CN116987128A - Mannose derivative modified by (D) -alpha-imino acid and application thereof - Google Patents

Mannose derivative modified by (D) -alpha-imino acid and application thereof Download PDF

Info

Publication number
CN116987128A
CN116987128A CN202310922804.6A CN202310922804A CN116987128A CN 116987128 A CN116987128 A CN 116987128A CN 202310922804 A CN202310922804 A CN 202310922804A CN 116987128 A CN116987128 A CN 116987128A
Authority
CN
China
Prior art keywords
tumor
alpha
imino acid
mannose derivative
mannose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310922804.6A
Other languages
Chinese (zh)
Inventor
张俊波
尹广星
阮晴
江雨豪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Normal University
Original Assignee
Beijing Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Normal University filed Critical Beijing Normal University
Priority to CN202310922804.6A priority Critical patent/CN116987128A/en
Publication of CN116987128A publication Critical patent/CN116987128A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The invention relates to the technical fields of radiopharmaceuticals chemistry and clinical nuclear medicine, in particular to a mannose derivative containing (D) -alpha-imino acid modification and application thereof. The mannose derivative containing (D) -alpha-imino acid modification is mannose derivative containing different carbon chain lengths and having a structure shown as a general formula (I), and is marked by radionuclideThe obtained radioactive preparation has high uptake in tumors and good tumor/non-target ratio, and is a novel tumor radioactive drug which is worth popularizing.

