WO2023087169A1 - Deux sondes fluorescentes ciblant l'antigène membranaire spécifique de la prostate, leur procédé de préparation et leur utilisation - Google Patents

Deux sondes fluorescentes ciblant l'antigène membranaire spécifique de la prostate, leur procédé de préparation et leur utilisation Download PDF

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WO2023087169A1
WO2023087169A1 PCT/CN2021/131122 CN2021131122W WO2023087169A1 WO 2023087169 A1 WO2023087169 A1 WO 2023087169A1 CN 2021131122 W CN2021131122 W CN 2021131122W WO 2023087169 A1 WO2023087169 A1 WO 2023087169A1
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prostate cancer
pharmaceutically acceptable
acceptable salt
targeting
fluorescent probe
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Chinese (zh)
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邢念增
胡海宇
武岭岭
赵钦欣
王庆华
张青扬
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中国医学科学院肿瘤医院
中国医学科学院药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom

Definitions

  • the invention relates to two prostate-specific membrane antigen-targeted fluorescent probes, a preparation method and an application thereof, and belongs to the fields of biotechnology and medicine preparation.
  • PCa prostate cancer
  • PSMA Prostate-specific membrane antigen
  • PSMA Prostate-specific membrane antigen
  • the relative molecular mass is about 100*10 3 . 750 amino acids, including 707 in the extracellular segment, 24 in the transmembrane segment, and 19 in the intracellular segment. Its intracellular and extracellular segments contain multiple antigenic epitopes, which are closely related to various proteins, and affect the molecular characteristics and protein localization of PSMA to a large extent.
  • oleic acid is a monounsaturated fatty acid, which can not only enhance the affinity between fluorescent molecules and cell membranes, but also inhibit or kill tumor cells (Eiber M, Fendler WP, Rowe SP, Calais J, Hofman MS , Maurer T, et al. Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy. J Nucl Med. 2017, 58:67s-76s.). Therefore, fluorescent probes combined with anti-PSMA ligands are of great significance in fluorescence-guided targeted prostate surgery.
  • the object of the present invention is to provide the Cy fluorescent probe compound targeting prostate cancer or its acceptable salt and the Cy fluorescent probe compound targeting prostate cancer and cell membrane or its acceptable salt, its preparation method and its application .
  • the present invention provides following technical scheme:
  • F represents a marker molecule
  • the marker molecule refers to a marker that can directly or indirectly generate a detectable signal.
  • L 1 and L 2 represent linking groups, and L 1 connects the marker molecule F and the linking group L 2 .
  • L 2 connects linking group L 1 , targeting groups T 1 and T 2 .
  • T 1 and T 2 represent targeting groups respectively, and T 1 can recognize related proteins in tumor cells for detection of tumor cells.
  • L 2 and T 2 may or may not exist.
  • F represents a labeling molecule
  • the labeling molecule refers to a label that can directly or indirectly generate a detectable signal.
  • radioisotopes fluorophores, fluorescent proteins.
  • the radioisotope is selected from 111 In( ⁇ ), 99 mTc( ⁇ );
  • the fluorophore is selected from 7-dimethylaminocoumarin-4-acetic acid succinimidyl ester, 5/6-carboxyfluorescein and tetramethylrhodan Ming, BODIPY-493/503, BODIPY-FL, BODIPY-TMR, BODIPY-TMR-X, BODIPY-TR-X, BODIPY630/550-X, BODIPY-650/665-X, Alexa 350, Alexa 488, Alexa 532 , Alexa 546, Alexa 555, Alexa 635, Alexa 647, Cyanine 3 (Cy 3), Cyanine 3B (Cy 3B), Cyanine 5
  • L2 represents a linking group, which can be absent or present, and is selected from serine, threonine, cysteine, tyrosine, and lysine;
  • T1 stands for Targeted Prostate Cancer Specific Membrane Antigen Group, which can be selected from:
  • T2 represents targeting cell membrane groups, including trans-oleic acid, linoleic acid, C10-30 alkyl acid, C10-30 alkenyl acid, and C10-30 alkynyl acid.
