expression In the anterior and middle lobes of the normal pituitary, there is a certain level of dopamine D 2 receptor expression, which mediates the secretion of hormones such as prolactin against prolactin (also known as prolactin, hereinafter referred to as PRL) and melanocyte stimulating hormone.
  • PRL prolactin
  • melanocyte stimulating hormone melanocyte stimulating hormone
  • Dopamine D 2 receptor is highly expressed in PRL type pituitary adenoma, and the dopamine D 2 receptor agonist has a good clinical effect in the treatment of PRL type pituitary adenoma. It has become the treatment of choice for most prolactinomas. With the development of molecular biology and radiology technology, great progress has been made in the study of dopamine D 2 receptor molecules. In addition to PRL-type adenomas, dopamine D 2 receptor expression was detected in a significant proportion of non-PRL adenomas, including growth hormone and gonadotropin and non-functional pituitary adenomas, dopamine The therapeutic effect of D 2 receptor agonists has been deeply explored and analyzed.
  • the invention provides a novel nuclear magnetic resonance imaging compound, an intermediate thereof, a nuclear magnetic resonance imaging agent and application thereof, and a nuclear magnetic resonance imaging method.
  • an aspect of the invention provides a benzamide methylpyrrolidine compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, and halogen;
  • R 2 is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen;
  • R 3 is selected from an alkyl group having 1 to 5 carbon atoms (optionally selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl; more preferably selected from methyl, ethyl , propyl, isopropyl, butyl or isobutyl; more preferably selected from methyl, ethyl, propyl), or H;
  • X 1 is selected from the group consisting of an alkylene group having 1 to 10 carbon atoms (preferably a linear or branched alkylene group having 1 to 6 carbon atoms, more preferably selected from a methylene group, an ethylene group, and an anthracene group).
  • Base isopropylidene, n-n-butyl, isobutylene, tert-butyl, sec-butylene, n-n-pentyl, n-hexylene; more preferably methylene, ethylene, arylene Base, n-butylene, sub-n-hexyl), or a deletion;
  • X 3 is selected from an alkyl group having 1 to 5 carbon atoms (preferably selected from the group consisting of methylene, ethylene, n-propylene, isopropylidene, n-butylene, isobutylene, and tert-butyl) , sec-butylene, n-n-pentyl, or n-hexylene; more preferably methylene, ethylene);
  • X 4 is selected from the group consisting of oxygen, sulfur, and methylene
  • Ln is selected from Gd or Eu
  • halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • R 1 is selected from the group consisting of methyl, ethyl, methoxy, and ethoxy;
  • R 2 is selected from the group consisting of methyl, ethyl, methoxy, and ethoxy;
  • R 3 is selected from the group consisting of H, methyl, ethyl, and propyl;
  • X 1 is selected from the group consisting of methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, or a deletion;
  • X 3 is a methylene group or an ethylene group
  • X 4 is selected from the group consisting of oxygen and sulfur
  • Ln is selected from Gd or Eu.
  • the compound of the formula (IA) has a structure represented by the formula (IA-1),
  • the compound of the formula (IA-1) has a structure represented by the formula (IA-1a),
  • the compound of the formula (IA-1a) has a structure represented by the formula (IA-1aa),
  • the compound of the formula (IA) has a structure represented by the formula (IA-2),
  • the compound of the formula (IA-2) has a structure represented by the formula (IA-2a),
  • the compound of the formula (IA-2a) has a structure represented by the formula (IA-2aa),
  • the pharmaceutically acceptable salt comprises an anionic salt and a cationic salt of a compound of formula I;
  • the pharmaceutically acceptable salt comprises an alkali metal salt, an alkaline earth metal salt, an ammonium salt of a compound of formula I;
  • the alkali metal comprises sodium, potassium, lithium, cesium, the alkaline earth Metals include magnesium, calcium, and barium;
  • the pharmaceutically acceptable salt comprises a salt of a compound of formula I with an organic base; alternatively, the organic base comprises a trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline , dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.
  • the organic base comprises a trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline , dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.
