WO2022017375A1 - AGENT DE CONTRASTE DE SPECT POUR DIAGNOSTIC DE TUMEUR SPÉCIFIQUE DE FAP-α - Google Patents

AGENT DE CONTRASTE DE SPECT POUR DIAGNOSTIC DE TUMEUR SPÉCIFIQUE DE FAP-α Download PDF

Info

Publication number
WO2022017375A1
WO2022017375A1 PCT/CN2021/107347 CN2021107347W WO2022017375A1 WO 2022017375 A1 WO2022017375 A1 WO 2022017375A1 CN 2021107347 W CN2021107347 W CN 2021107347W WO 2022017375 A1 WO2022017375 A1 WO 2022017375A1
Authority
WO
WIPO (PCT)
Prior art keywords
tumor
compound
complex
fap
hfapi
Prior art date
Application number
PCT/CN2021/107347
Other languages
English (en)
Chinese (zh)
Inventor
贾兵
杨广杰
李小达
高瀚男
Original Assignee
北京大学
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 北京大学 filed Critical 北京大学
Publication of WO2022017375A1 publication Critical patent/WO2022017375A1/fr

Links

Images

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
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA

Definitions

  • the invention relates to a radionuclide-labeled diagnostic drug complex, including a precursor compound for preparing the complex and a pharmaceutical composition or a drug-forming kit, in particular to a broad-spectrum tumor SPECT targeting FAP- ⁇ imaging agent.
  • Tumor is a complex composed of tumor cells and their surrounding stromal cells and acellular components.
  • the occurrence and development of tumors is a dynamic process of mutual promotion and co-evolution of tumor cells and their microenvironment.
  • the tumor microenvironment includes cells and extracellular matrix, and the formed components are mainly cellular components, including immune cells, endothelial cells, and fibroblasts.
  • the main stromal cells account for about 50% of the total number of tumor cells.
  • CAFs play an important role in tumor growth, metastasis, drug resistance and treatment resistance, and are one of the hotspots in tumor diagnosis and treatment research.
  • FAP- ⁇ seprase or fibroblast activation protein
  • DPP dipeptidyl peptidase
  • DPPIV dipeptidyl peptidase IV
  • DPPIV/CD26 dipeptidyl peptidase IV, DPPIV/CD26
  • FAP- ⁇ has a unique endopeptidase activity, which can cleave gelatin, denatured type I collagen and ⁇ 2-antifibrin, while DPPIV does not, so the two can be distinguished.
  • FAP- ⁇ is selectively expressed on the surface of stromal fibroblasts in more than 90% of epithelial malignant tumors, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, skin melanoma, etc.
  • epithelial malignant tumors including breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, skin melanoma, etc.
  • Benign and precancerous epithelial tumors such as colorectal adenomas, phyllodes of the breast, and fibroadenomas, typically do not express FAP- ⁇ .
  • FAP- ⁇ is generally not expressed in normal human tissues, only exists in the cervix and endometrium, and is transiently expressed during embryonic development.
  • SPECT Single Photon Emission Computed Tomography
  • PET PET
  • PET PET
  • PET diagnosis has significant advantages in detection sensitivity, image resolution and clarity, and positioning accuracy, but its equipment, drugs and inspection costs are more expensive.
  • the preparation of drugs used in SPECT diagnosis is relatively simple, with low cost, moderate clinical examination cost, high penetration rate, and easy promotion and acceptance.
  • tumor-specific SPECT imaging agents in clinical use, with low target specificity and poor imaging effect. Therefore, it is necessary to vigorously develop broad-spectrum tumor-specific SPECT imaging technology.
  • a precursor compound for the formation of radionuclide complexes having the following structure:
  • the present invention also provides a complex formed after the above-mentioned precursor compound is labeled with a radionuclide.
  • the complex according to the present invention has a radionuclide of99mTc .
  • the complex in addition to the aforementioned precursor compounds, the complex also has two other co-ligand compounds complexed with 99m Tc: N-tris(hydroxymethyl)methylglycine (Tricine) and Triphenylphosphine trim-sulfonic acid sodium salt (TPPTS).