  • the Cy fluorescent probe compound targeting prostate cancer shown in the above formula I can specifically be:
  • the targeted prostate cancer-specific membrane antigen group can be selected from:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 are independently selected from hydrogen atom, sulfonic acid group, sulfonamide, hydroxyl, amino, F, Cl, Br, I, nitro, C1 ⁇ 6 alkyl, C1 ⁇ 6 alkenyl, C1 ⁇ 6 Alkynyl, C1 ⁇ 6 alkoxy, C1 ⁇ 6 alkylamino, C1 ⁇ 6 carboxylic acid, C1 ⁇ 6 methyl carboxylate, C1 ⁇ 6 alkylamide (specifically hydrogen atom, sulfonic acid group, methyl, ethyl); or R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 6 and R 7 , R 14 and R 15 , R 16 and R 17 , R
  • R 20 , R 21 , R 22 , R 23 are independently selected from hydrogen atom, sulfonic acid group, sulfonamide, hydroxyl, amino, F, Cl, Br, I, nitro or C1 ⁇ 6 alkyl, C1 ⁇ 6 alkenes Base, C1 ⁇ 6 alkynyl; said C1 ⁇ 6 is selected from C1, C2, C3, C4, C5, C6;
  • R 24 is selected from independently selected from hydrogen, sulfonic acid group, sulfonamide group, hydroxyl, amino, F, Cl, Br, I, or C1 ⁇ 6 alkyl, C1 ⁇ 6 alkenyl, C1 ⁇ 6 alkynyl;
  • n represents an integer of 0-4, specifically 0, 1, 2, 3, 4;
  • n an integer of 0-4, specifically 0, 1, 2, 3, 4;
  • p represents an integer from 0 to 9, specifically 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;
  • X is selected from F, Cl, Br, I;
  • L1 is selected from C1 ⁇ 9 alkyl, C1 ⁇ 9 alkenyl, C1 ⁇ 9 alkynyl, and said C1 ⁇ 9 is selected from C1, C2, C3, C4, C5, C6, C7, C8, C9;
  • R 25 and R 26 are each independently selected from
  • the Cy-type fluorescent probe compound targeting prostate cancer shown in the above formula I is selected from Cy3, Cy3.3, Cy5, Cy5.5, Cy7, Cy7 except for the L2 -targeting prostate cancer-specific membrane antigen group. .5, the structure is as follows:
  • the targeted prostate cancer specific membrane antigen group is selected from
  • the targeting cell membrane group can be selected from oleic acid, trans oleic acid, linoleic acid, octadecanoic acid;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 are independently selected from hydrogen atom, sulfonic acid group, sulfonamide, hydroxyl, amino, F, Cl, Br, I, nitro, C1 ⁇ 6 alkyl, C1 ⁇ 6 alkenyl, C1 ⁇ 6 Alkynyl, C1 ⁇ 6 alkoxy, C1 ⁇ 6 alkylamino, C1 ⁇ 6 carboxylic acid, C1 ⁇ 6 methyl carboxylate, C1 ⁇ 6 alkylamide; or R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 6 and R 7 , R 14 and R 15 , R 16 and R 17 , R 17 and R 18 , R 18 and R 19 are adjacent to benzene ring, n
  • R 20 , R 21 , R 22 , R 23 are independently selected from hydrogen atom, sulfonic acid group, sulfonamide, hydroxyl, amino, F, Cl, Br, I, nitro or C1 ⁇ 6 alkyl, C1 ⁇ 6 alkenes Base, C1 ⁇ 6 alkynyl; said C1 ⁇ 6 is selected from C1, C2, C3, C4, C5, C6;
  • R 24 is selected from independently selected from hydrogen, sulfonic acid group, sulfonamide group, hydroxyl, amino, F, Cl, Br, I, or C1 ⁇ 6 alkyl, C1 ⁇ 6 alkenyl, C1 ⁇ 6 alkynyl;
  • n represents an integer representing 0-4, specifically 0, 1, 2, 3, 4;
  • n an integer of 0-4, specifically 0, 1, 2, 3, 4;
  • p represents an integer from 0 to 9, specifically 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;
  • X represents F, Cl, Br, I
  • L1 is selected from C1 ⁇ 9 alkyl, C1 ⁇ 9 alkenyl, C1 ⁇ 9 alkynyl, and said C1 ⁇ 9 is selected from C1, C2, C3, C4, C5, C6, C7, C8, C9;
  • L2 is selected from C1-20 alkyl, C1-20 alkenyl, C1-20 alkynyl, and the C1-20 is selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20;
  • L3 is selected from serine, threonine, cysteine, tyrosine, lysine;