  • the trialkylamine comprises trimethylamine, triethylamine, N Ethyldiisopropylamine; optionally, the N-alkylmorpholine comprises N-methylmorpholine;
  • the pharmaceutically acceptable salt comprises a salt of a compound of formula I with an acid; optionally, the acid comprises a mineral acid, an organic acid; alternatively, the mineral acid comprises hydrochloric acid, hydrobromic acid , hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; optionally, the Acids include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, Ethane sulfonic acid, p-toluenesulfonic acid, glutamic acid, pamoic acid;
  • Another aspect of the present invention provides an intermediate for preparing a benzamide methylpyrrolidine compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which has a structure represented by the formula (a-1) ,
  • R is selected from H or propyne.
  • R is selected from H or propyne.
  • Another aspect of the present invention provides a nuclear magnetic resonance imaging agent comprising the above compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the nuclear magnetic resonance imaging agent is used for the detection of a dopamine D2 receptor.
  • the nuclear magnetic resonance imaging agent is for use in the diagnosis of a disease associated with dopamine D2 receptor expression; alternatively, the disease is a pituitary adenoma.
  • Another aspect of the present invention provides a nuclear magnetic resonance imaging method, wherein the compound of the above formula (I) or a pharmaceutically acceptable salt thereof is used as a nuclear magnetic resonance imaging agent.
  • Another aspect of the present invention provides a nuclear magnetic resonance detecting method of a dopamine D2 receptor, wherein the compound of the above formula (I) or a pharmaceutically acceptable salt thereof is used as a nuclear magnetic resonance imaging agent.
  • the nuclear magnetic resonance detection comprises dopamine D2 receptor imaging, dopamine D2 receptor detection, or pituitary adenoma detection.
  • Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a nuclear magnetic resonance imaging agent for the diagnosis of disease.
  • the disease is a disease associated with dopamine D2 receptor expression, optionally the pituitary adenoma.
  • the structure of the compound of the present invention consists of three parts, a benzoylmethylpyrrolidine moiety having a function of binding to the dopamine D2 receptor, and a paramagnetic lanthanide rare earth metal ion Gd ( ⁇ ) or Eu ( ⁇ ). a chelated octadentate ligand moiety, and a triazole linking arm moiety that couples the two moieties together, for example, using an alkyne-azido click chemistry.
  • the compound of the formula (I) or a pharmaceutically acceptable salt thereof of the present invention has binding to the dopamine D2 receptor and relies on intramolecular chelation
  • the ruthenium and osmium chelating structures formed by the group specifically enhance the contrast of the tissue on the image of the dopamine D2 receptor in the magnetic resonance imaging, thereby facilitating the diagnosis of the type of lesion.
  • Another aspect of the present invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for detection of nuclear magnetic resonance relaxation rate and nuclear magnetic resonance imaging.
  • Another aspect of the present invention provides a nuclear magnetic resonance relaxation rate detecting, nuclear magnetic resonance imaging detecting reagent comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for nuclear magnetic resonance relaxation rate detection, nuclear magnetic resonance imaging detection, and pituitary adenoma detection.
  • Another aspect of the present invention provides a nuclear magnetic resonance relaxation rate detection, a nuclear magnetic resonance imaging detection, and a pituitary adenoma detection reagent comprising the above compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in the diagnosis of a dopamine D2 receptor, and a medicament for the treatment of a disease associated with dopamine D2 receptor expression. application.
  • the diseases associated with dopamine D2 receptor expression include, but are not limited to, pituitary adenomas of different subtypes and the like.
  • Another aspect of the present invention provides an agent for diagnosing a dopamine D2 receptor, which comprises the above compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a medicament for the treatment of a disease associated with dopamine D2 receptor expression, comprising a compound of formula (I) above, or a pharmaceutically acceptable salt thereof.
  • the above compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a low cytotoxic effect.
  • Figure 1 is a graph showing the dose-effect relationship of in vitro cytotoxicity of compounds 1-5 at different concentrations.
  • Figure 2 is a T1-weighted image of Compound 1 and Gd-DTPA contrast agents at various concentrations.
  • Figure 3 is an in vitro T1-weighted image of different concentrations of Compound 1 and Gd-DTPA contrast agent administered to GH3 cells and PC12 cells with different dopamine D 2 receptor expression levels.