  • Tricine N-tris(hydroxymethyl)methylglycine
  • TPPTS Triphenylphosphine trim-sulfonic acid sodium salt
  • the complex according to the present invention has the following structure:
  • the present invention also provides a pharmaceutical composition containing the above-mentioned 99mTc- labeled complex.
  • the pharmaceutical composition according to the present invention is an intravenously injectable pharmaceutical composition.
  • the present invention also provides a kit for conveniently preparing the above-mentioned 99mTc- labeled complex
  • the kit contains the above-mentioned precursor compound of the present invention, N-tris(hydroxymethyl)methylglycine (Tricine) and triphenylphosphine Lyophilized formulation of trimetasulfonic acid sodium salt (TPPTS).
  • Tricine N-tris(hydroxymethyl)methylglycine
  • TPTS triphenylphosphine Lyophilized formulation of trimetasulfonic acid sodium salt
  • the kit can be prepared by lyophilizing the buffer solution containing the ligand compound into a vial.
  • the above-mentioned precursor compound, N-tris(hydroxymethyl)methylglycine (Tricine), triphenylphosphine trim-sulfonic acid sodium salt (TPPTS) are placed in the solution of succinic acid/sodium hydroxide, filtered.
  • the kit was obtained after lyophilization.
  • the present invention also provides the use of the above-mentioned precursor compounds or radionuclide-labeled complexes of the present invention in the preparation of tumor SPECT imaging agents.
  • FAP-alpha is associated with a variety of diseases involving remodeling of the extracellular matrix, and FAP-alpha inhibitors are widely studied as a therapeutic option for several diseases, most of which are oncology applications.
  • Jansen's team published a series of FAP- ⁇ inhibition of N-4-quinolinyl-glycine-(2S)-cyanoproline backbone in the 2014 paper (Journal of Medicinal Chemistry, 2014, 57, pages 3053-3074) agent, one of which has a specific structure as follows:
  • the series of optimized compounds reported by the team showed nanomolar inhibition and high selectivity, with very satisfactory logD values, plasma stability and microsomal stability.
  • the selected FAP-alpha inhibitors described above exhibited high oral bioavailability, plasma half-life, and the ability to selectively and completely inhibit FAP-alpha in vivo in mouse model assessments.
  • the document also discloses a complex for imaging formed by the ligand compound and a radionuclide. Most of these labeled complexes are used for PET imaging, such as: etc. (the wavy line links the above-mentioned small molecule FAP inhibitor structure).
  • the document also discloses two SPECT imaging agents, the structures of which are shown below:
  • the present invention discovered a new SPECT imaging agent targeting FAP- ⁇ .
  • the present invention adopted a new chelating ligand.
  • a new coordination method to obtain a complex with a new structure, and the structure of the complex is as follows:
  • the complex of the present invention has more stable coordination than the prior art based on tricarbonyl 99m Tc complex, thereby showing excellent in vivo and in vitro stability; due to the use of a one-step labeling method
  • the kit-based technology has better druggability and is suitable for industrial production and clinical promotion.
  • FIG. 1 The synthetic route of HpFAPi.
  • FIG signal radioactive HPLC 3 figures.
  • Figure 5 Binding and blocking experimental results of 99m Tc-HFAPi and FAP- ⁇ recombinant protein.
  • Figure 6 Binding and blocking experimental results of 99m Tc-HpFAPi and FAP- ⁇ recombinant protein.
  • Figure 7 SPECT/CT imaging of 99m Tc-HFAPi in the U87MG tumor-bearing mouse model.
  • Figure 8 SPECT/CT imaging of 99m Tc-HpFAPi in U87MG tumor-bearing mouse model.
  • FIG. 9 Imaging of 99m Tc-FAPI-34 disclosed in the 2020 literature by Uwe Haberkorn's team.
  • FIG. 10 Biodistribution and blocking experimental data of 99m Tc-HFAPi in U87MG mouse model.
  • Figure 11 Biodistribution and blocking experimental data of 99m Tc-HpFAPi in U87MG tumor-bearing mice. .
  • Figure 12 18 F-FDG-PET and 99m Tc-HFAPi-SPECT imaging of breast cancer patients.