Description

Mannose derivative modified by (D) -alpha-imino acid and application thereof
Technical Field
The invention relates to the technical fields of radiopharmaceuticals chemistry and clinical medicine, in particular to a mannose derivative containing (D) -alpha-imino acid modification and application thereof.
Background
It is well known that tumors are one of the major killers for human health in the 21 st century, and seriously endanger human health. Studies have shown that: early diagnosis of tumors is of great practical significance for saving the life of patients and prolonging the life span of patients. There are a number of clinical diagnostic methods currently used for tumors, including mainly tissue biopsy and imaging. However, biopsy requires a biopsy and is invasive. Imaging methods, particularly molecular imaging, allow noninvasive detection of tumor and lesion locations. The nuclear medicine imaging can visualize, qualify and quantify the mechanism process from the molecular and cell level, and has the advantages of non-invasiveness, high sensitivity and the like. Nuclear medicine imaging comprises Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), belongs to functional imaging, and further strengthens the advantages of nuclear medicine imaging by combining with CT, MRI and other imaging technologies.
Mannose is a monosaccharide, and is also a hexose. Like glucose, it can enter cells via the glucose transporter (GLUT), and during metabolism, it is also phosphorylated by hexokinase to form mannose-6-phosphate. Mannose can regulate immune system, inhibit tumor growth and metastasis, and increase cancer survival rate in human body. Based on the above characteristics, in combination with nuclear medicine imaging, mannose can be radionucleide labeled for tumor imaging. 99m Tc nuclide has wide application in radioactive diagnosis medicine due to its excellent nuclide property and easy source. Isocyano (-NC) can be used with 99m Tc (I) hexacoordination compound forming an octahedron 99m Tc]Tc-(CNR) 6 + . Wherein isocyano (-NC) will act as a bifunctional linker 99m The Tc nuclide is connected with mannose molecules to finally obtain mannose derivatives with excellent properties as tumor imaging agents. The linker (linker) has attached to it a targeting group and a chelating group attached to the radionuclide and plays an important role in modulating the pharmacokinetics and pharmacodynamics of the radiopharmaceutical. Based on the above background, the present invention contemplates the synthesis of (D) -alpha-imino acid modified mannose derivatives using (D) -alpha-imino acid modified fragments as linkers, which are subjected to 99m Tc labelling, by improvement 99m The pharmacokinetic properties of Tc-labeled complexes remain on the one handThe complex has high uptake in tumors, and on the other hand, the uptake of the complex in non-target organs is reduced, so that the tumor/non-target ratio is improved, a new way is opened up for searching for novel tumor radiopharmaceuticals, and the complex has important scientific significance and wide clinical application prospect and is an important task facing the field.
Disclosure of Invention
The invention provides a mannose derivative containing (D) -alpha-imino acid modification and application thereof, and the mannose derivative has the advantages of good in-vitro stability, simple preparation, high tumor uptake, good target-to-non-target ratio and important application prospect, and is used for tumor diagnosis after radiolabeling. Specifically, the invention provides the following technical scheme:
a mannose derivative comprising a (D) -a-imino acid modification, said mannose derivative having the structural formula (I):
wherein n represents an integer of 2 or more.
Preferably, in the above-mentioned (D) - α -imino acid modified mannose derivative, when n=5, the structural formula is one of the following, and is prepared from the compound 99m Tc complex is low in non-target organ, high in tumor uptake value, high in tumor/blood and tumor/muscle ratio, and good in tumor diagnosis and treatment effect.
The present invention also provides a radioactive preparation comprising the radiolabeled (D) - α -imino acid modified mannose derivative as described above.
Preferably, the radionuclide moiety is a metal radionuclide 99m Tc、 99 Tc、 94m Tc、 94 Tc、 52 Mn、 186 Re or 188 Re. Preferably, the above-mentioned radioactive preparation has the structural formula (II):
the invention also provides application of the radioactive preparation in preparing tumor radiopharmaceuticals.
The invention has the beneficial effects that: the invention provides a mannose derivative containing (D) -alpha-imino acid modification, which has high uptake of a radioactive preparation obtained by radionuclide labeling in tumors and good tumor/non-target organ ratio, and is a novel tumor radioactive drug with popularization value.
Detailed Description
The present invention provides a mannose derivative containing (D) -alpha-imino acid modification and its application, in a preferred embodiment, the present invention provides a compound having the general structural formula [ [ 99m Tc]Radioactive preparation of Tc-CNIADM:
wherein n represents an integer of 2 or more.
The preparation method comprises the following steps:
(1) Synthesis of ligand CNIADM
1c synthesis: weighing a proper amount of compound 1b into a 50mL round bottom flask, adding a proper amount of N, N-Dimethylformamide (DMF) for dissolution, and then adding Et 3 N, stirring at room temperature for 30min until the solid is completely dissolved, adding DMF solution of compound 1a thereto, reacting overnight at room temperature, removing the solvent by distillation under reduced pressure after the reaction, and purifying by column chromatography (dichloromethane: methanol=10:1) to obtain compound 1c.
1d synthesis: an appropriate amount of compound 1c and 2,3,5, 6-Tetrafluorophenol (TFP) were weighed into a 50mL round bottom flask, dissolved in DMF, stirred at room temperature for 30min, then added with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), reacted overnight at room temperature, after the reaction was completed, the solvent was distilled off under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 1d.
Synthesis of CNIADM: weighing a proper amount of D-mannosamine hydrochloride (DMAH) and sodium hydroxide into a 50mL round-bottom flask, adding anhydrous methanol for dissolution, stirring for 30min at room temperature, adding a compound 1D, reacting for 24h at room temperature, distilling under reduced pressure after the reaction is finished to remove a solvent, and purifying by column chromatography (dichloromethane: methanol=5:1) to obtain the ligand CNIADM.
The specific synthetic route is as follows:
wherein n represents an integer of 2 or more.
(2)[ 99m Tc]Preparation of Tc-CNIADM
Dissolving sodium citrate and L-cysteine in normal saline, and adding SnCl 2 ·2H 2 O, adjusting the pH of the solution to 6.0, and then sequentially adding a proper amount of ligand CNIADM and freshly leached Na 99m TcO 4 The reaction is carried out for 20min at 100 ℃ to obtain the marker [ 99m Tc]Tc-CNIADM。
Prepared by the above method [ 99m Tc]The Tc-CNIADM complex has the radiochemical purity of more than 95 percent, good in vitro stability, is a water-soluble substance, has high tumor uptake in tumor-bearing mice and good target-to-non-target ratio, and is favorable for popularization and application as a novel tumor imaging agent.
Example 1
The present example provides a mannose derivative (CN 5 DPDM) containing (D) -proline modification of the following structural formula:
CN5DPDM is carried out 99m Tc marking to obtain a kind of 99m Tc-marked mannose derivatives containing (D) -proline modification, abbreviated as [ [ 99m Tc]Tc-CN5DPDM。
The preparation method comprises the following steps:
synthesis of CN5DPDM
2c synthesis: to a 50mL round bottom flask was added compound 2b 219mg (1.90 mmol), DMF was added to dissolve, and Et was added 3 N2.4 mL (17.3 mmol), after stirring at room temperature for 30min, 2a 500mg (1.73 mmol) of compound was added and reacted overnight at room temperature. After the completion of the reaction, the solvent was distilled off under reduced pressure, and purified by column chromatography (dichloromethane: methanol=10:1) to give 2c 309mg as a yellow oily product in 75% yield. 1 H NMR(400MHz,Methanol-d 4 )δ4.45-4.29(m,1H),3.46(tt,J＝6.7,2.0Hz,2H),2.43-2.31(m,2H),2.27-2.11(m,2H),2.03-1.94(m,2H),1.74-1.57(m,4H),1.53-1.46(m,2H),1.43-1.34(m,2H).
2d synthesis: to a 50mL round bottom flask was added 300mg (1.26 mmol) of compound 2c and 227mg (1.37 mmol) of 2,3,5, 6-tetrafluorophenol, dissolved in DMF, and after stirring at room temperature for 30min, 220mg (1.15 mmol) of EDCI was added. The reaction was carried out at room temperature overnight, and after completion of the reaction, the solvent was distilled off under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give 150mg of the product as a yellow oil in 34% yield. 1 H NMR(400MHz,Chloroform-d)δ7.05-6.74(m,1H),4.80(dd,J＝8.8,3.8Hz,1H),3.74-
3.50(m,2H),3.42-3.33(m,2H),2.38(t,J＝7.5Hz,2H),2.28-2.14(m,2H),2.16-1.94(m,2H),1.77-1.66(m,4H),1.56-1.44(m,2H).
Synthesis of CN5 DPDM: to a 25mL round bottom flask was added 14mg (0.36 mmol) of sodium hydroxide and 69mg (0.36 mmol) of D-mannosamine hydrochloride, and the mixture was dissolved in anhydrous methanol, and after 30min of reaction at room temperature, 150mg (0.39 mmol) of compound 2D was added, and after the completion of the reaction, the reaction was allowed to stand overnight, the solvent was distilled off under reduced pressure, and the mixture was purified by column chromatography (dichloromethane: methanol=5:1) to give 39mg of a yellow oily product in 31% yield. 1 H NMR(400MHz,Methanol-d 4 )δ5.05(d,J＝1.6Hz,1H),4.24(dd,J＝4.6,1.6Hz,1H),3.98(dd,J＝9.7,4.6Hz,1H),3.83-3.77(m,2H),3.76(t,J＝2.1Hz,1H),3.73(t,J＝2.9Hz,1H),3.65-3.61(m,1H),3.58-3.55(m,1H),3.50-3.48(m,1H),2.38(t,J＝6.5Hz,2H),1.99-1.88(m,2H),1.65-1.57(m,6H),1.52-1.41(m,4H). 13 C NMR(101MHz,Methanol-d 4 )δ173.99,173.05,158.03,92.22,72.12,69.76,67.22,61.41,59.12,53.79,40.90,33.70,29.83,28.71,25.74,24.44,23.51,22.35.HR-MS(ESI)for C 18 H 30 N 3 O 7 [M+H] + :found 400.2086,calcd 400.2078.
2.[ 99m Tc]Preparation of Tc-CN5DPDM