  • Figure 4 is a graph showing the ratio of in vitro nuclear magnetic imaging T1 signal after administration of Compound 1-5 and Gd-DTPA contrast agent to GH3 cells and PC12 cells with different dopamine D 2 receptor expression levels.
  • Figure 5 is a magnetic T1-weighted image of the body core after administration of Compound 1 and Gd-DTPA contrast agent to dopamine D 2 receptor knockout mice.
  • the reaction mixture was diluted with 80 ml of DCM, and washed with saturated NaHCO 3 and saturated aqueous NaCI solution three times, and the organic layer was dried over Na 2 SO 4 , filtered, and the filtrate was concentrated in yellow oil, and separated by silica gel column, mobile phase petroleum ether: acetic acid The ester was collected as a pale yellow oil (yield: 85.6%).
  • the reaction mixture was diluted with 80 ml of DCM, and washed with saturated NaHCO 3 and saturated aqueous NaCI solution three times, and the organic layer was dried over Na 2 SO 4 , filtered, and the filtrate was concentrated in yellow oil, and separated by silica gel column, mobile phase petroleum ether: acetic acid The ester was reduced to a concentration of 0.756 g (yield: 73.2%).
  • reaction mixture was concentrated and saturated aqueous NaCl, and extracted 3 times with ethyl acetate, the organic layer with distilled water, saturated aqueous NaHCO 3, washed with saturated aqueous NaCl 3 times each, dried Na 2 SO 4, filtered and concentrated the residue was dried in a vacuum The mixture was dried to a brown oil to give a brown oil: 6.455 g.
  • the compound 2f prepared in Preparation 33 was dissolved in 15 ml of TFA, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated to give a brown oil.
  • the compound 3f prepared in Preparation 35 was dissolved in 15 ml of TFA, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated to give a brown oil.
  • the compounds of the present invention can also be obtained by other organic reaction routes, and those skilled in the art can obtain the present invention by designing an organic reaction route based on the disclosure of the present invention or even on a technical basis. compound of.
  • the rat pituitary tumor cell line GH3 is a product of the American ATCC company.
  • DMEM medium and high quality fetal bovine serum were purchased from Gibco.
  • Dimethylsulphoxide (DMSO), trypsin was purchased from Sigma, USA, MTT was purchased from Genview, USA, penicillin and streptomycin were purchased from North China Pharmaceutical Co., Ltd., and other reagents were commercially available analytical grades.
  • HERAcell150 CO 2 cell incubator Hellet, Germany
  • IMT-2 inverted microscope Olympus, Japan
  • 550 enzyme-linked immunosorbent assay BIO-RAD, USA
  • consumables for Petri dishes 96 cell culture plates (Costar, USA), etc.
  • the frozen rat pituitary tumor cell line GH3 cells were resuscitated, and the DMEM medium containing 100 mL/L fetal bovine serum and 100 U/mL penicillin and 100 U/mL streptomycin was used at 37 ° C, 5% CO 2 and saturated humidity.
  • the cells were cultured in a constant temperature incubator, periodically passaged according to the growth conditions, and experiments were carried out using the cells after the third passage.
  • Compounds 1-5 were formulated into 5 different concentrations in DMEM medium containing 10% fetal bovine serum: 5 ⁇ M/L, 10 ⁇ M/L, 50 ⁇ M/L, 500 ⁇ M/L, 5000 ⁇ M/L. concentration;
  • blank group only DMEM medium containing 10% fetal bovine serum was added;
  • the third passage of pituitary adenoma GH3 cells was divided into 6 groups (5 groups of experimental groups and 1 group of control groups).
  • the passage cells were inoculated into three 96-well cell culture plates at 4000/100 ul per well, and divided into 6 groups according to the above grouping scheme, and 8 replicates were set for each group.
  • the cells were attached to the cells for 24 hours, the cells were replaced with the corresponding concentrations of the compound 1-5, and cultured in a constant temperature incubator at 37 ° C, 5% CO 2 and saturated humidity.
  • 20 ⁇ l of a 5 mg/ml MTT solution (MTT of 3-(4,5-dimethylthiazole-2)-2,5-diphenyl was added to each well in the wells to be tested.