  • High performance liquid chromatograph HPLC-1260 Infinity
  • digital-to-analog signal conversion module 35900E
  • HPLC radioactive signal detector Gabi star ⁇ -raytest
  • Semi-preparative C18 reversed-phase column YMC-Pack ODS-A, 250 ⁇ 10.0mml.DS-5 ⁇ m, 12nm
  • analytical C18 reversed-phase column YMC-Pack ODS-A, 250 ⁇ 4.6mml.DS -5 ⁇ m, 12 nm
  • Precision electronic balance BP211D
  • Freeze dryer FD-1D-50 was purchased from Beijing Boyikang Experimental Instrument Co., Ltd.
  • Radioactive ⁇ -counter (Wizard-2470) was purchased from PerkinElmer, USA.
  • the radioactivity meter (CRC-25R) was purchased from Capintec, USA.
  • Small animal SPECT/CT imager (NanoScan SPECT/CT) was purchased from Mediso, Hungary.
  • Method 1 to separate and purify the target product by high performance liquid chromatography Agilent 1260 HPLC system is equipped with YMC-Pack ODS-A C18 semi-preparative column (250 ⁇ 10mml.D.S-5 ⁇ m, 12nm). Gradient elution for 25min, flow rate 3.2mL/min, mobile phase A is deionized water (containing 0.05%TFA), mobile phase B is acetonitrile (containing 0.05%TFA), elution gradient is set to 85%A at the beginning and 15%B, 85%A and 15%B at 5min, 45%A and 55%B at 25min.
  • Method 2 for separating and purifying the target product by high performance liquid chromatography Agilent 1260 HPLC system is equipped with YMC-Pack ODS-A C18 semi-preparative column (250 ⁇ 10mml.D.S-5 ⁇ m, 12nm). Gradient elution for 25min, flow rate 2.0mL/min, mobile phase A is deionized water (containing 0.05% TFA), mobile phase B is acetonitrile (containing 0.05% TFA), elution gradient is set to 80% A at the beginning and 20%B, 80%A and 20%B at 5min, 40%A and 60%B at 25min.
  • Step 2 Preparation of (S)-tert-butyl 2-carbamoyl-4-oxopyrrolidine-1-carboxylate (compound 3)
  • Step 3 Preparation of (S)-2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylate tert-butyl ester (compound 4)
  • Step 6 Preparation of tert-butyl (S)-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-carbamic acid tert-butyl ester (Compound 7 )
  • Step 8 Preparation of 6-hydroxyquinoline-4-carboxylic acid (compound 10)
  • 6-Methoxyquinoline-4-carboxylic acid (compound 9, 1.0 g, 4.92 mmol) and HBr aqueous solution (40%, 35 mL) were added to a 50 mL round-bottomed flask, and the reaction was stirred at 100 °C for 30 hours under nitrogen protection . The mixture was evaporated to dryness in vacuo to give 1.76 g of crude product. The crude product was used directly in the next step without further purification. LC/MS: 189.9 [M+H] + .
  • Step 10 Preparation of 3-(4-(tert-butoxycarbonyl)piperazine-1-)propyl 6-(3-(4-(tert-butoxycarbonyl)piperazine-1-)propoxy)quinoline Ethyl lino-4-carboxylate (Compound 12)
  • Step 11 Preparation of 6-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (Compound 13)
  • Step 12 Preparation of 4-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-carbamoyl)quinoline Lin-6-yl)oxy)propyl)piperazine-1-carboxylate tert-butyl ester (Compound 14)
  • Step 13 Preparation of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-(piperazine- 1-yl)propoxy)quinoline-4-carboxamide (FAPi)
  • the synthetic route of HpFAPi is divided into 15 steps, of which the first 13 steps are consistent with HFAPi, and the last two-step synthetic route is shown in Figure 2.
  • the specific steps are as follows:
  • HFAPi weigh 1 mg of HFAPi and dissolve it in 1 mL of 75% ethanol in water with a concentration of 1 ⁇ g/ ⁇ L; then prepare a mixed solution containing 25 ⁇ g (25 ⁇ L) of HFAPi, 2.0 mg of Tricine, 3.0 mg of TPPTS, 29.55 mg of succinic acid and 17.0 mg of sodium hydroxide 1mL, filtered through a 0.22 ⁇ m filter membrane, added to a 10mL sterile vial, freeze-dried the mixture, sealed and capped to obtain a freeze-dried kit that can be used for 99m Tc labeling.
  • HpFAPi weigh 1mg of HpFAPi and dissolve it in 1mL of 75% ethanol in water with a concentration of 1 ⁇ g/ ⁇ L; then prepare a mixed solution containing 25 ⁇ g (25 ⁇ L) HFAPi, 2.0mg Tricine, 3.0mg TPPTS, 29.55mg succinic acid and 17.0mg sodium hydroxide 1mL, filtered through a 0.22 ⁇ m filter membrane, added to a 10mL sterile vial, freeze-dried the mixture, sealed and capped to obtain a freeze-dried kit that can be used for 99m Tc labeling.