  • R 25 , R 26 , R 27 are independently selected from
  • Cy-type fluorescent probe compound targeting prostate cancer shown in the above formula I can be:
  • the first aspect of the technical solution of the present invention is a Cy-type fluorescent probe compound targeting prostate cancer or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is an organic acid salt or an inorganic acid salt of the compound,
  • the pharmaceutically acceptable salt is an organic base salt or an inorganic base salt of the compound, and the organic base can be pyridine, triethylamine, diethylamine, N-methylmorpholine, tetramethylethylenediamine No said organic base can be phosphate, hydrogen phosphate, carbonate, bicarbonate, potassium carbonate, bicarbonate, hypochlorite, hypobromite, silicate.
  • the second aspect of the technical solution of the present invention is to provide the application of the Cy-type fluorescent probe compound targeting prostate cancer in the first aspect or a pharmaceutically acceptable salt thereof in the preparation of a reagent for detecting prostate cancer-specific membrane antigen.
  • the detection is the detection of prostate cancer specific membrane antigen at the molecular level.
  • the third aspect of the technical solution of the present invention is to provide the application of Cy-type fluorescent probe compounds targeting prostate cancer or pharmaceutically acceptable salts thereof in the preparation of reagents for targeted detection of prostate cancer. Biopsy-level targeted detection of prostate cancer.
  • the prostate cancer is a prostate cancer expressing PSMA at a high level, which can be distinguished from normal prostate cells and tissues.
  • the fourth aspect of the technical solution of the present invention also provides the application of the Cy-type fluorescent probe compound targeting prostate cancer or a pharmaceutically acceptable salt thereof in the preparation of a prostate cancer diagnostic reagent.
  • the Cy fluorescent probe compound targeting prostate cancer of the present invention has good affinity and specificity to prostate cancer cells expressing PSMA.
  • Cy-like fluorescent probe compounds targeting prostate cancer and cell membranes can increase fluorescent signals, reduce background signals, and have good stability within a certain period of time, as well as temporal and spatial resolutions in small animal live imaging .
  • the Cy-type fluorescent probe compound targeting prostate cancer has no inhibitory effect on cells at a concentration of 25 ⁇ M within 24 hours, that is, the toxicity is low.
  • the invention designs and synthesizes a novel fluorescent probe molecule specifically targeting prostate cancer, which greatly improves the specificity and sensitivity of prostate cancer detection, provides high-precision and high-sensitivity real-time imaging navigation for individualized precision surgery, and realizes prostate cancer accurate diagnosis and treatment.
  • Fig. 1 is a synthesis route diagram of probe molecules 1 and 2 in the embodiment of the present invention.
  • Figure 2 shows the absorption and emission spectra results of probes 1 and 2.
  • Fig. 3 shows the cell viability results of probes 1 and 2 on prostate cancer cells (C4-2) within 24 hours.
  • Figure 4 shows the co-localization fluorescence imaging results of probes 1 and 2 in prostate cancer cells (C4-2, PC3).
  • Figure 5 shows the flow cytometric results of probes 1 and 2 in prostate cancer cells (C4-2, PC3).
  • Fig. 6 shows the imaging results of probe 2 of the present invention in small animals.