  • Tetrazolium bromide trade name is thiazolyl blue, English is 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, solvent is dimethyl sulfoxide, That is, DMSO), incubation was continued for 4 h at 37 ° C, the culture was terminated, and the culture supernatant in the well was carefully aspirated, 100 ⁇ l of dimethyl sulfoxide (DMSO) was added to each well, and shaken for 10 min. The wavelength of 490 nm was selected, and the absorbance value OD 490 of each well was measured on an enzyme-linked immunosorbent detector.
  • DMSO dimethyl sulfoxide
  • Figure 1 is a dose-effect relationship diagram of in vitro cytotoxicity of compounds 1-5 at different concentrations. It can be seen that the test compound has no significant effect on the proliferation of pituitary adenoma cells at a concentration of 5-5000 ⁇ M/L, and the series of compounds have a low cytotoxic effect. From this, it is understood that the benzamide methylpyrrolidine compound synthesized by the present invention has low toxicity as a contrast agent for nuclear magnetic resonance imaging of pituitary adenoma cells.
  • Example Compounds 1-5 and gadopentetate (Gd-DTPA, diethylene pentamine acetate, clinical nuclear magnetic contrast agent) contrast agent were prepared at the same concentration, and Example Compounds 1-5 and Gd-DTPA were respectively used.
  • PBS phosphate buffer, in which the concentration of the phosphate buffer solution was 0.01 mol/L, pH 7.2
  • PBS phosphate buffer, in which the concentration of the phosphate buffer solution was 0.01 mol/L, pH 7.2
  • the Eppendof tube was placed on a Bruker small animal nuclear magnetic resonance machine (Bruker, Germany) for magnetic resonance scanning T1-weighted imaging.
  • Figure 2 is a T1-weighted image of Compound 1 and Gd-DTPA contrast agents at various concentrations.
  • the signal of the example compound and the Gd-DTPA contrast agent were measured, and the signal intensity was measured by selecting a ROI (return on interesting) in each sample size, and the average of the measurement results was taken. The experiment was repeated three times.
  • the signal intensities of the compoundes 1-5 and Gd-DTPA contrast agents of Examples were subjected to correlation regression linear analysis, and the slopes thereof were 1-5 and the relaxation rate (R) of the Gd-DTPA contrast agent (see Table 1).
  • the results showed that the compound/Gd-DTPA signal ratio of any of the compounds of Examples 1-5 was about 1, and the results showed that the compound of Example 1-5 and the Gd-DTPA contrast agent were subjected to magnetic resonance T1 imaging at the same concentration.
  • the signal difference is similar to the relaxation rate difference. That is, at room temperature, the compound of the example 1-5 has a good nuclear magnetic imaging effect as the Gd-DTPA contrast agent. It is further shown that the benzamide methylpyrrolidine compound synthesized by the invention has good contrast ability and can be used as a contrast agent for magnetic resonance imaging.
  • gadopentetate is a small molecule nuclear magnetic resonance or magnetic resonance contrast agent currently widely used, and is a non-selective non-specific contrast agent.
  • the DMEM medium of /mL penicillin and 100 U/mL streptomycin was cultured in a constant temperature incubator at 37 ° C, 5% CO 2 and saturated humidity, and periodically passaged according to the growth condition, and the cells were subjected to the third passage.
  • GH3 and PC12 cells were seeded in a six-well plate at a cell density of 1*10 6 cells/ml, respectively. After the cells were attached, different concentrations of the compound of Example 1-5 and Gd-DTPA contrast agent (0, 5 ⁇ M, 10 ⁇ M, 50 ⁇ M, 500 ⁇ M and 5mM, PBS with a concentration of 0.01mol/L and pH 7.2 were added to GH3 and PC12 cell culture medium for 4h, then washed with PBS three times, and completely digested with 0.25% trypsin. Centrifuge at 1200 rpm for 4 min and resuspend in a 0.5 mL Eppendof tube. The Eppendof tube was placed on a Bruker small animal nuclear magnetic resonance machine (Bruker, Germany) for magnetic resonance scanning T1-weighted imaging.