  • the radiochemical purity (RCP) of the label was determined using HPLC (equipped with a Raytest Gabistar radioactivity detector and an Agilent-35900E digital-to-analog converter) and a YMC-Pack ODS-A C18 analytical column (250 ⁇ 4.6 mml.DS -5 ⁇ m, 12 nm), gradient elution for 20 minutes, flow rate 1 mL/min, wherein mobile phase A is deionized water (containing 0.05% TFA), and mobile phase B is acetonitrile (containing 0.05% TFA).
  • the elution gradient was set to 90% A and 10% B at the beginning, 60% A and 40% B at 17.5 min, and 90% A and 10% B at 20 min.
  • a mixture comprising three ligands HFAPi, Tricine, TPPTS and succinic acid/sodium hydroxide solution is first prepared into a freeze-drying kit. Before tumor imaging, only a certain volume of Na 99m TcO 4 eluate is added, and the 99m Tc labeled complex of the present invention can be prepared by heating in a water bath for 15 minutes.
  • the above preparation requires only one step of sealing and liquid addition process, and the opening operation of the radioactive solution is not involved in the middle, so the radioactive pollution to the environment and the impurities or biological contamination brought by the environment to the drug solution are greatly avoided.
  • the labeling method disclosed by the Uwe Haberkorn team in 2020 is relatively complicated.
  • the Na 99m TcO 4 eluate was added to the kit for preparing carbonyl complexes, and the reaction was heated for 20 minutes to obtain an intermediate of technetium tricarbonyl, and then The FAPI ligand compound was then added, the pH value was adjusted with acid solution and buffer, and then heated for 20 minutes to obtain its 99m Tc-labeled complex. It can be seen that the above preparation method of the present invention is more simple and easy to obtain, especially the freeze-dried kit can be fully commercialized, easy to quality control and mass production, and conforms to the requirements of pharmaceutical drugability.
  • the rhFAP- ⁇ protein was dissolved in ELISA coating buffer (1 ⁇ ) (concentration of 1 ⁇ g/mL), and 0.2 ⁇ g/200 ⁇ L per well was coated in a 96-well plate at 4° C. overnight. After coating, the coating solution was discarded, and the 96-well plate was washed 3-5 times with PBS. A blocking solution (5% calf serum/PBS buffer, pH 7.4) was added to a 96-well plate and incubated at 37°C for 2 hours. After blocking, the 96-well plate was washed 3-5 times with PBS.
  • the prepared 99m Tc-HpFAPi was added to the sample wells coated with rhFAP- ⁇ , 0.4 ⁇ Ci/200 ⁇ L of radiolabel was added to each well, and 4 parallel wells were set up. Prepare 4 sample wells and add an equal amount of 99m Tc-HFAPi, then add 1000-fold molar amount of HFAPi, and mix well. The 96-well plate was incubated at 37°C for 1 hour. Another three radioimmunoassay tubes were prepared, and an equal amount of radioactive label 99m Tc-HFAPi was added, which was reserved as a standard sample.
  • each mouse was injected with 100 ⁇ L (37MBq) via the tail vein, and SPECT/CT imaging was performed at 0.5, 1, 2 and 4 hours after injection.
  • Mice in the blocking group were injected with 100 ⁇ L (500 ⁇ g) of HFAPi at the same time as the imaging drugs, and were imaged 0.5 hours after administration. Mice were anesthetized with 1.5% isoflurane-oxygen during imaging.
  • SPECT images were reconstructed and fused with CT images to obtain 3D images. Posterior view was used for visualization and tumor location was marked with arrows. The imaging results are shown in Figure 7.
  • picture. 7 and 8 of the present invention are 3D imaging images of SPECT/CT of 99m Tc-HFAPi and 99m Tc-HpFAPi at 0.5, 1, 2, and 4 hours, respectively.
  • the high and low gray values in the image correspond to the more or less concentrated amount of radiopharmaceuticals in the target organ.
  • the large spot at the bottom of the mouse body, near the tail is the bladder position, and the two small spots above the large spot are the position of the bladder.