  • Figure 7a shows fluorescence imaging of prostate cancer in mice under fluorescence laparoscopy
  • Figure 7b shows real-time tumor resection under fluorescence guidance
  • Figure 7c shows fluorescence imaging after tumor resection
  • Figure 7d shows surgical specimens confirmed by HE staining as prostate cancer.
  • Figure 8a shows prostate cancer tissue (upper part) and normal prostate tissue (lower part);
  • Figure 8b shows prostate cancer with high expression of PSMA (upper part) and prostate cancer with low expression, even normal prostate tissue with no expression (lower part);
  • the results in Fig. 8c and Fig. 8d suggest that the probe 2 has good imaging performance on clinical prostate cancer samples, but not on normal prostate tissue.
  • the invention designs and synthesizes a novel fluorescent probe molecule specifically targeting prostate cancer, which greatly improves the specificity and sensitivity of prostate cancer detection, provides high-precision and high-sensitivity real-time imaging navigation for individualized precision surgery, and realizes prostate cancer accurate diagnosis and treatment.
  • Substrate 1 (10g, 62.8mmol) and bromoethane (6.84g, 62.8mmol) were dissolved in toluene solvent (32mL). After the reaction was complete, the reaction system was distilled off the solvent under reduced pressure, washed, dried under vacuum, and directly for the next step. Finally, 4.8 g of reddish-brown solid product 2 was obtained with a yield of 28.5%.
  • Substrates 6 (2.0g, 11.6mmol) and 5 (3.1g, 11.6mmol) were dissolved in acetic anhydride (33mL). After the reaction was over, they were distilled under reduced pressure, and the residue was re-dissolved in absolute ethanol (33mL), followed by adding 4 (4.9 g, 1.2 mmol) and sodium acetate (2.85 g, 34.8 mmol). After the reaction, vacuum distillation, washing, extraction, and vacuum distillation, the residue was purified by column chromatography to obtain product 7 as a dark green solid, 2.4 g, with a yield of 30%.
  • Substrate 8 (930 mg, 2.73 mmol) was added to dichloromethane solvent (27 mL), EDCI (629 mg, 3.28 mmol), HOBt (443 mg, 3.28 mmol) and DIPEA (424 mg, 3.28 mmol) were added, and substrate 9 was added (1.33g, 2.73mmol), after the reaction was completed, extraction, vacuum distillation, and column chromatography of the residue gave compound 10 as a white solid, 1.6g, yield 70%.
  • Substrate 10 (1.6 g, 1.97 mmol) and 10% palladium on carbon (160 mg) were dispersed in methanol solvent (32 mL) for catalytic hydrogenation. After the reaction was completed, suction filtration, vacuum distillation, and chromatographic purification of the residue gave product 11 as a colorless oil, 1.3 g, with a yield of 97%.
  • Substrate 7 (80mg, 0.138mmol) was dissolved in dichloromethane (1.4mL), EDCI (32mg, 0.166mmol), HOBt (22mg, 0.166mmol) and DIPEA (21.5mg, 0.166mmol) were added sequentially, and the substrate After 11 (83mg, 0.138mmol), continue to stir at room temperature for 1.5h. After the reaction was completed, it was washed and distilled under reduced pressure. After the residue was purified by column chromatography, it was dissolved in dichloromethane (2.76 mL), and trifluoroacetic acid (2.76 mL) was added. After the reaction was completed, it was purified by direct chromatography.
  • Probe 1 was obtained as a green solid, 29 mg, with a two-step yield of 21.7%.
  • Substrate 12 (814mg, 1.62mmol) was uniformly dispersed in dichloromethane solvent (16mL), EDCI (372mg, 1.94mmol), HOBt (262mg, 1.94mmol) and DIPEA (96mg, 1.94mmol) were added in sequence, and the bottom Compound 11 (1.1g, 1.62mmol). After the reaction was completed, the solvent was extracted and distilled off under reduced pressure. The residue was purified by column chromatography to obtain compound 13 as a colorless oil, 1.49g, with a yield of 77%.
  • Substrate 13 (1.49g, 1.28mmol) and 10% palladium on carbon (149mg) were dispersed in methanol solvent (20mL) for catalytic hydrogenation to give product 14 as a white solid, 1.04g, with a yield of 78.9%. used directly in the next step.
  • Substrate 15 (342mg, 1.01mmol) was uniformly dispersed in dichloromethane solvent (10mL), and after adding EDCI (232mg, 1.21mmol), HOBt (164mg, 1.21mmol) and DIPEA (156mg, 1.21mmol), added Compound 14 (1.04g, 1.01mmol), after the completion of the reaction, was extracted, evaporated under reduced pressure, and purified by column chromatography to obtain Compound 16 as a white solid, 0.559g, with a yield of 42.8%.
  • Substrate 16 (559 mg, 0.443 mmol) was dissolved in acetonitrile solvent (13.5 mL), and diethylamine (3.17 g, 43.3 mmol) was added. The reaction system was stirred at room temperature for 40 min. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain product 17 as a white solid, 200 mg, with a yield of 43.2%, which was directly used in the next step.
  • Substrate 7 (40mg, 0.067mmol) was dissolved in dichloromethane (1.34mL), EDCI (19.4mg, 0.101mmol) and HOBt (13.6mg, 0.101mmol) were added successively, followed by substrate 17 (57mg, 0.054mmol ), after the completion of the reaction, washing, distillation under reduced pressure, after the residue was purified by column chromatography, after the product was dissolved in dichloromethane solution (2.68mL), trifluoroacetic acid (2.68mL) was added, and the reaction was completed under argon protection. Afterwards, the solvent was distilled off under reduced pressure, and the residue was directly purified by HPLC.
  • Probe 2 was obtained as a green solid, 15.2 mg, with a two-step yield of 16.3%.
  • 1 H NMR 600MHz,DMSO-d 6 ) ⁇ 8.27(s,2H),7.72(s,1H),7.64(s,2H),7.49-7.42(m,3H),7.30(s,2H), 6.36-6.30(m,2H),6.25(s,1H),5.34-5.28(m,2H),4.26(s,2H),4.20(s,2H),4.08(s,1H),3.99(s, 1H),3.85(s,2H),3.63(s,2H),3.59-3.545(m,4H),3.53-3.49(m,3H),3.39(s,2H),3.18(s,2H),3.07 (s,2H),2.98(s,2H),2.79-2.65(m,4H),2.26(s,2H),2.14(s,2H),2.00(s,2H
  • Embodiment 2 probe 1, the measurement of the absorption emission spectrum of 2
  • Embodiment 3 probe 1, 2 are to prostate cancer cell (C4-2) cytotoxic experiment
  • Cell viability was determined by MTS method.
  • One experimental group and nine control groups were set up.
  • the adherent cells (C4-2 cells) in the 96-well plate were sequentially treated with probe 2 at concentrations of 0.2 ⁇ M, 0.4 ⁇ M, 0.8 ⁇ M, 1.6 ⁇ M, 3.2 ⁇ M, 6.25 ⁇ M, 12.5 ⁇ M and 25 ⁇ M, at 37° C.
  • 20 ⁇ L MTS was added to each well, and then cultured at 37 °C and 5% CO2 for 4 hours.
  • the absorbance OD value of each group was measured on a microplate reader, and the wavelength was set at 490 nm.
  • cell survival rate (%) (OD of experimental group/OD of control group) ⁇ 100%.
  • Probes 1 and 2 did not exhibit cytotoxicity to C4-2 at a concentration of 25 ⁇ M, indicating that probes 1 and 2 had low cytotoxicity. See Figure 3.
  • Fig. 3 shows the cell viability results of probes 1 and 2 on prostate cancer cells (C4-2) within 24 hours.
  • Prostate cancer cells (C4-2, PC3) were inoculated into 8-well plates (1 ⁇ 106 cells), and formed a monolayer within 48 hours. Incubate with fresh medium (200uL) containing probes 1, 2 and the small molecule inhibitor 2-PMPA, respectively, and then stain with Hoechst 33342. After the incubation is complete, confocal cells are imaged.
  • probes 1 and 2 had a good imaging effect in PSMA-positive prostate cell C4-2, and probe 2 was stronger than probe 1, but did not image in PSMA-negative prostate cell PC3;
  • the PSMA inhibitor 2-PMPA was added, the cell imaging was significantly weakened, indicating that probes 1 and 2 had good affinity and specificity for PSMA-positive prostate cancer cells. See Figure 4.
  • Embodiment 5 the flow cytometric experiment of probe 1,2 in prostate cancer cell (C4-2, PC3)
  • Prostate cancer cells (C4-2, PC3) were seeded into 24-well plates. Incubate with fresh medium (400uL) containing probes 1 and 2, respectively. After incubation, flow cytometry was performed.
  • BALB/c nude mice with an average weight of 20 grams at 6-8 weeks were subcutaneously injected with 200 ⁇ L of prostate cell C4-2 cell suspension at the end of the left hind limb to successfully establish a subcutaneous xenograft tumor model. After about two weeks, small animal live imaging tests were performed. . Probe 2 was injected separately into the tail vein. Live imaging monitoring of small animals was performed at 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h (excitation wavelength 745nm, emission wavelength 820nm).
  • probe 2 could be used to specifically target PSMA imaging, and the fluorescence intensity reached the maximum at 12h and lasted until 36h; in addition, the signal-to-noise ratio of probe 2 was the highest at 24h, reaching 3.64 ⁇ 0.16. It shows that probe 2 has good temporal and spatial resolution for PSMA-targeted imaging. See Figure 6.
  • Example 7 Evaluation of the application of probe 2 in real-time fluorescence laparoscopic surgical resection of mouse prostate cancer
  • Figure 8a shows that the above is the prostate Cancer, the bottom is the normal prostate tissue, further immunohistochemistry of PSMA, Figure 8b shows that the prostate cancer with high expression of PSMA on the top, the prostate cancer with low expression, or even the normal prostate tissue without expression, confirms our prediction. Then we co-incubated the postoperative frozen sections and clinical fresh samples with our probe at 37 degrees Celsius for 1h. The results in Figure 8c and Figure 8d suggest that our probe and clinical prostate cancer samples have good imaging properties, and and Normal prostate tissue is not imaged. It shows that probe 2 has a good targeting imaging property for prostate cancer. See Figure 8.
  • the invention designs and synthesizes a novel fluorescent probe molecule specifically targeting prostate cancer, which greatly improves the specificity and sensitivity of prostate cancer detection, provides high-precision and high-sensitivity real-time imaging navigation for individualized precision surgery, and realizes prostate cancer accurate diagnosis and treatment.

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Abstract

L'invention concerne deux sondes fluorescentes ciblant l'antigène membranaire spécifique de la prostate, leur procédé de préparation et leur utilisation. Les sondes ont une bonne affinité et une bonne spécificité pour les cellules du cancer de la prostate exprimant un PSMA. Dans l'imagerie in vivo de petits animaux, des signaux de fluorescence peuvent être augmentés, des signaux de fond peuvent être réduits, et une bonne stabilité, une résolution temporelle et une résolution spatiale sont obtenues en un certain temps. De nouvelles molécules de sonde fluorescente ciblant le cancer de la prostate spécifiques sont conçues et synthétisées, ce qui permet d'améliorer de manière considérable la spécificité et la sensibilité de la détection du cancer de la prostate; celles-ci peuvent être utilisées pour tester un échantillon clinique du cancer de la prostate; et une navigation d'imagerie en temps réel à haute précision et à haute sensibilité est également fournie pour une chirurgie précise individualisée, ce qui permet de réaliser un diagnostic et un traitement précis du cancer de la prostate.
PCT/CN2021/131122 2021-11-16 2021-11-17 Deux sondes fluorescentes ciblant l'antigène membranaire spécifique de la prostate, leur procédé de préparation et leur utilisation WO2023087169A1 (fr)

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