  • Bruker small animal nuclear magnetic resonance machine Bruker, Germany
  • Figure 3 is an in vitro T1-weighted image of different concentrations of Compound 1 and Gd-DTPA contrast agent administered to GH3 cells and PC12 cells with different dopamine D 2 receptor expression levels.
  • Fig. 3A there was no significant difference in the nuclear magnetic signal intensity between the Gd-DTPA contrast agent in the GH3 and PC12 cells in which the dopamine D 2 receptor expression was different
  • Fig. 3B the example compound 1 was dopamine D 2 receptor-containing cells present in NMR signal intensity dependent change of the concentration gradient, while the NMR signal intensity higher dopamine D 2 receptor expression in PC12 cells was significantly lower than dopamine D 2 receptor is expressed in the amount of Nuclear magnetic signal intensity in GH3 cells.
  • Wild type mice (normal expression of dopamine D 2 receptor) and dopamine D 2 receptor knockout mice were divided into two groups and placed on a Bruker small animal nuclear magnetic resonance machine (Bruker, Germany) for magnetic resonance imaging.
  • the pre-fortified T1-weighted images of the pituitary imaging agent were obtained, and the compound of Example 1 and the Gd-DTPA contrast agent were administered to the tail vein (the dose was 0.5 mmol/kg of the mouse body weight), and 10 minutes later, the injection was carried out.
  • Mice with compound 1 and Gd-DTPA contrast agent were placed on a Bruker small animal nuclear magnetic resonance machine (Bruker, Germany) for magnetic resonance imaging, and T1-weighted images were obtained after enhancement of the pituitary imaging agent.
  • the imaging results are shown in Fig. 5. .
  • the pituitary of wild-type mice (Fig. 5A, 5E) and dopamine knockout mice (Fig. 5C, 5G) showed a low signal on T1 weighting before injection of compound 1 and Gd-DTPA contrast agent.
  • Fig. 5B There was a significant increase in the pituitary site signal in wild-type mice (Fig. 5B), while no increase signal appeared in the pituitary site of dopamine D 2 receptor knockout mice (Fig. 5D).
  • the signal of the pituitary site of wild-type mice (Fig. 5F) and the pituitary site of dopamine D 2 receptor knockout mice (Fig. 5H) showed significant enhancement.
  • This result indicates that the compound of the example has dopamine D 2 receptor targeting at the animal level in vivo compared to the Gd-DTPA contrast agent, and can display the dopamine D 2 receptor level by targeted nuclear magnetic resonance.
  • the benzamide methylpyrrolidine compound of the formula (I) and a pharmaceutically acceptable salt thereof can specifically bind to the dopamine D 2 receptor. That is, the benzamide methylpyrrolidine compound of the formula (I) and a pharmaceutically acceptable salt thereof can be targeted to recognize the dopamine D 2 receptor. Further, the benzamide methylpyrrolidine compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be used for magnetic resonance detection or nuclear magnetic resonance detection of pituitary adenomas.

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Abstract

L'invention concerne un benzamide méthylpyrrolidine ou un sel ou un intermédiaire pharmaceutiquement acceptable de celui-ci, un agent d'imagerie par résonance magnétique et son application, et un procédé d'imagerie par résonance magnétique. La benzamide méthylpyrrolidine présente une structure générale représentée par la formule (I), dans laquelle R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , et Ln sont définis dans la description.
PCT/CN2017/098003 2016-08-19 2017-08-18 Composé d'imagerie par résonance magnétique, intermédiaire de celui-ci, agent d'imagerie par résonance magnétique et son application, et procédé d'imagerie par résonance magnétique Ceased WO2018033132A1 (fr)

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CN201780048213.3A CN109563082B (zh) 2016-08-19 2017-08-18 核磁共振显像化合物、其中间体、核磁共振显像剂及应用、以及核磁共振成像方法

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CN107663228B (zh) * 2017-10-13 2021-01-19 北京市神经外科研究所 核磁共振显像化合物、核磁共振显像剂及应用、以及核磁共振成像方法
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CN114276308B (zh) * 2021-12-24 2023-08-11 南京科技职业学院 一类磁共振造影剂及其制备方法与应用
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