  • the dots represent the kidney location and the tumor location is in the armpit of the upper extremity (right side of the image).
  • the radioactive concentration in the bladder was always the largest, followed by the kidneys also showed higher drug uptake, while the uptake in the tumor was average.
  • the drug is gradually eliminated from various organs of the body over time, the normal organs of the body still take up more in 10-60 minutes, that is, the background is high, and the tumor/other organ uptake ratio is low.
  • the rest of the body was largely cleared, tumor uptake was similarly reduced, and the kidneys consistently showed higher radioactive concentrations.
  • the plaque indicated by the arrow is the location of the tumor
  • the circular plaque under the mouse body is the location of the bladder.
  • 99m Tc-HFAPi and 99m Tc-HpFAPi within 30-240 minutes of imaging, only the tumor and the bladder are always clearly visible, which means that the imaging agent of the present invention is highly metabolized at the tumor, and the in vivo metabolism is through urine. excreted.
  • the imaging agent of the present invention has very little uptake in other normal organs of the body, and almost no kidneys can be seen.
  • Radioactive signal which means that the imaging agent of the present invention has a high tumor/other organ uptake ratio, and has no obvious uptake in important large organs such as kidney and liver.
  • the 0.5-hour blocking experiment showed that the uptake of 99m Tc-HFAPi and 99m Tc-HpFAPi at the tumor was specific, that is, the binding of the FAP- ⁇ receptor in the tumor to the radiopharmaceutical can be activated by the same target competitive substitution of prodrugs.
  • the imaging agent of the present invention has better tumor uptake, tumor/other organ uptake ratio and lower background imaging. This has huge advantages in practical applications. For example: (1) SPECT imaging diagnosis is very sensitive to noise, and a low background is more conducive to accurate imaging. (2) It is more accurate and precise for the medical diagnosis of small primary lesions. (3) The high contrast of the tumor/non-tumor site is conducive to clearly showing the boundary between the lesion and the adjacent tissues, which is more favorable for delineating the tumor target area, so that precise radiotherapy can be targeted.
  • Example 7 Acute toxicity test of 99m Tc-HFAPi and 99m Tc-HpFAPi
  • mice Twenty-one Kunming rats (6 weeks old) were randomly divided into 3 groups with 7 rats in each group. Two groups were injected with 99mTc -HFAPi (37MBq/100 ⁇ L each) and 99mTc -HpFAPi (37MBq/100 ⁇ L each) through the tail vein respectively, and the other group was injected with 100 ⁇ L normal saline through the tail vein.
  • the experimental mice were placed in a sterile laminar flow cabinet and fed with SPF grade rat chow and high temperature sterilized water. The weight changes of mice were monitored daily after administration, and the routine blood indexes of mice (red blood cell count, hemoglobin, platelet, white blood cell count, lymphocyte count, etc.
  • mice were sacrificed by neck breaking method on the 7th day after administration, and the main organs such as heart, lung, liver, kidney, and intestine were observed for abnormality.
  • the monitoring results showed that compared with the normal saline control group, there was no difference in the indicators of the two experimental groups, indicating that no obvious drug acute toxicity was observed.
  • Example 8 18 F-FDG-PET and 99m Tc-HFAPi-SPECT imaging of breast cancer patients
  • a 47-year-old female patient was found to have a right breast tumor 1 month later, and the breast color ultrasound showed that the right breast was hypoechoic at 2:00, BIRADS class 4c, hypoechoic in the right axilla, and abnormal enlarged lymph nodes were not excluded.
  • nuclear medicine imaging of 18 F-FDG-PET and 99m Tc-HFAPi-SPECT were performed respectively, and the imaging results are shown in Fig. 12 . PET results showed that abnormally increased glucose metabolism was seen in the right breast at 2:00 and in the right armpit.