2.6mg of sodium citrate and 1mg of L-cysteine are dissolved in a proper amount of physiological saline, and 0.1mg of SnCl is added thereto 2 ·2H 2 O, adjust the pH of the solution to 6.0, then add 0.5mg of CN5DPDM ligand and freshly leached Na to it in sequence 99m TcO 4 The reaction was carried out at 100℃for 20 minutes to obtain [ of this example ] 99m Tc]Tc-CN5DPDM。
Test examples
1. Chromatographic identification of the radioactive preparation provided in example 1
(1) TLC method
Determination of the radiochemical yield and radiochemical purity of the markers by Thin Layer Chromatography (TLC) using a developing system of polyamide film-ammonium acetate (1M)/methanol (volume ratio: 2/1) under which R of each radioactive component is present f The values are shown in table 1.
TABLE 1R of the radioactive component in a Polyamide film-ammonium acetate (1M)/methanol (volume ratio: 2/1) System f Value of
Measured by the above chromatographic identification 99m Tc]The radiochemical yield and radiochemical purity of Tc-CN5DPDM complex are both greater than 90%, and the complex is used in subsequent experiments without further purification.
(2) HPLC method
Identification of the radiochemical purity of the markers was performed using High Performance Liquid Chromatography (HPLC): SHIMADZU high performance liquid chromatograph (CL-20 AVP), kromasil C18 reverse phase column (5 μm,250×4.6 mm), gabi rayest radioactivity detector. The elution gradient was shown in Table 2, at a flow rate of 1mL/min, with phase A being pure water containing 0.1% trifluoroacetic acid and phase B being acetonitrile containing 0.1% trifluoroacetic acid.
Table 2 gradient elution conditions of the complexes
HPLC identification result shows 99m Tc]The retention time of Tc-CN5DPDM was 9.85min.
2. Determination of lipid Water partition coefficient
100. Mu.L of the labeling solution was placed in a 4-mL centrifuge tube, and 1mL of n-octanol and 900. Mu.L of PBS (0.025M,
pH 7.4), vortexing, standing, centrifuging in a centrifuge for 5min (10000 rpm) after delamination of the solution, taking 3 parts of 100. Mu.L each from the two phases, and measuring the radioactivity counts in a gamma counter, respectively. Lipid partition coefficient P = organic phase radioactivity count/aqueous phase radioactivity count, lipid partition coefficient is typically expressed in log P. Measured [ 99m Tc]The log P value of Tc-CN5DPDM was-4.23.+ -. 0.14, indicating that it is a water-soluble material.
3. Stability determination
Will [ 99m Tc]The radiochemical purity of Tc-CN5DPDM is measured by HPLC after the Tc-CN5DPDM is incubated in normal saline at room temperature and in mouse serum at 37 ℃ for 4 hours, and the experiment result shows that the radiochemical purity is more than 95% after the Tc-CN5DPDM is incubated in normal saline at room temperature and in mouse serum at 37 ℃ for 4 hours, thus the in vitro stability is good.
4. In vivo biodistribution assay in tumor-bearing mice
Will be (0.1 mL,185 kBq) respectively [ 99m Tc]Tc-CN5DPDM labeling solution and we reported previously [ 99m Tc]Tc-CN7DM marking liquid (patent number ZL 202110839524X) is injected into the body of a mouse with A549 tumor through tail vein, the mouse is sacrificed after anesthesia for 120min, the heart, liver, lung, kidney, spleen, stomach, bone, muscle, small intestine, blood, tumor and other tissues or organs are taken out after dissection, the radioactivity count of each organ is respectively measured by using a gamma counter, and the uptake value of each organ is obtained after the mass conversion of each organ (taking the percentage ID/g as a single unit)Position), the biodistribution of the markers in tumor-bearing mice is shown in table 3.
TABLE 3 biodistribution results of markers after 120min in vivo administration in A549 tumor bearing mice (n=4, mean.+ -. SD,%ID/g)
From the results, it can be seen that [ 99m Tc]Tc-CN5DPDM keeps high uptake in tumor, other non-target viscera are low in uptake, blood is cleared quickly, the basal uptake of blood is only 0.05% ID/g after 2h of administration, the tumor/blood ratio is 100.20, and the tumor/blood ratio and the tumor/meat ratio are better than [ 99m Tc]Tc-CN7DM。
5.[ 99m Tc]SPECT/CT imaging experiment of Tc-CN5DPDM in tumor-bearing mice
Tail intravenous injection into A549 tumor-bearing mice [ 99m Tc]Tc-CN5DPDM (about 18.5 MBq), after 2h dosing, mice were anesthetized, parameters were set, mice were fixed, SPECT/CT imaging was performed, and finally scanned images were obtained by HiSPECT software and vivoquant 2.5 software.
From SPECT/CT imaging results of A549 tumor-bearing mice [ 99m Tc]The Tc-CN5DPDM has obvious tumor radioactivity concentration in the mouse body, low uptake of other non-target organs, clean background and consistent biodistribution result.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Thus, all such modifications or improvements which do not depart from the spirit of the invention are intended to be within the scope of the invention as claimed in the present application, as a result of the radionuclide labeling of the ligands modified with the (D) - α -imino acid structure using monosaccharides other than mannose. In addition, the radioactive preparation obtained by labeling the (L) -alpha-imino acid structure-modified monosaccharide ligand with a radionuclide is also within the scope of the invention.