Abstract

L'invention concerne un agent de contraste de SPECT pour le diagnostic de tumeur spécifique de FAP-α, ledit agent de contraste étant formé à l'aide d'une petite molécule inhibitrice de FAP-α d'un échafaudage de N-4-quinolinoyl-Gly-(2S)-cyanoPro modifié en tant que composé précurseur, à l'aide de 99mTc en tant que radionucléide, et à l'aide de N-tris (hydroxyméthyl) méthylglycine (Tricine) et de trisulfonate de triphénylphosphine (TPPTS) en tant que ligands synergiques. Par rapport à la technologie actuelle, le présent agent de contraste affiche une biodistribution in vivo particulièrement supérieure, une absorption tumorale plus élevée, un rapport d'absorption tumeur/organe plus élevé, et un attribut de coordination plus stable, et présente en outre une stabilité in vivo et in vitro particulièrement supérieure; en raison d'une caractéristique spéciale d'une structure de coordination de l'agent de contraste présent, la technologie de kit de test utilisant une méthode de marquage en une étape peut être utilisée, et par conséquent, celui-ci possède une meilleure aptitude au développement de médicament, et est approprié pour une production industrielle et une popularisation clinique.
PCT/CN2021/107347 2020-07-24 2021-07-20 AGENT DE CONTRASTE DE SPECT POUR DIAGNOSTIC DE TUMEUR SPÉCIFIQUE DE FAP-α WO2022017375A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010725069.6A CN111991570B (zh) 2020-07-24 2020-07-24 一种FAP-α特异性肿瘤诊断SPECT显像剂
CN202010725069.6 2020-07-24

Publications (1)

Publication Number Publication Date
WO2022017375A1 true WO2022017375A1 (fr) 2022-01-27

Family

ID=73467539

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/107347 WO2022017375A1 (fr) 2020-07-24 2021-07-20 AGENT DE CONTRASTE DE SPECT POUR DIAGNOSTIC DE TUMEUR SPÉCIFIQUE DE FAP-α

Country Status (2)

Country Link
CN (1) CN111991570B (fr)
WO (1) WO2022017375A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111991570B (zh) * 2020-07-24 2021-05-18 北京大学 一种FAP-α特异性肿瘤诊断SPECT显像剂
CN112409414B (zh) * 2020-12-01 2021-10-26 北京师范大学 锝-99m标记含异腈的FAPI衍生物及制备方法和应用
CN112625065A (zh) * 2020-12-22 2021-04-09 北京师范大学 锝-99m标记含肼基尼古酰胺基的FAPI衍生物及制备方法和应用
CN117545481A (zh) * 2021-02-01 2024-02-09 五一一制药股份有限公司 成纤维细胞活化蛋白-α显像剂的放射性标记配体及其制备方法
CN113880810B (zh) * 2021-09-24 2023-02-28 厦门大学 一种核素标记的配合物及其制备方法和应用
TW202317541A (zh) 2021-10-28 2023-05-01 行政院原子能委員會核能研究所 一種靶向成纖維細胞活化蛋白之化合物或其鹽，其製備方法及其用途
CN114163478B (zh) * 2021-12-15 2023-03-24 北京师范大学 锝-99m标记含D-脯氨酸修饰的FAPI衍生物及制备方法和应用
CN116554146A (zh) * 2022-01-29 2023-08-08 中国科学院生物物理研究所 一种FAP-α特异性放射性药物及其应用
CN115304582B (zh) * 2022-07-20 2023-05-12 北京法伯新天医药科技有限公司 FAP-α特异性肿瘤诊断显像剂
CN115160293B (zh) * 2022-08-24 2023-12-08 北京师范大学 锝-99m标记含L-脯氨酸修饰的谷氨酸-脲衍生物及制备方法和应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104667306A (zh) * 2015-02-09 2015-06-03 刘丽 99mTc标记RGD多肽三聚体肿瘤显像药剂的化学结构及制备方法
CN106581700A (zh) * 2016-12-02 2017-04-26 北京大学 一种靶向her2的新型多肽放射性药物及其制备方法和应用
CN108144072A (zh) * 2017-12-27 2018-06-12 北京大学 用于诊断凝集素受体高表达肿瘤的放射性药物
WO2018222987A1 (fr) * 2017-06-01 2018-12-06 Tarveda Therapeutics, Inc. Constructions ciblées
WO2019154886A1 (fr) * 2018-02-06 2019-08-15 Universität Heidelberg Inhibiteur de fap
CN110743017A (zh) * 2019-10-22 2020-02-04 北京大学 一种靶向半乳糖凝集素-1的放射性药物及其制备方法
CN111228521A (zh) * 2020-01-17 2020-06-05 中国科学院生物物理研究所 一种Dar2多肽放射性药物及其制备方法
CN111991570A (zh) * 2020-07-24 2020-11-27 北京大学 一种FAP-α特异性肿瘤诊断SPECT显像剂

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109045313B (zh) * 2018-09-11 2020-02-18 北京大学 一种靶向her2的d型多肽放射性药物及制备方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104667306A (zh) * 2015-02-09 2015-06-03 刘丽 99mTc标记RGD多肽三聚体肿瘤显像药剂的化学结构及制备方法
CN106581700A (zh) * 2016-12-02 2017-04-26 北京大学 一种靶向her2的新型多肽放射性药物及其制备方法和应用
WO2018222987A1 (fr) * 2017-06-01 2018-12-06 Tarveda Therapeutics, Inc. Constructions ciblées
CN108144072A (zh) * 2017-12-27 2018-06-12 北京大学 用于诊断凝集素受体高表达肿瘤的放射性药物
WO2019154886A1 (fr) * 2018-02-06 2019-08-15 Universität Heidelberg Inhibiteur de fap
CN110743017A (zh) * 2019-10-22 2020-02-04 北京大学 一种靶向半乳糖凝集素-1的放射性药物及其制备方法
CN111228521A (zh) * 2020-01-17 2020-06-05 中国科学院生物物理研究所 一种Dar2多肽放射性药物及其制备方法
CN111991570A (zh) * 2020-07-24 2020-11-27 北京大学 一种FAP-α特异性肿瘤诊断SPECT显像剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FREDERIK L. GIESEL, CLEMENS KRATOCHWIL, THOMAS LINDNER, MANFRED M. MARSCHALEK, ANASTASIA LOKTEV, WENCKE LEHNERT, JüRGEN DEBUS: "68 Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers", THE JOURNAL OF NUCLEAR MEDICINE, SOCIETY OF NUCLEAR MEDICINE, US, vol. 60, no. 3, 1 March 2019 (2019-03-01), US , pages 386 - 392, XP055732757, ISSN: 0161-5505, DOI: 10.2967/jnumed.118.215913 *
LINDNER THOMAS, ALTMANN ANNETTE, KRÄMER SUSANNE, KLEIST CHRISTIAN, LOKTEV ANASTASIA, KRATOCHWIL CLEMENS, GIESEL FREDERIK, MIER WAL: "Design and Development of 99m Tc-Labeled FAPI Tracers for SPECT Imaging and 188 Re Therapy", THE JOURNAL OF NUCLEAR MEDICINE, SOCIETY OF NUCLEAR MEDICINE, US, vol. 61, no. 10, 1 October 2020 (2020-10-01), US , pages 1507 - 1513, XP055888991, ISSN: 0161-5505, DOI: 10.2967/jnumed.119.239731 *

Also Published As

Publication number Publication date
CN111991570A (zh) 2020-11-27
CN111991570B (zh) 2021-05-18

Similar Documents

Publication Publication Date Title
WO2022017375A1 (fr) AGENT DE CONTRASTE DE SPECT POUR DIAGNOSTIC DE TUMEUR SPÉCIFIQUE DE FAP-α
CN116617420A (zh) 靶向成纤维细胞活化蛋白α的化合物、药物组合物及用途
WO2018192405A1 (fr) Sonde moléculaire d'imagerie à double cible, son procédé de préparation et application
JP7324763B2 (ja) 分子イメージングのための二重標識プローブ及びその使用
KR20100121530A (ko) 관류 영상화를 포함하는 용도를 위한 조영제
WO2022021528A1 (fr) Sonde polypeptidique ciblant le récepteur ace2, sa méthode de préparation et son utilisation
Zhang et al. Synthesis and biological evaluation of a novel 99mTc (CO) 3 complex of ciprofloxacin dithiocarbamate as a potential agent to target infection
KR102658933B1 (ko) 이중 표적화 화합물 및 이의 제조 방법과 응용
Li et al. 18F-or 177Lu-labeled bivalent ligand of fibroblast activation protein with high tumor uptake and retention
Lin et al. Synthesis and evaluation of 18F labeled crizotinib derivative [18F] FPC as a novel PET probe for imaging c-MET-positive NSCLC tumor
CN112043839A (zh) 靶向转铁蛋白受体的放射性同位素标记多肽显像剂及其应用
US20220211884A1 (en) Rk polypeptide radiopharmaceutical targeting her2 and preparation method thereof
US20150217006A1 (en) Al-f-18-labeled, al-f-19-labeled and ga-68-labeled gastrin-releasing peptide receptor (grpr)-antagonists for imaging of prostate cancer
WO2023236778A1 (fr) Composé trifonctionnel et son utilisation
CN114364690A (zh) 用于诊断和治疗的新型放射性标记的cxcr4靶向化合物
Liu et al. Synthesis and evaluation of novel radioiodinated nicotinamides for malignant melanoma
WO2023130587A1 (fr) Dérivé d'éther de méthylbenzène hydrosoluble, sonde nucléotidique et marqueur nucléotidique à positrons, leurs procédés de préparation et leurs utilisations
US20230277699A1 (en) Tumor stroma imaging agent and preparation method thereof
CA3208649A1 (fr) Precurseur et radiotraceur pour theranostique neuroendocrine
Zhang et al. Synthesis and biological evaluation of a new nitroimidazole-99mTc-complex for imaging of hypoxia in mice model
KR20220006286A (ko) 전립선암 진단 및 치료를 위한 전립선특이 막 항원 표적 화합물 및 이를 포함하는 전립선암 진단 및 치료용 조성물
CN115304582B (zh) FAP-α特异性肿瘤诊断显像剂
WO2018226971A1 (fr) Compositions peptidiques pour imagerie moléculaire d'immuno-oncologie et administration ciblée de médicaments
WO2023030509A1 (fr) Dérivé de peptide-urée, composition pharmaceutique le contenant et application associée
AU2010258599B2 (en) PET imaging of fibrogenesis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21846274

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21846274

Country of ref document: EP

Kind code of ref document: A1