Claims (5)

1. A mannose derivative comprising a (D) -a-imino acid modification, wherein the mannose derivative has the structural formula (I):
wherein n represents an integer of 2 or more.
2. A radioactive preparation comprising a mannose derivative modified with a (D) - α -imino acid according to any of claims 1, labelled with a radionuclide.
3. The radioactive preparation according to claim 2, characterized in that the radionuclide is 99m Tc、 99 Tc、 94m Tc、 94 Tc、 52 Mn、 186 Re or 188 Re。
4. The radioactive preparation according to claim 3, wherein the radioactive preparation has the structural formula (ii):
wherein n represents an integer of 2 or more.
5. Use of a radioactive preparation according to any one of claims 2-4 for the preparation of a tumor radiopharmaceutical.
CN202310922804.6A 2023-07-26 2023-07-26 Mannose derivative modified by (D) -alpha-imino acid and application thereof Pending CN116987128A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310922804.6A CN116987128A (en) 2023-07-26 2023-07-26 Mannose derivative modified by (D) -alpha-imino acid and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310922804.6A CN116987128A (en) 2023-07-26 2023-07-26 Mannose derivative modified by (D) -alpha-imino acid and application thereof

Publications (1)

Publication Number Publication Date
CN116987128A true CN116987128A (en) 2023-11-03

Family

ID=88522574

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310922804.6A Pending CN116987128A (en) 2023-07-26 2023-07-26 Mannose derivative modified by (D) -alpha-imino acid and application thereof

Country Status (1)

Country Link
CN (1) CN116987128A (en)

Similar Documents

Publication Publication Date Title
JP6770207B2 (en) 99mTc-labeled isocyanide-containing glucose derivative and its preparation method and application
CN112175025B (en) Glucose derivative containing benzene ring and application thereof
CN111138504B (en) A kind of99mTc-CNPEDG complex and preparation method and application thereof
CN112409414B (en) Technetium-99 m labeled FAPI derivative containing isonitrile as well as preparation method and application thereof
CN111518137B (en) Technetium-99 m marked isonitrile-containing amino acid derivative and preparation method and application thereof
CN112625065A (en) Technetium-99 m marked FAPI (FAPI) derivative containing hydrazino nicotinamide and archaea, and preparation method and application thereof
CN110078767B (en) Technetium-99 m labeled 2-nitroimidazole complex containing hydrazino nicotinamide group and preparation method and application thereof
CN110183493B (en) 99 mTechnetium labeled complex and application thereof in diagnosis of non-small cell lung cancer
CN114163478B (en) Technetium-99 m labeled D-proline modified FAPI derivative and preparation method and application thereof
CN113200960B (en) Technetium-99 m labeled PEG chain modified FAPI derivative containing isonitrile as well as preparation method and application thereof
CN117624278A (en) Specific tumor diagnosis probe and imaging agent for targeting heat shock protein 90
US20240109929A1 (en) Mannose derivative and application thereof
CN109705193B (en) Radiolabelled tEB-TMTP1 compound and preparation method and application thereof
JPH11504002A (en) Hydroxyalkylphosphine compounds for use as diagnostics and therapeutics and methods for their preparation
CN114031652B (en) Glucose derivative containing cyclohexane and application thereof
CN102219818A (en) Thymidine derivates as well as preparation method and applications thereof in preparing tumor developing agents as ligand
CN116987128A (en) Mannose derivative modified by (D) -alpha-imino acid and application thereof
CN112409436B (en) Radionuclide-labeled estrogen receptor molecule targeting compound and application thereof
CN114853827B (en) Glucose derivative ligand compound and preparation method and application thereof
CN112250680B (en) Novel berberine derivative and synthesis method and application thereof
CN115160293B (en) Technetium-99 m labeled glutamic acid-urea derivative containing L-proline modification, preparation method and application
TWI650138B (en) Multivalent glyco-complex, imaging agent and uses thereof
CN109438265B (en) Compound with affinity with brown adipose tissue and preparation method and application thereof
Wang et al. Synthesis and biological evaluation of 99mTc (CO) 3 (His–CB) as a tumor imaging agent
JPH03504011A (en) Method for stereotactic quantification of local energy metabolism in warm-blooded organisms and compositions therefor

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination